Textbook of Natural Medicine, Third Edition, Two Volumen Set

Contributors Kathy Abascal, BS, JD, RH(AHG) Vashon, Washington Steve Austin, ND Nutrition Editor Emerson Ecologics Update Portland, Oregon JeffreyGlen Baker, ND Health Science Liaison Health Science Education Great Smokies Diagnostic Lab Asheville, North Carolina Stephen Barrie, ND Malibu, California Robert Barry, ND Seattle, Washington Peter W. Bennett, ND,LAC Private Practice Victoria, British Columbia Jeffrey S. Bland, PhD, FACN, CNS President and Chief Science Officer Chairman Institute for Functional Medicine Metagenics, Inc. Gig Harbor, Washington Peter B. Bongiomo, ND, Dip1 Ac InnerSourceHealth.com New York, New York JenniferL. Booker, ND Private Practice Olympia, Washington Dennis Bourdette, MD Chairman and Roy and Eulalia Swank Research Professor Neurology Oregon Health and Science University Portland, Oregon

J. Alexander Bralley, PhD Chief Executive Officer Metametrix Clinical Laboratory Norcross, Georgia

Donald J. Brown, ND Director of Natural Products Research Consultants Seattle, Washington Car10 Calabrese, ND, MPH Research Professor National College of Naturopathic Medicine; Senior Investigator Helfgott Research Institute Portland, Oregon

Qiang Cao, LAC,OMD, ND Professor School of Acupuncture and Oriental Medicine Bastyr University; Wedgwood Acupuncture & Botanical Medicine Seattle, Washington Leon Chaitow, ND, DO Register of Osteopaths British Osteopathic Asssociation; Honorary Fellow School of Integrated Health University of Westminister, London London, United Kingdom Anthony J. Cichoke, DC,PhD, DACBN Author; Fellow of the International Association for the Study of Pain; American ChiropracticAssociation; Medical Enzyme Research Society; Nationally Syndicated Radio Show, "The Dr. Enzyme Self-HELP Show" Portland, Oregon George Wm. Cody, JD, MA InterdisciplinaryArts and Sciences University of Washington Bothell, Washington

Randall S. Bradley, ND Private Practice Omaha, Nebraska vii

Kevin L. Conroy, ND Faculty, Assistant Professor, Supervisor Immune Wellness Center Naturopathic Medicine Bastyr University Kenmore, Washington Walter J. Crinnion, ND Chair Department of Environmental Medicine and Public Health National College of Naturopathic Medicine Tempe, Arizona

Heidi B. Hascall, MA Doctoral Candidate Political Science University of Oregon Eugene, Oregon Jason A. Hawrelak, BNat (Hons), PhDc School of Natural and Complementary Medicine Southern Cross University; Australian Centre for Complementary Medicine Education and Research (a joint venture of the University of Queensland and Southern Cross University) Lismore, Australia

T.Michael Culp, MA, ND Integrative Health Solutions, Ltd. London, United Kingdom Peter J. D’Adamo, ND The DAdamo Clinic Wilton, Connecticut Rhonda Dorren, BSc Pharm Private Practice Calgary, Alberta Cathryn M. Flanagan, ND Private Practice Old Saybrook, Connecticut

Alan R. Gaby, MD Author, lecturer Carlisle, Pennsylvania Leo Galland, MD Director Foundation for Integrated Medicine New York, New York

Alan Goldhamer, DC Director TrueNorth Health Rohnert Park, California Mark D. Groven, ND Private Practice Seattle, Washington Patrick Hanaway, MD Medical Director Great Smokies Diagnostic Lab Asheville, North Carolina

Kathleen A. Head, ND Editor-in-Chief Alternative Medicine Review; Technical Advisor Thorne Research Sandpoint, Idaho Gina Honeyman-Lowe, DC Advisory Board for Fibromyalgia Research Foundation Specialty, Metabolic Rehabilitation Boulder, Colorado

Ton Hudson, ND Professor National College of Naturopathic Medicine; Clinical Professor Southwest College of Naturopathic Medicine Portland, Oregon Corene Humphreys, BHSc, ND, DipMedHerb, DipHom South Pacific Association of Natural Therapists; New Zealand Charter of Health Practitioners; Medical Education Great Smokies Diagnostic Lab Asheville, North Carolina Mary James, ND, AANP Senior Staff Physician Health Science Liason; Editorial Review Board Alternative Medicine Review; Medical Education Great Smokies Diagnostic Lab Asheville, North Carolina Herb Joiner-Bey, ND Adjunct Professor Naturopathic Medicine Bastyr University Seattle, Washington

Contributors Julie S.Jurenka, BS, MT(ASCP) Technical Research Assistant Contributor for Alternative Medicine Review Sagle, Idaho Gregory S. Kelly, ND Medical Director Signature Health Partners VP Healthcoach Systems Santa Barbara, California Parris M. Kidd, PhD Director PMK Biomedical El Cerrito, California Lori Kimata, ND, HS NP,AANP, ACNO Midwife Sacred Healing Arts Honolulu and Haleiwa, Hawaii Richard Kitaeff, MA, MD, Dip1 Ac, LAC Naturopathic Physician and Acupuncturist Director New Health Medical Center; Staff Acupuncturist Northwest Hospital (Seattle); Edmonds, Washington

Private Practice Seattle, Washington Pina LoGiudice, ND, LAC Medical Director InnerSourceHealth.com Syosset, New York Richard S. Lord, PhD Director Metametrix Clinical Laboratory Science & Education Norcross, Georgia John C. Lowe, MA, DC Director of Research Fibromyalgia Research Foundation Boulder, Colorado Bobbi Lutack, MS, ND Private Practice Evergreen Center for Integrative Medicine Seattle, Washington Michael R. Lyon, BSc, MD Medical & Research Director Canadian Center for Functional Medicine Coquitlum, British Columbia

Thomas A. Kruzel, MT, ND Scottsdale Natural Medicine & Healing Clinic, LLC Scottsdale, Arizona

Stephen P. Markus, MD Creekside Center for Integrative Medicine Bellevue, Washington

Elizabeth Kutter, PhD Head Laboratory of Phage Biology Member of the Faculty in Biophysics Scientific Inquiry The Evergreen State College Olympia, Washington

Morgan Martin, ND, LM Chair Naturopathic Midwifery Department Bastyr University Kenmore, Washington

Andrew Lange, BSc, ND Private Practice Boulder, Colorado

Buck Levin, PhD, RD Adjunct Associate Professor of Nutrition Bastyr University Kenmore, Washington Douglas C.Lewis, ND Former Chair Department of Physical Medicine School of Naturopathic Medicine Bastyr University

Robert M. Martinez, DC,ND Private Practice Kirkland, Washington Steven C. Milkis, ND Clinical Faculty Bastyr University Seattle, Washington Alan L. Miller, ND Technical Advisor Thorne Research, Inc.; Senior Editor Alternative Medicine Review Sandpoint, Idaho

Laurie K. Mischley, ND Private Practioner University Health Clinic Specialty Care & Research Center; Adjunct Faculty Bastyr University Seattle, Washington Stephen €! Myers, PhD, BMed, ND Professor, Director Australian Centre for Complementary Medicine Education and Research (a joint venture of the University of Queensland and Southern Cross University) Lismore, Australia Mark Harrison Nolting, ND, LAC Naturopathic Physician; Acupuncturist; Associate Medical Director American WholeHealth Inc. Edmonds, Washington Lara Pizzomo, MA (Divinity), MA (Literature),LMT Senior Medical Editor Salugenecists, Inc. Seattle, Washington Dirk Wm. Powell, ND Faculty Bastyr University; Private Practioner Kent, Washington Peter T.Pugliese, MD President Peter T. Pugliese and Associates Reading, Pennsylvania David W.Quig, PhD Vice President Scientific Support Doctor’s Data Inc. St. Charles, Illinois Paul Reilly, ND, LAC Adjunct Faculty Bastyr University Kenmore, Washington Corey Resnick, ND Integrative Therapeutics Inc. Lake Oswego, Oregon

Nancy Roberts, ND Sequoia Naturopathic Seattle, Washington

Sally J. Rockwell, PhD, CCN Owner Diet Designs; Private Practice Seattle, Washington Robert A. Ronzio, PhD Director of Research and Development Q Health Resorts, Inc. McMinnville, Oregon Sam RUSSO,ND, MSAc President Vermont Association of Naturopathic Physicians; Private Practice Winooski, Vermont Trevor K. Salloum, ND Private Practice Kelowna, British Columbia Alexander G. Schauss, PhD, FACN Director National and Medicinal Products; Research AIBMR Life Sciences, Inc. Puyallup, Washington Michael A. Schmidt, PhD Ames Associate NASA Ames Research Center Moffett Field, California Lynne Shinto, ND Assistant Professor Department of Neurology; Assistant Professor Ob/G yn-Integrative Medicine Division Center for Women’s Health Oregon Health & Science University Portland, Oregon Pamela Snider, ND Consortium Director Academic Consortium for Complementary and Alternative Healthcare; Vice President, Board of Directors Integrated Health Care Policy Consortium; Faculty, Former Associate Dean College of Naturopathic Medicine Bastyr University Seattle, Washington

Contributors

Virender Sodhi, MD(Ayurveda),ND Ayurvedic and Naturopathic Clinic Bellevue, Washington Nick Soloway, LMT, DC,LAC Private Practice; Faculty Big Sky Somatic Institute Helena, Montana Leanna J. Standish, ND, PhD, LAC Research Professor Bastyr University Kenmore, Washington

R.W. Watkins, MD, MPH, FAAFP Associate Clinical Professor Department of Family Medicine UNC Chapel Hill School of Medicine Chapel Hill, North Carolina The Wanek Medical Center, Institute for Functional Medicine Greensboro, North Carolina

Terry Willard, CIH, PhD President, Clinical Herbalist Herbology Wild Rose College Calgary, Alberta

Nancy Sudak, MD Clinic Physician Northland Health and Wellness; Clinical Instructor and Medical Director UMD Quickcare Clinic, University of Minnesota; Member Board of Directors American Board of Holistic Medicine; Member Textbook Faculty Institute for Functional Medicine Duluth, Minnesota

Michelle Won& BS Executive Director Hawaii State Consortium for Integrative Healthcare Honolulu, Hawaii

Sherry Torkos, RPh Pharmacist Health Author Ontario, Canada

Jared Zeff, ND, LAC Professor of Naturopathic Medicine Adjunct Professory Naturopathic Medicine Bastyr University Bathel, Washington

Alex Vasquez, DC, ND Private Practice Houston, Texas Carl P.Verdon, PhD Research Chemist Centers for Disease Control and Prevention Inorganic Toxicology and Nutrition Branch National Center for Environmental Health Centers for Disease Control and Prevention Atlanta, Georgia Aristo Vojdani, PhD, MT Director Immunosciences Lab, Inc. Beverly Hills, California

Eric L. Yarnell, ND, RH(AHG) President Botanical Medicine Academy; Adjunct Professor Department of Botanical Medicine Bastyr University Seattle, Washington

Ira D. Zunin, MD, MPH, MBA Medical Director Manakai 0 Malama Integrative Healthcare Group and Rehabilitation Center; President Hawaii State Consortium for Integrative Healthcare Honolulu, Hawaii

Preface The scientific support for the philosophical and therapeutic foundation of natural medicine has evolved remarkably over the past 35 years. Concepts that were once considered ”quaint” at best are now recognized as fundamental to good health and the prevention and treatment of disease. This textbook, with its roughly 10,000 citations to peer-reviewed research literature, provides well-documented standards of practice for natural medicine. Based on a sound combination of philosophy and clinical studies, this work provides the astute practitioner with a reliable informational resource to provide health care that identifies and controls the underlying causes of disease, is supportive of the body’s own healing processes, and is considerate of each patient’s unique biochemistry. This textbook is composed of six sections, each focused on a fundamental aspect of the practice of natural medicine. ”Philosophy of Natural Medicine” covers the history and conceptual basis of natural medicine. “Supplementary Diagnostic Procedures” provides a primer on diagnostic procedures not commonly taught

in conventional medical schools. Diet analysis, food allergy testing, immune function assessment, fatty acid profiling, and hair mineral analysis are examples of these analytical procedures. The next section, ”Therapeutic Modalities,” provides a descriptive, practical, scientific, and historical review of the common modalities of natural medicine, including botanical medicine, nutritional therapy, therapeutic fasting, exercise therapy, hydrotherapy, counseling, acupuncture, homeopathy, and soft tissue manipulation. “Syndromes and Special Topics” considers underlying issues relevant to many diseases. “Pharmacology of Natural Medicines” covers the pharmacognosy, pharmacology, and clinical indications for the most commonly prescribed botanical medicines, special nutrients, and other natural agents. Finally, ”Specific Health Problems” provides an in-depth natural medicine approach to more than 70 specific diseases and conditions. The comprehensive therapeutic rationales are well documented and based on the pathophysiology and causes of each condition.

Joe Pizzorno Michael Murray Seattle 2005

xiii

Acknowledgments We would like to thank Inta Ozols, the original commissioning editor; and the staff at Elsevier (Kellie White, Kim Fons, Trish Tannian, Kristine Feeherty, Paula Ruckenbrod, and JulieBurchett).

Philosophy of Natural Medicine Nature is doing her best each monienf to nuke us well. She existsfor no other end. Do not resist. With the least inclination to be well, we -Henry David Thoreau should not be sick.

1 Eastem Origins of Integrative Medicine and Modem Applications 3 2 Functional Medicine in Natural Medicine 13 3 A Hierarchy of Healing: The Therapeutic Order 27 4 The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing 41 5 The History of Naturopathic Medicine, Part 11: Decline 6 7 8 9 10

and Rejuvenation-Politics and Professionalization 67 Philosophy of Naturopathic Medicine 79 Placebo and the Power to Heal 89 Positive Mental Attitude 111 Research in Natural Medicine 117 Women in the History of Medicine 127

One of the features of the various schools of natural medicine that differentiate them from conventional (allopathic) medicine is their strong philosophical foundation. The basic philosophical premise of naturopathic medicine, for example, is that there is an inherent healing power in nature and in every human being. We believe that a primary role of the physician is to bring out or enhance this innate healing power within his or her patients. In many ways, thiswas the most difficult section of the textbook to write, as no comprehensive history of the social, political, and philosophical development of naturopathic medicine had ever been written, and even in the halcyon years of the 1920s and 1930s, the profession was never able to agree upon a concise philosophy. This situation has now changed. We provide here a well-documented chapter detailing the roots of American naturopathy. After a century of maturation, the profession has now widely agreed to a comprehensive definition, set of principles, and system of case analysis that

provide a systematic guide for the application of these concepts in a clinical setting. The seven fundamental principles of naturopathic medicine are as follows: 1. The healing power of nature (uis rnedicutrix nntrirue) 2. First do no harm (priniuni non nocere) 3. Find the cause (tolle causarn) 4. Treat the whole person 5. Preventive medicine 6. Wellness 7. Doctor as teacher

These principles translate into the following questions the practitioner applies when analyzing a case: What is the first cause; what is contributing now? How is the body trying to heal itself? What is the minimum level of intervention needed to facilitate the self-healing process? What are the patient’s underlying functional weaknesses? What education does the patient need to understand why he or she is sick and how to become healthier? How does the patient’s physical disease relate to his or her psychological and spiritual health? We have further expanded on the philosophical basis of naturopathic medicine by having these concepts addressed by several authors whose backgrounds allow each of them a unique and, we believe, complementary insight into some of the fundamental questions of the goals of health care. Although the dominant school of medicine has essentially ignored these issues, we believe that the true physician cannot function without a sound philosophical basis to guide his or her actions. Without a more than superficial understanding of health and disease, the physician is more likely to function as a technician, temporarily alleviating symptoms while allowing the real disease to progress past the point of recovery.

1

Eastern Origins of Integrative Medicine and Modern Applications Ira D. Zunin,MD, MPH Michelle Wong, BS CHAPTER CONTENTS Introduction 3 Terminology 3 Comparison of Eastern and Western Medicine: Origins and Philosophies 4 Historical Origins 4 Philosophies in Contrast 5 Overview and Comparison of Eastern Traditions 5

INTRODUCTION Emaho, the Tibetan word for ”wondrous,” aptly describes the history of healing. The healing art of medicine is neither fixed in one theory of disease nor has its origins in a single body of perceptions. Its roots reveal rich and fascinating strands to its heritage. Each strand has developed potent theories and recommendations that inform prevention, illness, and treatment. These differences profoundly influence the vision and values among the members of a given culture-how to live well and how to address illness and health. Specifically, the contrast in Eastern and Western approaches have been like strangers from afar, now newly becoming aware of each other and saying hello in an emerging field called ”integrative medicine.” Each has its advantages and limitations. Recognizing and skillfully combining the best of both approaches is an ongoing challenge and a noteworthy, positive advance for humanity. Only in the past 10 years has medicine in the West begun to diligently examine and include indigenous traditions in medical practice. The term integrative medicine emerged in the early 1990s to describe an evolving paradigm shift in modern medicine. Integrative medicine holds that rather than using only one medical system, Reader’s note: An essentially identical version of this chapter appeared in integrative Medicine: A Clinician’s Journal (VZ.2) and is reprinted with approval from InnoVision Communications.

Modern Applications:The Age of Integration 8 The Birth and Evolution of a Medical Profession in the United States: Complementary and Alternative Medicine Professions 9 Tools for Integration 10

drawing from multiple traditions clearly better serves the public. Integrative medicine in the West is the first movement this century to examine indigenous healing modalities with scientific rigor, while retaining respect for their history and culture. Given the current dominance of modern medicine rooted in science and replicable evidence, this movement, with its emphasis on quality research evidence for safety and efficacy of indigenous modalities, has furthered acceptance in the West and spawned a resurgence of interest in their countries of origin. To date, Eastem healing traditions have made some of the greatest advances in integration with modern medicine. This chapter seeks to find the balance between respect for long-standing healing traditions and submitting these traditional methods to critical examination in order to procure the most appropriate and effective practice of indigenous traditions in modem medicine. To understand the issues implicit to integration and why this transition in medicine is occurring now, the reader should review the historical origins of Eastern and Western traditions, understand the contrast in philosophies, and examine in greater detail the landscape of the Eastern healing traditions.

Terminology First, a disclaimer to the reader on terminology is necessary. Because of its newness and rapid growth, terminology used to define this emerging field has evolved 3

quickly and consensus on this terminology has not yet been reached. Consequently, semantic confusion is rampant. Definitions and meanings change with the times and with shifts in paradigm; as another shift in paradigm approaches with the "age of integration," meanings are expected to adjust accordingly once again. Current terms often connote power hierarchies or ethnocentric judgment. For the sake of discussion, this chapter uses terms appropriate to this specific period in history. For example, "modern medicine" is used to describe the most conventional medicine practiced and determined by the evolving scientific method, and "complementary and alternative medicine" (CAM) is used to describe less conventional practices that are not yet understood through the scientific method. Similarly, theories on medicine or health generally fall into two frameworks named by convention: Western, originating from Greco-Roman philosophy, and Eastern, encompassing Asian-Pacific philosophy. The very definition of "modern" medicine implies fluidity, and it is fitting to use such terminology during this period of expanding medical boundaries.

COMPARISON OF EASTERN AND WESTERN MEDICINE: ORIGINS AND PHILOSOPHIES Historical Origins The world's major healing traditions are commonly categorized as Eastem, influenced by Asian-Pacific philosophy, or Western, molded by Greco-Roman philosophy, and later, the scientific revolution of the sixteenth and seventeenth centuries. The foundation of Eastern healing traditions inextricably embraces the philosophies of early Eastern thought, those of Buddhism, Taoism, and Hinduism, and of their founders. These philosophies still provide the underpinnings for contemporary Eastern cultures, allowing Eastern indigenous healing traditions to maintain widespread acceptance and practice. Several unique but related traditions developed in the East before the Christian era and are still heavily practiced today as discrete systems. These include Chinese Medicine, Ayurveda (traditional Indian medicine), and Tbetan Medicine. Other Eastem traditions enjoy moderate practice in their indigenous areas, including Persian Medicine, medicine as set forth in the Dead Sea Scrolls, and folk shamanism and animism. The origins, philosophies, and practice of Chinese Medicine, Ayurveda, and Tibetan Medicine are closely examined and compared later in this chapter, along with their current transformations in the West. In contrast, modem medicine in the West has developed quite independently from religion. It was, and continues to be, shaped by science. Modem scientific

thought evolved from the Greek philosophers beginning with Euclid around 300 BC and later Plato, Socrates, and Aristotle. These men used reasoning and deduction to develop theories to espouse what they deemed absolute truth. The mathematic theories of these Greek philosophers set the foundation for Renaissance scientists more than 1500 years later, who developed the "scientific method. " During the sixteenth and seventeenth centuries, Copernicus, Galileo, Bacon, Descartes, and Newton continued to reform modem scientific thought in the West. Early in the seventeenth century, Descartes crystallized the objective notion that "knowledge is seeing." Furthermore, Descartes proposed that the mind clearly views ideas or objects to discern knowledge. Through the mind's processes of reason and deduction, both ideas and knowledge are objectified and this forms reality..' The philosophy of reductionism is important because it was based on the notion of separation of mind and body. Modern thought, stemming from the Cartesian theory of dualism, states: "Nothing about the body, neither imagination nor emotion nor perception nor any detail of the biological nature of the body, need be known in order to understand the nature of the mind."2 Descartes' philosophy went further to embrace reductionism, which conceived that all aspects of life could be reduced to smaller basic features or "simple natures" of reality. He contended that mathematics (rational thought) or direct observation (empiricism) expresses the basic fundamental structure of all other knowledge? These principles of Descartes and his contemporaries, along with the foundation of Greek philosophy, set forth the scientific method, which describes a system of thought rather than a set of formal procedures. This constant process of empirical observation, logical reasoning, and skepticism to discern knowledge, which differs from the Greeks as it does not claim to find ultimate truths, is stiU the thought process used to validate modem medicine. The scientific method was not a mainstay of modem medicine until the turn of the twentieth century. The Flexner Report (1910) standardized medical education through the basic sciences, and with World War I, shifted the focsus of medical care toward cures for acute conditions that were defined with the precision of the scientific method. Yet the definition of "modern" medicine experienced further radical shifts in the nineteenth and twentieth centuries. It changed in dynamic ways from heroic medicine, which "cured," for example, by bloodletting and purging, to quackery movements spurred by the Romantic era, and finally to scientific "biomedicine" in the midtwentieth century. In the early nineteenth century, modem medicine was pluralistic in nature as "professional care was mostly provided by botanical healers and midwives, supplemented by surgeons,

barber-surgeons, apothecaries, and ’uncounted cancer doctors, bonesetters, inoculators, abortionists, and sellers of nostrums.’ ”4 During much of this same period, the profession of naturopathy flourished to the benefit of many. At this time, the medical profession was still in its early stages in the United States. By the early to midtwentieth century, medicine became much more narrowly defined through the scientific method. In the past 10 years, however, the United States has experienced another shift, arguably a shift again to the medical pluralism from more than 100 years ago. This raises an important question: Is this merely historical pattern or the birth of a unique era? If one defines science as an ongoing methodical study of the world in order to discern knowledge, then it must inherently evolve and expand over time. Therefore the definition of science should continue to expand, beyond objectivity, toward phenomena that have not yet been explicitly defined or successfully examined by scientific inquiry. The application of theses ideas in modem medicine is thus evolutionary. If the culture of medicine is experiencing yet another paradigm shift, that culture will necessarily move beyond the older ethos of the scientific method that defined its previous paradigm. Master Hong succinctly comments on this point, ”What gong] master possesses isn’t magic. It is just this [Qi In the twentyscience that has not yet been e~amined.”~ first century, the culture of medicine is once again embracing its diverse options for health care, shifting yet again toward pluralism, and reflecting the social landscape of a new generation. What is happening invites all healers to enlarge their ideas of disease and health and to welcome an expanded and deeper perspective.

Philosophies in Contrast ”Viva la difference.” The differences in Eastern and Western medical traditions stem directly from their foundational differences in world views. Judith Farqhuar describes these essential differences in world views as ”the differencebetween a world of fixed objects and a world of transforming effects. . . . Like the solid inertial world of modern natural science traditions, the . . . transformative world of Chinese medicine seems to exist prior to all argument, observation, and intervention. Perhaps with a certain discomfort, Western readers must acknowledge that ’their’ abstractions about such things make as much sense as ’ours.’ “6 One of the most obvious and far reaching differences between Eastern and Western medical traditions is the concept of inter- and intrapersonal relationships. Stemming from the Socratic model and Cartesian dualism, Western medicine heavily delineates between mind and body, between doctor and patient, and between healthy and diseased. On the other hand, medicine originating in the East finds little distinction in these areas. Instead,

it views continuity and balance as vital to health. Illness is defined by imbalances of patterns that should naturally be in harmony. Multiple aspects of the being including the mind, body, and spirit are integral to this harmony. In contrast, illness in modern Western medicine is described by a specific pathology, caused by discrete foreign pollutants and often cured by another foreign element. In its extreme, the patient is an accident attached to the disease under treatment. Unlike Eastern healing traditions, in which the religions and philosophies of Buddhism, Taoism, and Hinduism hold such a foundational role, modern Western medicine, developed from reductionism, always separates religion and science. Instead, Western medicine is mainly guided by science in which truth is derived from the empirically correct interpretation. The intuitive experiences of others are often discounted rather than being incorporated into one’s knowledge base, because “that is not science, that is faith.”7In the Western philosophical framework, faith (that which cannot be proven through the scientific method) is seen as of lesser value than knowledge gained by direct experience. The fundamental concepts of Eastern healing traditions are deeply embedded in the philosophies of their cultures. Consequently, they are perceptions, ideas, and values shared by most society members. Although health is integral to one’s everyday life in Eastern societies, it is only one part of Western society. Likewise, health is defined in the East as a unity of individual, environmental, and societal factors. Although the Western definition of health has moved toward encompassing physical, mental, social, and spiritual arenas, each is still defined as a separate entity, and theories of pathology still drive mechanism perceptions of health disorders. These distinct differences in vision and approach shape the patient-doctor relationship. In Eastern traditions, the unique balance of the factors cited earlier is critical to diagnosis and treatment of a patient’s disharmony rather than disease. Physicians in Western medicine look beyond the patient-doctor relationship to an external body of knowledge to diagnose and treat, guided by categories of symptoms. A general comparison of Eastern and Western concepts in regard to health is shown in Table 1-1.

Overview and Comparison of Eastern Traditions As mentioned, while several indigenous healing traditions in the East have been preserved, Chinese, Ayurvedic, and Tibetan Medicine remain among the most heavily practiced traditions in their respective regions. All three traditions stem largely from similar philosophical foundations; thus in all, health and disease

Comparison of Western and Eastern concepts Western

Eastern

World views

Reductionist

Holistic

Mechanism of disorder

Pathologic mechanism

Imbalance of harmonies

Foundational structure

Logic, mathematics

Eastern religions and philosophies

Patientdoctor relationship

Access external body of knowledge for diagnosis and treatment

Unique balance critical to diagnosis and treatment

~~

Comparison of Tibetan, Ayurvedic, and Chinese medicine Tibetan

Ayurveda

Chinese

Defined by balance or imbalance of states

Health and disease

3 humors: wind, bile, phlegm

3 humors (doshas): air, fire, water principles

Qi, blood, Shen

Principle of opposites

Hot/cold

Hot/cold

Yinlyang

5 Elements

Air, water, fire, ether, earth

Ether, water, fire, earth, air

Air, water, fire, metal, earth

Fundamental textures

Diagnostics Treatment modalities

Origin Religious Text Recent history (post-Newtonian, within past century)

Pulse (most important), urine, tongue, morphology Behavioral (lifestyle, meditation), diet, herbals, external treatment (acupuncture, massage)

Dietary alterations, yoga, exercise, herbal formulas, surgical techniques

Acupuncture, herbals, Qi gong

Intimately related to Buddhist philosophy but stands on its own

Intimately related to Hindu philosophy but stands on its own

No formal tie to Taoism or Buddhism

Gyu-zhib.il(

Rig Veda (second millennium BC) 800 BC

2598 BC Nei Jing

Enjoyed the greatest continuity

Transformation by Cultural Revolution

ffiyud-bzhi)

Transformation by Chinese invasion

are seen as inextricably interrelated. They play integral parts in the delicate balance of harmony and disharmony. What creates and influences these patterns of harmony are the intricate details that define them as unique systems of healing. Table 1-2 provides a comparison of these three traditions. Several other healing traditions have developed in the East, which have encountered more moderate levels of practice in their indigenous regions and abroad. These include Persian Medicine, traditions from the Dead Sea Scrolls, shamanism, and animism. Although there are numerous detailed differences,they, too, share basic philosophical similarities with the other Eastern traditions.

Origins Tibetan Medicine and Ayurvedic Medicine have similar historical origins, as Ayurveda is the root of Tibetan Medicine. Ayurvedic origins are found as early as the second millennium BC in the Rig Veda, with its second classical stage in the Brahmanical period in 800 BC, where it continued as an unbroken lineage until the

Moslem conquest of India in the thirteenth century. During that time in the sixth century BC, the historical Buddha, Shakyamuni, was born in India, and after achieving Enlightenmentunder a Bodhi tree in Bodhgaya and delivering the teachings of the Four Noble Truths, Buddhism was born.* The Tibetan medical tradition offers that the Buddha, often called the “Great Physician,” taught the medical texts himself, including the Gyu-zhi, the most important Tibetan medical text. The Sanskrit version of the Gyu-zhi, however, was probably not written until around 400 AD.* While some scholars may debate whether the historical Buddha’s teachings are the precise origin of Tibetan and thus Ayurvedic medicine, Buddhism’s influence on these two healing traditions is unquestionable. Like Ayurveda, the origins of Chinese medicine date back to the second millennium BC, to the era of the great Yellow Emperor, Huangdi (-2698-2598 BC). The classic ‘Lineage refers to the descendants of a common ancestor considered to be the founder of the line.

Eastern Origins of Integrative Medicine and Modern Applications

medical text written during his reign is Huangdi Nei Jing (The Yellow Emperor‘s Inner Cannon). Yet perhaps of more influence to the systematic and well-structured Chinese medicine known today is the Nun Jing (The Classic of D~ficultIssues), written around the first or second century AD. As Harrison notes in the chapter on Acupuncture in this edition, the Nei Jing deals more with ”demonological medicine and religious healing,” while the Nan ling develops Chinese medicine as an original system, with well-defined and organized principles, diagnostics, and therapeutics? Chinese medicine has also witnessed various transformations, most notably its recent evolution into Traditional Chinese Medicine (TCM), the modem form of Chinese medicine practiced in China and worldwide. Influenced by the advent of modem science, Chinese medicine was required during the 1950s to establish increased legitimacy in the face of the new Marxist ideology, which emphasized “natural science” and delegitimized Confucian influences. Its decline began as early as 1914, when the minister of education announced discontinued use of traditional medicine. Several changes to traditional Chinese medicine followed, which stifled its growth. The previous pluralism of classic medical readings merged into Chung-I, which described a general practice and theory of Chinese medicine. Initially, the People’s Republic of China (PRC) denounced folk, demonic, and Buddhist temple medicine.1° However, in 1951, Mao-Tse-Tong revived and then canonized portions of the tradition with his ”Chinese medicine is a great treasure-house” speech.’* In Mao’s Cultural Revolution, Chinese medicine was transformed to TCM and embraced as a means to preserve the ”spirit of a nation.” The “new medicine” movement highlighted traditional medicine’s ability to arouse one’s own bodily defenses against illness while excluding metaphysical ideologies. TCM thus embodied one general theory of Chinese medicine and discouraged diverse readings and interpretations by practitioners and students. Of the three traditions, Tibetan medicine enjoyed the most continuity in lineage until the Chinese invasion consummated in 1959. With the Moslem invasion of India in the thirteenth century, much of the Ayurvedic medical system was destroyed, along with many Buddhist texts. Fortunately, by the seventh century AD, Ayurvedic medicine had traveled to Tibet and was safely preserved in the Himalayan Mountains. Once in Tibet, Buddhism and its medicine first adapted to the indigenous shamanic religious culture, Bon, whose greatest contribution to the Tibetan medical system was its knowledge of the indigenous medical herbs of the sub-Himalayan plateaus. With King Strongtsan Gampo’s formal introduction of Buddhism to Tibet in the early seventh century, the influence of Buddhism on its medicine flourished. This continued up until the Chinese invasion in 1959.

Despite its isolation in practice, Tibetan medicine shares several principles with other Eastern healing traditions. Its strongest ties are with Chinese medicine to the north and Ayurvedic medicine to the south. Eastern traditions of healing are undoubtedly intertwined in a rich tapestry, stemming partly from an extraordinary meeting of healers. During the seventh century, the Tibetan King Gampo held the world’s first recorded international medical conference. Noted physicians from India, China, Greece, Nepal, Persia, and Mongolia dialogued in a cross-cultural exchange, and texts from each medical tradition were translated.

Fundamental Philosophies: Tools to Assess Balance The notion that ill health stems from the imbalance of certain fundamental forces or “textures” stands at the core of many Eastern healing traditions. While the traditions may vary as to which fundamental forces, textures, or elements are involved in diagnosis and treatment, certain philosophies are shared. In these, the five elements, fundamental textures, and principles of opposites govern the universe. The five-element theory is the most common approach used to diagnose and restore health. The five elements are commonly understood to define, control, and at the same time be governed by a constellation of internal and external phenomena. These phenomena include human emotions, human senses, body organs, and climate. Humoral pathology, central to Ayurvedic, Tibetan, Persian, and Greek systems, is the core principle that unifies the mind with the body and the individual with his environment. It defines the balance or imbalance of the textures that influence one’s state of health. These humors define an array of biologic, physiopathologic, and psychologic phenomena related to the body, the mind, and the environment. In both Tibetan and Ayurvedic medicine, three humors, or primary qualities, maintain aspects of health. In Tibetan medicine they are Vuyu (Tib. Rlung), P i t h (Tib. Khrid), and Kapha (Tib. Bad-hn), translated as ”wind,” “bile,” and ”phlegm,” respectively. Yet the English translation is imprecise and limits the meanings of wind, bile, and phlegm principles, which further describe the mind, energy, and inert matter. Analogies can be drawn using conventional physics. Wind can be compared with kinetic energy, bile with caloric energy, and phlegm with mass energy. With reference to personality, those governed by air tend to be wiry and impulsive; bile types are muscular and quick to anger; and those ruled by phlegm are normally heavy set and tend to avoid conflict. Additionally, the humors are the products of the three delusions, which are the root cause of all suffering in the Buddhist tradition: phlegm, a product of ignorance, bile from anger, and wind from attachment. Understanding the humors as

products of the three delusions underlines the interrelationship between Buddhism as a spiritual practice and the healing professions. In Ayurvedic medicine, these humors are the three Doshas, known as Vat; Pit, or fire principle; and Kaph, or water prinaple, and carry specific actions. Vat is the bodily air prinaple and governs movement; Pit is the bodily fire prinaple that controls metabolism; Kaph is the biologic water prinaple that provides physical structure. These principles are also associated with the metabolic activities of anabolism, catabolism, and metabolism. In addition, they are associated with certain personalities and certain physical characteristics of dry or oily, light or heavy, and hot or cold. For a more complete discussion of the Doshas and their related properties and functions, see Chapter 34. Chinese medicine, on the other hand, lacks this system of detailed humoral pathology yet encompasses a similar principle that certain fundamental qualities must be in balance to achieve a healthy state. These fundamental textures are the universal Qi, Blood h e ) , Essence (jing), and Spirit (shed. Like the humors of Tibetan and Ayurvedic medicine, Q is universal and encompasses and connects all animate phenomena internally (body, mind, organ, senses) and externally (organism to environment). Q1 generates change both on a small scale and in the larger picture of Yin and Yang, those opposite forces of light and dark, female and male, that embody all organisms. Qi has five major functions: movement, protection, harmonious transformation, stability and retention, and warming of the body. The definition of blood in Chinese medicine goes beyond the physical concept of blood in Western medicine, as it is the Yin complement to the clinical Yang Q, functioning to nourish, circulate, and moisten the body. Essence is specific to organic life and slowly perpetuates life forward. Whereas Qi is the fluid movement of ordinary time, Essence spans a lifetime and embodies all characteristics involved with birth, maturation, and death. Lastly Spirit is unique to human life but is beyond mindconsciousness.It is what prompts humanity and relationships with one's self and other humans, and it examines all facets of humanity-moral, social, mental, physical, and emotional. While the concept of Yin and Yang is at the core of Chinese medicine, principles of opposites to achieve balance and optimal health are central to a l l three traditions. The Tibetan and Ayurvedic systems employ "hot" and "cold" to depict opposites. These fundamental opposites, fundamental textures, and five elements are intricately related to one another, providing a holistic framework in which to consider health and illness.

Diagnostics and Treatments In accordance with its foundational philosophies, diagnostics in Eastem traditions take into account the person

as a whole. The patient's physiologic characteristics, mental dispositions, and other personal, social, economic, and environmental details are assessed. In addition, diagnosis includes the following examinations: general physical, pulse, urine, tongue and eyes, skin and ears. The core principle in treatment is to restore the person's health to equilibrium, through severalbehavioral, lifestyle, diet, manual, and medicinal treatment approaches. Treatment methods in the Tibetan tradition are arranged in a hierarchy of usage: (1) behavioral practices (lifestyle, meditation), (2) diet, (3) herbal medicines, and (4)external treatments (acupuncture, massage, moxa, and surgery). Treatment therapies in Ayurveda include dietary alterations, yoga, exercise, herbal formulas, and surgical techniques. Ayunreda places special emphasis on diet as a modality, as it considers the human body a mental and physical product of the food consumed. Main treatment methods in Chinese medicine include acupuncture, herbal medicine, and sometimes Qi Gong.

MODERN APPLICATIONS: THE AGE OF INTEGRATION [The interpreter's] task is rather to seize the vital conception of the art-work, to blend it with his own ego and the views of his period, and thus to imbue it with life and efectiveness. His artistry is a product of its mental culture. It develops and changes with the evolution of artistic requirements. His formative and emotional powers are derived from the spirit of the epoch to which he belongs. Much that charmed former generations has no effect in ours; so much is part and parcel of its passing. Only what is exalted over time and place remains as eternal gain; and here, again, another generation finds new treasures that earlier ones passed by unheeding. This is the unfailing criterion of true greatness, that its creations continually beget ever-new, everchanging values, that they bring to each successive generation new revelations. -Max Spicker, 1912 As the social landscape changes, the culture of medicine continually redefines what is considered "conventional." Numerous recent studies have shown that since the early 1990s, consumers have been demanding alternatives to modem care.12Only since then has integrated medicine, including naturopathy, penetrated the Ivory Tower and research institutions in the United States. Driven by scientific advancement and a need for increased knowledge, this movement toward a more pluralistic medicine has now brought us beyond the age of information and into the "age of integration." With the current plethora of health information, it is becoming more apparent that optimal healing is not the property of any one tradition or system. As a result, previously marginalized traditions have experienced

Eastern Origins of Integrative Medicine and Modern Appli a resurgence in interest and usage. They are now finally finding inclusion. Integrative clinics that incorporate multiple healing systems thrive throughout the country and at major academic medical institutions. Employers and managed care agencies are beginning to offer limited coverage for acupuncture, chiropractic, naturopathy, and massage services. The Academic Consortium for Integrative Medicine has been formed among top-ranked medical schools to integrate CAM into their curriculums. The NIH has devoted an institute just for CAM and allots a budget of $113.2 million for research and educational initiative^.'^ Despite the recent explosion of integrative medicine entering research, education, and clinical arenas, several barriers still limit the growth of integrative medicine in the United States. The most pressing and present barrier to clinical integration is reimbursement. To persuade insurers to cover the costs of CAM therapies, research evidence built on rigorous clinical trials and data that demonstrate cost-efficacy of these modalities are necessary. Perhaps an even greater barrier to integration is the challenge of how to establish safe and effective practices for these modalities, while carefully preserving the lineage of indigenous traditions. To examine this issue, the authors outline the birth and evolution of indigenous traditions as medical professions in the United States and later provide units on clinical practice, risk management, professional communications, practice management, and research that serve as essential tools for integration. The current dilemma in the development of these CAM professions is how to perpetuate lineages during this integration with other health care professions, while not lowering standards for CAM practitioners. This present boom in alternative health care has resulted in the current state of integrative medicine: a confusing situation with too many practitioners offering a wide range of skills but leaving consumers without tools to decipher which are the most effective or true to tradition. Now the middle path must be taken by raising the bar for practice standards. If the bar is too low, traditions will no longer be protected and they will not be as efficacious in practice. Consequently, practitioners may not be appreciated by either patients or traditional providers. If the bar is too high, few will find access and few will be able to practice. Either way, invaluable traditions may be lost.

The Birth and Evolution of a Medical Profession in the United States: Complementary and Alternative Medicine Professions In the last years of the twentieth century, the United States witnessed the beginning transformations of indigenous healing traditions into CAM professions. After the counter-culture years of the 1960s and 1970s

that challenged institutionalized medicine, interest in “natural healing” practices surged. As a result, chiropractic care and naturopathy were the first traditions to become formalized in modem medicine. Since then, Chinese medicine-namely acupuncture-has made the largest entrance into health care in the United States, with more than 50 TCM and acupuncture schools in the United States and Canada accredited by the Accreditation Commission for Acupuncture and Oriental Medicine (ACAOM), adoption of licensure laws in the majority of states, and an increasing number of insurers offering coverage for TCM treatments. A far second to Chinese medicine has been the development of Ayurvedic and Tibetan medicine, which are still in the early phases of their evolution as professions in the United States. Every medical tradition, even the current scientificbased modem medicine, began at the margin and progressed through a similar cycle to become an established practice or profession. Currently, CAM modalities are finding similar challenges as they endure this evolution toward becoming established professions. Typically, in stage 1, lone practitioners of the tradition arrive in the United States and provide informal workshops to the public and interested health care providers. These CAM practitioners practice their traditions informally. Stage 2 develops only after public and provider acceptance of safety and efficacy. Stage 2 marks the development of professional education and associations; providing standards for school accreditation; credentialing; and, ultimately, licensure by state boards. With regulation through professional associations, third-party payers become amenable to insurance reimbursement for CAM treatments. Finally, stage 3 results in set state and national standards for the profession, including education, practice, and methods to evaluate safety and efficacy, as well as widespread acceptance and practice. Achieving a code for Medicare reimbursement is one measure of success of the integration of CAM with modern health care. In this current era, the accomplishment of stage 3 is inherently dependent on the respectful and appropriate blending of these CAM traditions with the dominant medical paradigm based in science. At this time in the United States, the professions of naturopathy, chiropractic, acupuncture, and massage are in stage 2 or early stage 3 of their professional and legislative developments, where accredited schools in all these fields have been undoubtedly established and licensure is being governed by state boards. For instance, acupuncture currently has two established organizations that help to set standards for training and practice: the ACAOM and the National Certification Commission for Acupuncture and Oriental Medicine (NCCAOM). ACAOM is recognized by the U.S. Department of Education to accredit first professional master’s degree and master’s level programs in acupuncture and

Oriental medicine and is currently petitioning to begin accrediting postgraduate, clinical doctoral programs. Acupuncturists are currently licensed according to state boards, but licensure laws vary from state to state. Many states recognize NCCAOM certification as a national standard, and thus practitioners can earn licensure with NCCAOM certification in these states. However, licensure laws still vary widely by state. Acupuncture as practiced by approximately 5000 medical doctors in the United States is currently the fastest growing medical specialty. The American Academy for Medical Acupuncture now offers specialty board certification in the field. Nevertheless, while several thirdparty payers are beginning to offer insurance coverage for acupuncture, barriers such as standardization in education, practice, and research still exist.

Clinical

Prevention and identification of medical emergencies in the CAM clinic Prevention and appropriate medical responses to adverse reactions of CAM therapies Recommendations for interdisciplinarycare of common complaints Guidelines for selected scope of practice issues Herbs as neutraceutical Risk Management

Malpractice Informed consent Expert testimony Charting Regulatory issues Insurance

TOOLS FOR INTEGRATION

Professional Communications

As providers of CAM services join professional networks and become increasingly integrated into conventional health delivery, the CAM professions gain both credibility and exposure. Integration brings with it a new set of responsibilities. Utilization is growing and evolving so quickly that the educational institutions preparing C A M providers for licensure are hard-pressed to keep up with the trend. As a result, CAM provider education often does not fully prepare its graduates to meet the growing expectations of the public, the medical community, or the legal system. Providers must gain competency in "tools for integration" that lead to a new set of skills for clinical practice, risk management, professional communications, practice management, and research. These tools include, but are not limited to, those listed in Box 1-1. The emerging field of integrative medicine has arrived at the end of the beginning. It is no longer simply a vision of what could be. Billions of dollars are now spent out of pocket for several hundred million visits to integrative providers and for herbs and neutraceutical each year. The majority of medical schools now offer some form of CAM education for physicians in training. Yet until now the consumer has carried the day. As physicians move forward into the twenty-first century, they are ready to enter the beginning of the middle. The transition is rapidly under way and is best facilitated by successful clinical models for integration and quality studies that demonstrate clinical outcomes of integrative services and the extent to which these services provide cost offsets compared to conventional care. As the more developed CAM professions continue to evolve and new traditions like Tibetan or Ayurveda move into a new phase, it will be increasingly important to respect the lineage of indigenous traditions as they enter U.S. culture. In credentialing practitioners, it must

Patient presentations Referral protocols Operations Human resources Patient relations Using information technology Research

A survey of conventional research tools Customizing conventional research tools to study CAM Evaluating research publications Using research findings Performing original research CAM, Complementary and alternative medicine.

be acknowledged that training is traditionally based on lineage passed on by oral tradition. This makes an argument for dual pathways for credentialing that allow for both apprenticeship and degree programs with standardized testing. Researchers must also recognize the unique set of challenges when studying the health benefits of these traditions, as traditions become more subject to the gold standard of randomized controlled trials (RCTs) to gain acceptance. The work of medical anthropologists will become crucial to preserving cultural sensitivity as research in CAM progresses. Several compromises need to occur for smooth integration in research. For instance, outcome studies must seek to capture quality of life. Addressing the different taxonomy of illness when studying indigenous traditions is also essential. In practice, it is also increasingly necessary to build bridges between the indigenous community, evolving CAM professions, and established medical institutions.

Eastern Origins of Integrative Medicine and Modern Applications

Researchers, academicians, and health care professionals from multiple backgrounds need to understand these issues in integration in order to provide optimal health with wisdom for this generation and the next. Only through partnership can the best medicine be offered

and this evolution in the culture of health care be assisted. In the words of Albert Einstein, “Whoever undertakes to set himself up as judge in the field of Truth and Knowledge is shipwrecked by the laughter of the gods.”

1.Lakoff G, Johnson M. Philosophy in the flesh: the embodied mind and its challenge to Western thought. New York Basic Books, 1999~395-398. 2. Lakoff G, JohnsonM. Philosophy in the flesh the embodied mind and its challenge to Western thought. New York Basic Books, 1999:408. 3. Robinson G. Introducing Descartes. Cambridge, UK: Icon Books, 1999:20. 4. Kaptchuk T, Eisenberg D. Varieties of healing. 1: Medical pluralism in the United States. Ann Intern Med 2001;135:189. 5. Liu H, Perry P (Contributor).The healing art of Q1 Gong: ancient wisdom from a modem master. New York Warner Books, 19996. 6. Farquhar J. Knowing practice: the clinical encounter of Chinese medicine. In Kaptchuk T, ed. The web that has no weaver: understanding Chinese medicine, ed 2. Chicago: Contemporary Books, 2000:67. 7. Binion T. In The Urantia book. Evolution of the scientific method. Chicago: Uversa Press. 1998:2.

8. Rechung R, Kunzang J. libetan medicine. Berkeley: University of California Press, 19733. 9. Nolting M. Acupuncture. In Pizzorno J, Murray M, eds. Textbook of natural medicine, ed 2. New York: Churchill Livingstone, 1999:254. 10. Unschuld P. Medicine in China: a history of ideas. Berkley: University of California Press, 1985:250. 11. Farquhar J. Rewriting traditional medicine in post-Maoist China. In Bates D, ed. Knowledge and the scholarly medical traditions. New York: Cambridge University Press, 1995251. 12. EisenbergD, Davis R, Ettner S, et al. Trends in alternativemedicine use in the United States, 1990-1997 results of a follow-up national survey. JAMA 1998;2801569-1575. 13. Figure from National Center for Complementary and Alternative Medicine, for fiscal year 2003.

Functional Medicine in Natural Medicine Buck Levin, PhD, RD Jeffrey S. Bland, PhD Michael A. Schmidt, PhD CHAPTER C O N T E N T S PART I:THE PHILOSOPHY OF FUNCTIONAL MEDICINE 13 Introduction 13 Theoretical Aspects 14 The Philosophy of Function in a Medical Context 14 Function as a Mediator for Opposition Thinking in the Sciences 15 EnergyJMatter 10 Body Systems from a Functional Medicine Perspective 19 PART 11: THE CLINICAL APPLICATION OF FUNCTIONAL MEDICINE 21 Basic Concepts in Functional Practice 21 Biochemical Individuality 21

INTRODUCTION This textbook bears witness to the remarkable evolution of naturopathic medicine in the United States since Benedict Lust first opened his American School of Naturopathy on 59th Street in New York City in 1902. During the intervening century, naturopathic physicians have become recognized as primary health care providers in about one fourth of all states. Naturopathic practice has become part of publicly funded clinics. Accredited training has become available in all regions of the country. In addition, naturopathic philosophy has influenced medical philosophy as a whole, including the functional approach that we have espoused in our own work. Naturopathic recognition of key medical principles, including tolle cuusurn (idenhfy and treat the causes), prirnum non nocere (first do no harm), and docere (doctor as teacher) has helped the authors clarify their vision of a functional approach to health that

Health as a Positive Vitality 21 Life Processes as Homeodynamic 21 Assessment and Treatment from a Functional Perspective 21 Illness as Information 22 Treatment Decisions 22 Concept of Total Load 23 Depth of Action 23 Mechanism and Outcome 23 Prevention, Early Detection, and Functional Medicine 24 Approach to the Patient 24 Laboratory and Instrumental Diagnosis from a Functional Perspective 24 Pattern Recognition 25 Summary 25

worked develop an approach to health care that can be incorporated into the everyday practice of all health care practitioners regardless of training or specialty. Moreover, the authors have tried to carve out an approach that capitalizes not only on the foremost accomplishments of basic and applied science but on the strengths of specialty fields and specialized approaches to clinical practice. The authors hope that naturopaths, osteopaths, chiropractors, medical doctors, nutritionists, dietitians, herbalists, homeopaths, acupuncturists, Ayurvedic physicians, and other diversely trained practitioners can find in functional medicine an approach that naturally extends and enhances their current practice. Functional medicine is not a "new" or "alternative" approach that requires a change in basic clinical orientation or political allegiance. It only requires a willingness to take seriously one's basic medical philosophy and engage the science of our time with the spirit of true discovery, open-mindedness, and due diligence. This chapter specifically addresses 13

Philosophy of Natural Medicine

the consequences of such an approach for naturopathy and its clinical practice.

THEORETICAL ASPECTS The Philosophy of Function in a Medical Context Most dictionary definitions of “function” indicate the word derived from the Greek term ergonr which means “the kind of action or activity proper to a person or thing; the purpose for which something is designed or exists.”’ This definition indicates that the concept of function must be viewed in the same category as the concepts of “purpose” and “design.” In addition, understanding the function of a person or thing is not possible without also understanding the purpose for which that person or thing is designed. In early Greek philosophy the term ergon was frequently contrasted with the term pathemfa-things that happened to a person or thing? This comparison focused on the difference between things with the capacity to act (poiein) and things that were, in contrast, “passive activations” (patheJ3En-ergia-being in activity or functioning-was considered to be the telos (end purpose) of being alive. Today, when people refer to disease as ”pathology based,” they are actually linking disease, etymologically,to this realm of pathemafa and pathe. They define disease as something that ”happens to” a person, something that is not a part of that person’s purposeful activity. Etymologically, the term “functional medicine” moves people away from this pathologic model and aligns them with a medicine that views disease as part of something that is purposeful and is proceeding actively in accordance with some design. The history of philosophy-at least as far back as the writing of Aristotle in the third century ~c-has witnessed an ongoing debate between “vitalistic” and “mechanistic” approaches to life and health. Naturopathic medicine has consistently aligned itself with the vitalistic side of this argument. Naturopathy recognizes a vital force-vis rnedicatrix naturue or healing power of nature-that is present in all living things, including the human body For naturopaths, this vital force is ultimately responsible for healing. The functional medicine emphasis on purpose and design is closely related to this recognition of vital force in naturopathy. When functional practitioners recognize purpose and design in physiologic events (including “disease of unknown origin”), they are acknowledging that body function is guided by a universal, supraindividual set of principles. They are acknowledging that physiologic function originates from an infinite, complex, patterned matrix of occurrences that both precede and transcend individual human experience. The purpose

and design of functional medicine therefore echo the spirit of vitalism. This spirit of vitalism does not mean, however, that the healing force is totally mysterious or unapproachable. While the universal, patterned matrix of events is infinite and cannot be fully understood, it is nevertheless a complex pattern that can be observed and analyzed within the limits of a human perspective. Pursuit of this possibility is essential to a functional approach. The more that can be learned about the patterned matrix of universal events, the better the practitioner can support healing. The termsfom andfunctionare probably most familiar to us from the field of architecture. At the turn of the twentieth century, U.S. architect Louis Sullivan coined the phrase “form follows function,” recognizing that purpose precedes the blueprint. But in our philosophy of the body’s architecture, how do these terms apply? In the case of several body systems-the musculoskeletal system or the circulatory system, for example-shape and form give an initial hint about function, design, and purpose. Observing the body’s skeleton is difficult without concluding that it has been designed for structural support. With other physiologic systems, these connections are not nearly so obvious. Phrenology, described by English historian J.C. Flugel a century after its origin as ”psychology’s greatest faux pas,” argued that the quality of a person’s mental faculties was determined by the size of the brain area on which those faculties depended, and this quality could be judged by the contours of the skull adjacent to the area! This literal equating of brain function with brain form, launched in 1810 in Pans by FrancoisJoseph Gall and his student J.C. Spurzheim, met with some immediate difficulty in application. After discovering that the skull of French philosopher Rene Descartes was particularly small in the anterior and superior regions of the forehead, understood to be the seat of a person’s rational faculties, Spurzheim reportedly commented, ”Descartes was not so great a thinker as he was held to be.”5 The inability of phrenologists to make sense of function by reference to form alone is one example of a difficulty that continues to permeate twentieth-century medicine. Naturopathy has made great strides in linking form with function, by accommodating into its practice long-standing medical traditions that treat function by working with form. Naturopathy’s embrace of physical medicine-from craniosacral therapy and osseous manipulation to hydrotherapy and physiotherapy-has made the connection between form and function more accessible. A final common ground between functional and naturopathic medicine involves the idea of a ”medical philosophy.” The need for practical solutions in everyday

Functional Medicine in Natural Medicine

medical practice is great-so great that most practitioners do not see themselves as having the time or inclination to “philosophize.”Yet from a functional and naturopathic perspective, it is impossible to approach health without paying continual attention to one’s philosophy of medicine. The remainder of this section provides several examples of philosophic thinking that the authors believe continue to represent stumbling blocks for an integrated, twentyfirst-century medicine. Each example thinks ”dualistically” about medical concepts and, in so doing, loses sight of function.

Function as a Mediator for Opposition Thinking in the Sciences Padwhole The traditional philosophical dualism of “part/whole” has been directly addressed in the field of holistic health. Two national organizations, the American Holistic Health Association (AHHA),headquartered in Anaheim, CA, and the American Holistic Medical Association (AHMA), located in Raleigh, NC, have each referred to this dualism in defining their field of study According to the AHHA, Rather than focusing on illness or specific parts of the body, holistic health considers the whole person and how it interacts with its environment. It emphasizes the connection of body, mind, and spirit. Holistic Health is based on the law of nature that a whole is made up of interdependent parts. The earth is made up of systems, such as air, land, water, plants, and animals. If life is to be sustained, they cannot be separated, for what is happening to one is also felt by all of the other systems. In the same way, an individual is a whole made up of interdependent parts, which are the physical, mental, emotional, and spiritual. When one part is not working at its best, it will impact all the other parts of that person. Further, this whole person, including all of the parts, is constantly interacting with everything in the surrounding environment!

And according to the AHMA, Wellness is defined as a state of well-being in which an individual’s body, mind, emotions, and spirit are in harmony with and guided by an awareness of society, nature, and the universe. . . . (It) encompasses all safe modalities of diagnosis and treatment, including the use of medications and surgery, emphasizing the necessity of looking at the whole person?

On its Internet website, the AHMA states, ”Optimal health is much more than the absence of sickness. It is the conscious pursuit of the highest qualities of the spiritual, mental, emotional, physical, environmental, and social aspects of the human experience.”8 With respect to their characterization of ”part” and ”whole,” these definitions of holistic medicine are largely compatible with a functional approach. Because the

concept of function asks us to consider why a thing is here, what it is “doing” in the universe, it asks us to be holistic and take into account the holon-which in early Greek philosophy meant both ”universe” and “organism.” Wholeness becomes a necessary concept for understanding function, and holistic medicine has done medical philosophy an important service by renewing its focus on the whole. At the same time, the authors invite supporters of holistic medicine to consider an extension of their philosophy in two ways. First, they invite consideration of a multilevel understanding of wholeness that does not predetermine a frame of reference or specific context in which wholeness is to be evaluated. For example, if it is unknown whether planetary indices of geomagnetic disturbance-like sunspot relative number, area, and geomagnetic activity-are as valuable a “whole” or ”universe” against which to evaluate and treat cardiovascular disease as homocysteine imbalances (the ”whole” or “universe” of the cell) or ”heartlessness”and ”disheartenment” (a psychologic or sociocultural “whole” or “context”), benefits might be expected by keeping a radical open-mindedness about frames of reference, levels of wholeness, and their ultimate interrelationship in a holistic model. Instead of trying to simplify with three or four frames of reference based on early twentieth-century psychology (i.e., wholeness as the sum of physical, emotional, mental, and spiritual frames of reference) or a few contexts based on specialty (physical body, immediate external environment, global environment), such conclusions could simply be postponed until more is learned about levels of wholeness and their relationship. From a functional perspective, the authors suspect this relationship closely resembles the one described by U.S.engineer, designer, and architect Buckminster Fuller in his discussion of “functions” in his 1975 opus, Synergetics: “Functions occur only as inherently cooperative and accommodatively varying subaspects of synergistically transforming whole^."^ The relationship of part to whole is a second area in which a holistic perspective could be logically extended. We believe the concept of function necessitates a view of “part” and “whole” that is quite different from the image of a disassembled jigsaw puzzle or a shattered china teacup, which can be reassembled or glued back together to reestablish the ”whole” from which it came. In both examples, the parts have a visible connection to the whole, but in and of themselves they are a diverse array of pieces in all shapes and sizes, bearing no individual resemblance to the whole from which they came. From a functional perspective, the authors believe this image of part and whole should be changed. Instead of a shattered teacup or a disassembled puzzle, the authors propose a shattered hologram. When a hologram breaks,

it does not shatter into discrete pieces with different sizes and shapes that individually bear no resemblance to the original hologram. It splits into separate pieces, each of which visibly contains the complete and original hologram. From a medical perspective, this change means that health care practitioners would stop assigning partial functions to anatomically distinct body parts or systems and begin treating all parts as visibly containing the original hologram (i.e., whole body capability). For example, physicians have traditionally viewed the gastrointestinal (GI) tract, brain, and immune system as separate, identifiable parts unable to carry out each other’s basic functions. In the case of the GI tract, these functions have traditionally been limited to digestion, absorption, secretion, and motility. Researchers have discovered that the GI tract has its own immune system (GALT) and its own brain (memory T cells disseminated to the intestinal epithelium and lamina propria providing the functional basis for oral tolerance)1° and can carry on functions traditionally reserved for other systems of the body. Similarly, it is recognized that the eye does not simply ”see.”It helps set the body’s circadian rhythms through the production of melatonin’l and may therefore coordinate reproductive signaling as w e l l 2These findings encourage recognition of the whole inside each part. Equally encouraging have been the many “reflexologies” that have dotted the landscape of alternative medicine and have been given openminded consideration in naturopathy-foot reflexology, iridology, intestinal reflexology in colonics, contact reflex analysk-each pointing toward a ”shattered hologram” model in which the unbroken whole is visible in its seemingly separate parts.

Inside/Outside The classic debate over nature versus nurture, heredity/ environment, geneticdexperience has had troublesome consequences for a patient-centered approach to wellbeing. The authors have seen what can happen when the ”insides,” in their purist form, are equated with the chromosomal material inside the nucleus of the cell. What can happen is a philosophy of development that treats the three billion base pairs in the human genome as a largely unalterable blueprint working from the inside to define a person’s potential with respect to the ”great taskmaster outside” (i.e., the environment). This extremist view of inside/outside, equating insidethe true ”inner sanctum”-with the gene, has led to a national eugenics movement based on misinterpretation of ethnic differences in intelligence quotient (IQ), a national backlash against elementary school “mainstreaming” based on misinterpretation of learning disorders, and a popular anthropology of racial difference based on misinterpretation of the anthropologic facts.

Two examples from the history of biology can help place the dualism of “inside/outside” in a more functional context. The first example involves a chapter of a book written by Swiss zoologist Adolph Portmann in 1967. In his chapter, titled ”The Outside and the Inside,” Portmann writes: Biologists . . . have worked from the outside inwards, from what is visible and tangible to what is more and more deeply hidden. . . . But such probing makes us strangers to the appearance of the living creatures around us. . . . With a knowledge of the developmental conditions under which, for instance, a feather primordium develops and its pigment is formed, it is only the problem of shape that has been solved. But it still remains to be shown what brings about that special distribution of color in the pattern on the feather germ which is specifically directed towards the whole form in its final ~0ndition.I~

In his book Portmann argues that outsides of animals are expressions of their inwardness (i.e., their developmentally unfolding uniqueness and individuality). He also concludes that the ultimate purpose of this “insidesbecoming-outsides” is to help living creatures find each other and ”break the ban of i~olation.”’~ Portmann’s writing expresses a desire to blur (or even erase) the line between inside and outside. What is innermost “feels a desire” to become outermost, for the purpose of connecting up with the innermost sanctum of another. Health care practitioners are familiar with the notion of a milieu inttrieur-an interior, homeostatic, calm harbor maintained in the wake of outside, stormy seas. Pasteur ’s contemporary Claude Bernard first wrote about this concept in 1865 in his classic text, An Zntroduction to the Study of Experimentd Medicine,15 and it still serves as a cornerstone of understanding cellular events. But what health care practitioners are not familiar with, in this second example, is the extent to which Bernard was forced to dismiss the relevance of purpose and design in positing the milieu inttrieur: Neither physiologists nor physicians need imagine it their task to seek the cause of life or the essence of disease. That would be entirely wasting one’s time in pursuing a phantom. The words life, death, health, disease have no objective reality.16 Sickness and death are merely a dislocation or disturbance of the mechanism which regulates the contact of vital stimulants

with organic units.*7 Of course, the interior milieu regulates this contact. But by making such an absolute division between inside and outside, Bernard ends up placing all responsibility and focus on this “mechanism” that connects ”in” with ”out” and turning his back on the purpose and essence of life/death and health/disease. Both examples caution health care practitioners against drawing absolute lines between inside and outside. So does the concept of function itself. When it is recognized

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that function requires purpos,ome goal or endpoint toward which activity is directed-it is also recognized that function requires potential, a goal or endpoint that is capable of being reached but has not yet been attained in actuality. Without potentiality, there is no function. In functional medicine, no question is more critical than the question of this potentiality and its "location." To what extent is potential "inside" people, inside their cells, thoughts, and genes? How are "outside" events related to this potential? In immunology, at least since the end of World War 11, a self/nonself model has developed that is forcing health care practitioners to relabel long lists of diseases as diseases of autoimmunity, diseases in which the distinction between self and nonself has become confused. But from a functional perspective, an absolute division between self and nonself is a too-literal separation of inside from out. Autoimmune diseases cannot be a set of inside, interior dynamics in which "self" mistakes "self" for "nonself" and self-destructs. If this were the case, health care practitioners would not discover all the risk factors for autoimmune disorder on the outside, removed from the self. Yet that is exactly where they are being found. The 17-aminoacid sequence in bovine serum albumin that travels from cow's milk formulas to pancreatic beta cell surface proteins (p69) and increases risk for the autoimmune disease called juvenile-onset diabetes,'8 the links between xenobiotic exposure and systemic lupus erythematosus,19and the newly designated "autoimmune polyendocrine syndromes" and their responsiveness to dietary modification are all examples that point to dangers outside the self and their key role in the development of autoimmune disease. But it is not only negative potential that gets locked outside the self when a line is drawn too absolutely between inside and out; it is positive potential as well. Function requires purpose. Purpose requires potential. "Plurifunctioning" organisms must also be "pluripotential" organisms. And because the unbroken whole is visible in the parts, this pluripotential must reside in the parts as well, even in that innermost part called the human genome, locked away inside the nucleus of the cell.

Genomics One of the greatest dangers health care practitioners face over the next 50 years in health care is letting the genetics revolution further seduce us into an absolutist view of inside/out. Announcement of the completed DNA reference sequence for Homo sapiens by the Human Genome Project (HGP) in April 2003 catapulted us into a new age of bioinformatics and called for the generation of an entirely new vocabulary including terms like "genomics," "phenomics" (metabolomics), and "proteomics." The basic goals of the HGP were mind-boggling: (1)to identdy the 20,000-25,000 genes in human DNA and (2) to determine the sequences of three billion base pairs in human

DNA. The speedy transfer and creative application of this knowledge in the private sector has been equally astonishing. Changes in law enforcement, industrial manufacture, environmental biotechnology, agribusiness, anthropology research, and clinical medicine exemplify the far-reaching impact of the HGP. The potential for development of a personalized functional medicine has been increased dramaticallyby these advances in genomics, phenomics, and proteomics. For the first time in medical history, general contracting of body structures can be evaluated against architectural blueprints, and the outermost manifestations of disease can be examined against the innermost predilections. Remarkable insights into body function have already begun to flourish as a result of this newfound perspective. But a great temptation in the wake of this bioinformatic paradigm shift is to treat inside and outside as even more separate than before, further apart and further removed from mutual influence. On one side of this inside/outside dichotomy, health care practitioners in this field might be tempted to think of themselves as "insiders" who have now for the first time in human history penetrated the deepest recesses of self and stand poised to unlock its greatest potential. From this perspective, the genome might mistakenly be viewed as hard-wired cirmitry that explains every aspect of self, including individual development of disease. On the opposite side of the dichotomy, it might be tempting to dismiss the relevance of the outside and establish the phenome as an immovable object toward which the genome inexorably heads. Both types of temptation would miss a fundamental, underlying truth of genomics and phenomics. The bioinformatic paradigm shift is making clear that not only is there no absolute division between inside and outside, but the two dimensions are absolutely inseparable. Gene regulatory networks (GRNs)involved with the up- and down-regulation of gene expression can involve multitiered cascades that take researchers far outside the cell nucleus or even immediate intracellular context. While immediate events that coregulate rate of gene transcription may OCCUT in nearby upstream DNA segments (promoter regions) in the nucleus of the cell, promoters are themselves polymorphic and subject to whole body and whole life impacts. When viewed phenomically the genome can only be described as pluripotent. When viewed genomically, the phenome can only be described as interactively and unpredictably expressed. To account in full for a single genetic event, researchers must step far outside the genome into a constantly changing environment and the organism's purposeful interaction with it. For example, in 2002, a team of researchers at the Hokkaido University School of Medicine in Sapporo, Japan, discovered a polymorphism in the RANTES (Regulated upon Activation Normal T-cell Expressed

and Secreted) chemo-attractant cytokine gene promoter that is associated with late-onset (Polymorphism in the RANTES promoter gene have been associated with other disease conditions in which cytokine signaling plays a key role, including stomach ulcer and HN infection). Exact causes of RANTES polymorphism have yet to be identified, and underlying mutations involving insertion-deletion length, simple sequence repeat length, or single nucleotides could be involved. Whatever the classification, however, the full implications of the RANTES research cannot be understood unless researchers are willing to leap far outside the genome. Asthma is a condition increasingly associated with poor environmental quality, and any environment can become a repository for genotoxic substances known to cause singlestrand deletions and base pair substitutions in human DNA. In the case of asthma exposure to diisocyanates, aldehydes, anhydrides, chlorofluorocarbons, chloramines, or persulfates could conceivably be associated with mutations underlying the RANTES polymorphism. The more attention paid to this inseparability of inside and out, the better the chances for a truly personalized functional medicine. Molecular medicine is teaching us there is no untouchable inside. Our outside experience, including our dietary intake, continually modifies the expression of our genes. Control of gene expression is highly encrypted; that is, genes have inducer binding sites and promoter sequences that modify their expression. Numerous nutritional components have been shown to m o w that expression, including linoleic and alphalinoleic acid, isoflavones, quercetin, ellagic acid, vitamin A, and vitamin B6?* The potentiality is ever present, even when IQ suggests otherwise. At their innermost, genetic selves, humans are always also outside of themselves, linked to wholes through their potential.

CauseKffect In the fourth century K, in a treatise titled Physicu, the

Greek philosopher Aristotle described a doctrine of four causes: formal cause (eidos), producing in a thing its constitutive essence; material cause (hyle), providing a thing with its ”matter” and embodiment; efficient cause (kinoun), initiating change in a thing; and final cause (telos), providing an ultimate purpose for the change. Since the word cause has several meanings, Aristotle wrote, ”It follows that there are several causes of the same thing (not merely in virtue of a concomitant attribute), for example, both the art of the sculptor and the bronze are causes of the statue.”= What appears treatable or preventable to practitioners depends entirely on their philosophy of medicine. Whether dysfunction is treatable or preventable depends on what caused the dysfunction in the first place (i.e., on one’s concept of causality). Keith Block, MD, medical

director of the Cancer Institute at Edgewater Medical Center in Chicago, recently argued that the labeling of any cancer as “terminal” is both scientifically and spiritually unju~tifiable.~~ His argument is based on a view of cancer causality that includes an active role for the self in deciphering and acting on the cosmic event that cancer represents. But the views of Aristotle and Block, welcoming a complex view of causality into our understanding of health, are far from our classic heritage in the sciences. As French Nobel Prize winner Jacques Monod wrote, in his classic 1970 work, Chance and Necessity: The cornerstone of the scientific method is . . . systematic denial that “true”knowledge can be got at by interpretingphenomena in terms of final causes-that is to say, of “ p ~ r p o ~ e . ” ~ ~ Against this notion, this powerful feeling of destiny, we must be constantly on guard.z Monod’s philosophy is the authors’ reigning medical philosophy-me steeped in the Darwinian legacy of a universe with minimal original essence, minimal momentary stability, and an indefinite horizon of It is a philosophy that tells health care practitioners they must be careful when reading purpose into dysfunction, and that they should accept whole categories of disability and death as purposeless, chance events that are essentially not preventable. Naturopathy, with its focus on prevention, has helped to transform this perspective. Most naturopaths would readily subscribe to the mission statement of the Foundation for Preventive Medicine, based in New York City, when it describes its mission as ”enhancing the public’s awareness of recent information indicating that most causes of death in our society. . . are now regarded as potentially preventable. Preventive, functional, and naturopathic medicine all seem to agree that lack of wellbeing, lack of vitality, depression, and deficiency in energy are also associated with largely preventable conditionstV and that each time we transfer a health condition from the category of ”not preventable” to “preventable,” we are honoring our medical philosophy.”

Energymatter Most scientists subscribe to an energy-based view of human function. They believe that healthy function rests on the shouldersof gated ion channels, electrolytebalance, membrane potential, redox, electrochemical gradients, and high-energy phosphate bonds. In these scientists’ view, the release of heat energy from cells is what makes biologic order actually possible in the first place.28Yet in spite of its acceptance at a biologic and biochemical level, this energy-based paradigm has yet to become fully integrated into medicine. While electrocardiographic, magnetic resonance, and single photon emission imaging have become standard parts of the diagnostic repertoire,

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electroacupuncture biofeedback devices, despite their research record and use in many ~ountries,2~ remain unapproved for clinical use in the United States. Once again, naturopathic medicine has provided leadership in this area. Energy-based medicine has been given open-minded consideration in naturopathy, and whole traditions based on energeticprinciples-including acupuncture and Oriental medicinehave been treated as essential areas for understanding and research. Similarly, acceptance of homeopathy-an energy-based medicine used by a quarter of a million practitioners worldwidem-has been nurtured in the United States by the supportive position adopted by naturopaths and naturopathic institutions. From a functional perspective, the rightful place of ”energy medicine” in health care approaches is woven into the term “function” itself, which derives from the Greek en-ergiu, literally, ”functioning” or ”being in activity.” But clearly, practitioners are just starting to explore this energy-matter relationship in their medical philosophy. In nutrition, for example, they are just beginning to shed the nineteenth-century steam engine model, which perceived the body as a large furnace combusting matter (food) for the sake of extracting caloric energy. In this model, energy is not useful unless extracted out of matter, and matter, once depleted of its energy, is of little use as well. This food-as-fuel model has left us with an underappreciation of food’s matter and its energy. As raw material for caloric extraction, food becomes most important for its gross, undifferentiated macronutrient content-its 20 g of fat or 100 g of carbohydrate. Subtler distinctions involving omega-3-tmmega-6 or oligosaccharide-to-polysaccharide ratios have been slow to evolve. Likewise, food energetics, including the issues of raw food, live food, food enzymes, and active cultures, have been negligibly addressed. Interestingly, practitioners are finding that the role of light, in the form of food pigments, including the heme, chlorophylls, carotenoids, and flavonoids, is slowly revolutionizing the approach to food in the same way that light (and the frame of reference it represented) revolutionized the approach to mass and energy in physics.

Body Systems from a Functional Medicine Perspective Historical and Philosophical Perspective Students of science and medicine in the United States and other Western countries learn anatomy and physiology from a systems approach. They learn to view organ systems, individual organs, tissues, cells, and subcellular spaces as separate entities that interact with one another to create form and function. The better one understands any one system or entity, by this model, the more skilled he or she will be at treating dysfunction of that entity. This model served well in developing a rational method

of inquiry into the etiology of many diseases. Indeed, the advancement of medical science has long been measured by progress made in understanding the mechanisms of disease related to dysfunction in the body’s distinct compartments. Fundamental to the systems model has been the assumption that the more that is known about individual organs or systems, the better the medicine will be. Until recently, this assumption had been widely validated throughout medical history by remarkable progress in diagnosis and treatment of disease, surgical practice, and the development of medications for symptom reduction related to specific diseases. The progress that resulted from this compartmentalizing approach can be compared to advances in biology that followed Linnaeus’s development of a system of taxonomic classification of living organisms in the eighteenth century. The formalized system of learning allowed for sigruficantadvancement in the field of biology. By the 1970s, however, many biologists had become aware of the limitations of description and classification as an epistemology. Their science had outgrown the model. Through advancements in the disciplines of ecology and environmental science, they knew they could class@ all the plants and animals in an ecosystem and yet understand nothing about the functioning of the ecosystem as an integrated whole. The need had arisen to address the larger issues of how compartments within the ecosystem interact to give rise to its function and survival. From the perspective of these advancements in biology, one could view medicine as a specialized discipline within the broader field of human ecology. To understand health and disease, one would be required to examine the functional interadion of organ systems with the human environment. Furthermore, one would have to observe the functional interaction between the total human environment and the energy processing and control systems within it. Examining any discipline from a new point of view makes it possible to ask new questions and gain new insights. Looking at human health and medicine from the point of view of interactive function raises questions about the homeodynamic interplay between the external and internal environments of the individual. The functional viewpoint is the longer, larger view; it moves away from the narrow focus on pathology of various parts of the body. It removes the principal focus from diagnosis of pathology and places it on evaluation of genetic pluripotential and its translation into homeodynamic function. It views disease not as an enemy with which to grapple but as a manifestation of the breakdown of mechanisms that establish control and resilience. To restore these processes, functional medicine uses a broader range of methods than the cut-and-paste tools

of compartmentalized medicine. Among others, it employs nutrition, environmental adaptation, lifestyle changes, activity or stress pattern adjustment, or molecular pharmacology, and its selection of tools is based on the unique needs of the individual. The traditional anatomy/physiology model of Western medicine still has great value in diagnosis and treatment, and it has wide application in responding to many specific disease states. This traditional model breaks down, however, when it is applied to chronic conditions that transcend individual organs or organ systems. Among these chronic health problems are inflammation, fatigue, pain, immune dysfunction, and digestive problems. All of these conditions are characterized, not by endstage pathologies, but by altered physiologic function, and they require a more integrative model to design a therapeutic approach that can improve long-term outcome. This more integrative model is built on the understanding that dysfunction is not compartment or organ specific but is an alteration in integrated homeodynamic processes. The functional medicine approach incorporates evaluation of antecedents to a health problem, its triggering factors, mediators of altered physiologic function, and the relationship to signs and symptoms to develop an integrated view of the patient’s health status. It focuses less on defining the disease and more on understanding the functions that give rise to the expression of symptoms. A woman m ay approach her physician complaining of chronic intestinal pain and symptoms of irritable bowel syndrome, for example. A medical history and initial evaluation might uncover other symptoms, including joint pain, headache, low energy, sleep disturbances, and eczema. Rather than come up with a primary and secondary diagnosis and prescribe symptom-relieving medications, a functional medicine practitioner would delve further in evaluating the source of the inflammation. The practitioner might assess gastrointestinal function, hepatic detoxification ability, and immunologic status and then assess their relationship to oxidative stress mediators. Based on this ”second tier” of assessments, he or she would develop an integrated approach to mod* triggers and mediators using specific biologic response modifiers and lifestyle alterations of the individual.

Systems Integration and Functional Medicine The emerging science of today has blurred distinctions among organs, and separation of function into distinct compartments is less useful as a concept. Now it is known, for example, that identical signaling molecules are released and received by all organ systems, and each influencesthe function of the others. The view of the body as a collection of separate, interconnected parts is being replaced by an image of the body as a hologram. The endocrine system synthesizes a neurotransmitter that is

released by the nervous system and has a receptor site on the white blood cell. A blood cell synthesizes cytokines that are released by the immune system and have receptor cites on the glial cell in the brain. The liver synthesizes steroid hormones that are released by the endocrine system and have immune and nervous system receptors, and vice versa. In other words, all the organs and organ systems of the body are constantly engaging in “cross communication” that makes distinctions among them a matter of definition rather than function. In the past 10 years medicine has witnessed a revolution in molecular biology. For example, modifiers of gene expression are known to be not only produced by different organs but also by exposure to various agents in the diet and environment, including chemicals and electromagnetic radiation. Practitioners have learned that the processes that give rise to an individual’s health or disease are not controlled by genes alone. Instead, modification of function comes about through alteration in gene expression, transmitting new physiologic messages about individual regulation and control. This new view of health focuses on maintaining metabolic and homeodynamic freedom based on interconnectedness, pluripotential, diversity, and redundancy of function. Loss or decline in any of these parameters can be seen as an altered state of health. Altered physiologic diversity, for example, translates to a loss of metabolic freedom and a subsequent state of lower health reserve. Assessing health, therefore, depends on measuring this reserve rather than evaluating pathology. Functional challenge tests, an integral part of the practice of functional medicine, make it possible to measure specific reserves under conditions of stress. Examples of functional tests include the exercise treadmill test for cardiac function, oral glucose tolerance testing for blood sugar management, and food provocation challenges for food sensitivity. Functional medicine practitioners use the patient as his or her own ”universe,” or point of reference in which his or her unique set of interconnections, potentials, diversities, and redundancies is realized. Whether changing conditions involving time, temperature, electromagnetic energy gradients, infective organisms, or trauma lower degrees of metabolic freedom is a question that can be answered only in the context of the individual and his or her ability to maintain reserve and avoid reduced stability that comes from lost potential. Functional medicine focuses on maintenance of stability and pluripotential across organ domains. From this perspective, all organ-specific symptoms the patient possesses at any one moment reflect homeodynamic alterations at a broad, ”weblike” level and result in new meta-stable physiologic states characterized by lowered stability and reduced degrees of metabolic freedom and efficiency.The more freedom lost at this weblike level, the

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more symptoms become manifest, and the more closely they resemble classical pathology. It is the integrative, homeodynamic, regulatory role of the web that is being altered, however, not a circumscribed set of functions within a specific organ domain. As a diagnostician,a practitioner might look through a focused lens like a radiograph, blood chemistry, or computed tomography scan at an isolated, compartmentalized organ system. As a functional medicine practitioner, however, he or she views alteration in this seemingly distinct compartment as a reflection of change in the web, the whole of which is the individual and his or her unique life experience in the world.

model, is the state of positive vitality unique to each individual within his or her life context. Functional medicine employs new assessment tools to help quantify individual well-being and evaluate his or her physiologic, cognitive/emotional, and physical function. Functional medicine practitioners cannot narrowly focus on a patient’s symptoms, complaints, or history of illness. They must also evaluate the patient’s history of wellness by asking when in life the individual has felt best and what circumstances would be necessary to make that patient feel truly well again. Although relief of symptoms might be one goal of the application of functional medicine, the broader goal would be to support vitality in the patient’s life experience.

Life Processes as Homeodynamic

BASIC CONCEPTS IN FUNCTIONAL PRACTlCE The practice of functional medicine is guided by the three basic concepts of biochemical individuality, health as positive vitality, and life processes as homeodynamic.

Biochemical Individuality Each individual is unique. This uniqueness encompasses voluntary activities, such as decision making, personality development, and emotional response, and involuntary activities like metabolism of nutrients, cellular processing of information, and communications among the body’s organ systems. The concept of biochemical individuality is central to every aspect of the practice of functional medicine, from clinical assessment and diagnosis to the broad spectrum of treatment modalities. As traditionally practiced, medicine and nutrition have given only token consideration to the concept of individuality. In conditions such as phenylketonuria (PKU) or maple sugar urine disease (MSUD), for example, although medicine has long recognized that specific metabolic aberrations alter the afflicted individual’s nutrition and health needs, it has taken the view that these defects are so rare as to be inconsequential. A functional medicine practitioner, on the other hand, considers that all individuals have unique metabolic patterns that affect their nutrition and health needs. In comparing two individuals whose blood levels of B vitamins are nearly identical, for example, one might have five times as high a level of B vitamins in his or her cells as the other. Individuals also respond uniquely to environmental toxins, food additives, and prescription medications.

Health as a Positive Vitality Functional medicine views health as more than the absence of disease. Health, in the functional medicine

Homeodynamics as a principle of functional medicine contrasts to the concept of “homeostasis” in conventional medicine. Homeostasis describes the balance of interconnected components that keep a physical or chemical parameter of the body relatively constant. Homeodynamics posits a similar control system functioning to maintain biochemical individuality. Applied to the body, the term horneodynamic describes a range of continuously occurring metabolic and physiologic activities that enable an individual to adapt to changing circumstances, stresses, and experiences. The homeodynamics of one’s health are constantly at work to enable him or her to function as a unique individual. Supporting health at a homeodynamic level may require one to focus attention on cellular processes or organ function at sites that seem to be far removed from the patient’s area of discomfort and at levels that may be unusual from a conventional point of view.

ASSESSMENT AND TREATMENT FROM A FUNCTIONAL PERSPECTIVE Healing practices in any society evolve within a cultural context and draw on the belief systems and resources of the healers within that culture. In traditional societies, the background and support of healing derived from the natural world. In industrialized societies, evolving in a framework erected by Newton and Descartes, medicine formed a different understanding of the body and its function. The term diagnosis derives from the Greek word dia-gnosis, which means, literally, “through gnosis, through the knowledge gained through a perspective.” In conventional Western medicine, diagnosis is defined as ”the art of distinguishing one disease from another” or ”the determination of the nature of a case of a disease.’’ Clinical diagnosis is ”diagnosis based on symptoms, irrespective of the morbid changes producing them.” Differential diagnosis is “determining which of two or

Philosophy of Natural Medicine more diseases or conditions a patient suffers from, by systematically comparing and contrasting their symptoms.” Key concepts in these definitions are ”disease,” “symptoms,” and “suffers from,” and analysis of these concepts yields clues to the philosophic perspective underlying the Western medical approach to managing health. This underlying perspective is the key factor that differentiatesone healing system from another. It is the basis by which the authors examine patients and develop a plan of action or treatment. A physician whose perspective is oriented toward pharmacology views patients in terms of what drugs are needed. A nutritionist might look for specific nutrients or dietary changes that would benefit patients. A psychotherapist might ask which form of counseling or behavioral intervention is warranted. In each case, the course of action is dictated by the practitioner’s underlying perspective. The underlying perspective of functional medicine is based on process, dynamics, and purpose. Functional medicine focuses on dynamic processes that underlie and precede the pathologic state. Acknowledging the existence and necessity to understand pathology, functional medicine focuses on underlying processes and seeks solutions that address these processes. The practice of functional medicine does not focus on diagnosis that compartmentalizes diseases into known entities. Such a system, although it might be useful, is apt to presume that if a disorder can be named, it can be understood how it came about. Functional medicine practitioners recognize diagnosis categories, but they also investigate underlying dietary, nutritional, lifestyle, environmental, and psychosocial factors that might alter the patient’s state of health and investigatethe “purpose” behind the expression of illness.

Illness as Information From the traditional medical viewpoint, illness ”happens” to a human being; an outside force upsets a system of the body. The clinician, then, seeks to discover precisely what it was that caused the illness. Although this method is a useful view in diagnosis (since many factors including food, chemicals, and microorganisms affect our homeodynamics), it places constraints on both patient and clinician. On the other hand, if the human body is viewed as an energy-driven, energy-sensitive system that interacts constantly with its surroundings, illness can be viewed as a form of communication from one level to a level of conscious awareness. Conscious awareness enables the individual to begin to understand the factors that collectively led to the illness. Because it has a purpose, illness can be seen as a functional condition. It may function as an agent for change. It may itself be an epiphenomenon that requires treatment, but paying heed to the “message” that is

being communicated by the illness may be what finally enables healing to occur. Both scientific and popular literature often describe cases of recovery from serious illness that occurred as a result of the individual’s paying attention to the message contained in the symptoms. In clinical practice, illness communicates its messages in many ways, including symptoms arising from exposure to chemicals,rashes or breathing difficultiesfrom consming food allergens, neck pain from repetitive workplace activity, and stress-induced chest pains. Patients who present with these complaints are all getting messages about their bodies’ interactions with their surroundings. In neurology, occurrences of hysterical blindness or hemiplegia are examples of illness as information. In both conditions, physical symptoms arising from deep psychologic problems mimic severe organic disease.3l In making a diagnosis, the functional medicine practitioner must be aware of the message being sent and approach the patient’s illness not as an adversary to be overcome but as information that must be understood and acted on.

Treatment Decisions The experienced practitioner of functional medicine knows that illness typically arises from multiple influences, and his or her assessment and treatment takes this array of influences into account. In dealing with a problem like migraine headaches, for example, this approach contrasts with the traditional Western medicine approach. The latter would identify the symptom pattern, rule out vascular and intracranial pathology, and test for the presence of hypertension or renal disease. Treatment would be with drugs like sumatriptan, propranolol, or ergotamine. Biofeedback might be employed as an adjunctive therapy. The functional medicine practitioner, in contrast, would ask the migraine sufferer about dietary, nutritional, genetic, environmental, lifestyle, psychosocial, or spiritual factors that might be interacting in his or her life. The practitioner would inquire into functional changes that might underlie the expression of migraine symptoms. The goal would be to develop a range of potential patient-centered solutions to migraine headache.Remediation of migraine, for example, has been reported with oral magnesium therapy (M.A. Schmidt, unpublished data);essential fatty acid supplementation (S. Baker, personal communication, 1996); removal of food, chemical, and inhalant triggers32;sublingual neutralization therapy; spinal manipulation (P. Bolin, personal communication, 1996); acupuncture; homeopathy; and the botanical feverfew (Tanaceturn partheniurn).M The functional medicine practitioner might employ any one or a combination of these therapies, realizing that no single approach is effective with all migraine sufferers. Rea found the headache

Functional Medicine in Natural Medicine symptoms of 100% of a group of 30 migraine sufferers were triggered by chemicals under controlled challenge, but these were patients who reported chemical sensitivity.35A patient-centered approach that recognizes statistical tendencies and diagnostic categories, but is not constrained by them, is desirable. Another example of the value of the functional medicine approach is in assessing microbe-associated illness. The traditional approach to infectious disease regards the organism as an external threat that must be eradicated by intervention specifically targeting that organism. The microbe is the enemy, and drug therapy is the typical weapon. A broader, functional medicine approach would view the microbe as just one (albeit important) of the factors contributing to poor health. The functional medicine practitioner would consider the state of the host’s defenses and evaluate factors that influence host defenses by examining nutritional, metabolic, environmental, lifestyle, and psychosocial factors that influence immune vigdance. The philosophic basis of functional medicine leads to treatment decisions quite different from those typically encountered in an infectious disease model. For example, a patient with Down syndromewho suffers from recurrent infection with Streptococcus pneurnoniue or Hmophilus influenme may experience an increase in IgG2 and IgG4 production and a reduction in infection susceptibility with selenium supplementation.36A child with otitis media with effu-sion might be treated not with antimicrobials, but with elimination of allergenic f0ods.3~An endurance runner who suffers from upper respiratory tract infection associated with heavy training might be given antioxidant^.^^

Concept of Total Load Total load refers to the sum of influences affecting an individual’s life. Initially advanced by environmental medicine practitioners, the concept is now widely adopted. Included in the total load are chemicals, food, microbes, psychologic stressors, and other factors, each of which alone might not give rise to the symptoms of illness. Together, however, the factors that comprise the total load may overwhelm the patient’s metabolic management system. According to Rea, more than 20,000 patients at his Environmental Health Center in Dallas experienced relief of symptoms of a range of clinical disorders through reduction of total l0ad.3~ A person’s biochemical individuality affects his or her susceptibility to toxins, and intervention aimed at improving function can help reduce susceptibility or sensitivity. A defective sulfur metabolism pathway, for example, might cause an individual who reacts to sulfurrich foods to react to other substances in ways that lead to metabolic disturbance. Nutrient modulation might lessen his or her sensitivity to these environmental

substances. Efforts to reduce total load should be balanced by efforts to restore function, with the long-range goal being reduced susceptibility.

Depth of Action The functional perspective requires the practitioner to examine the processes that give rise to symptoms. Arriving at a diagnosis does not guarantee that practitioners understand what is happening or what the patient needs. For example, a practitioner might amve at a diagnosis of “mood disorder” in a depressed patient and assume he or she would benefit from a drug like fluoxetine. If the depression arose from a spiritual or relationship crisis, however, the drug therapy might actually interfere with the problem-solving processes that would lead to true healing. Mood and quality of life might appear to improve with drugs, but the patient’s long-term healing would not have been facilitated. A group of epileptic children who were videotaped as they interacted with their families illustrates the point. Emotionally fraught family encounters were, in many cases, followed by seizures. When the epileptic patients were later shown films of these episodes, and they saw the relationship between emotional events and seizures, they were able, in many instances, to become almost seizure free.40Granted, drug therapy might have helped these patients control seizures, but if drugs were the only means of intervention employed, the epileptic children would not have had the opportunity to experience healing at a deeper level.

Mechanism and Outcome Understanding biochemical mechanisms enables functional medicine practitioners to apply them in diagnosis and treatment. Understanding the mechanism of homocysteine accumulation, for example, allows them to recommend nutritional strategies like folic acid and vitamin BI2therapy. By understanding fatty acid synthesis and the arachidonic acid cascade, they can develop nutritional therapies that mod+ inflammation. Knowing that copper accumulation leads to Wilson’s disease allows them to use zinc therapy. Some treatment modalities bring positive outcomes for which the mechanism is not yet well understood. Spinal manipulation in asthmatics admitted to the emergency department, for example, can lessen anxiety and ease breathing. This treatment typically brings about a 25% to 70%improvement in measurement of peak blood fl0w.4~Using premanipulation and postmanipulation tympanographs, Fallon showed that spinal manipulation in children with otitis media led to normalization of abnormal tympanograms (J. Fallon, personal communication of prepublication findings, 1995). Similarly, in personal communication (1996), V. Fryman has shown

Philosophy of Natural Medicine

that cranial manipulation normalizes tympanographic measurements in some children. Knowledge that viscerosomatic and somatovisceral reflexes influence the flow of information within the human body suggests the possible mechanism by which manipulation affects visceral function, although the mechanism is not yet clearly understood. Improved function, patient outcome, and quality of life are central to the success of any healing system, however, whether or not we understand the mechanisms of action. Homeopathic medicine is a discipline that is not bound by mechanism but is rooted in careful analysis and pattern recognition. Reilly demonstrated that asthmatic patients who took homeopathic preparations showed signhcant improvement in only 1 week compared with those taking placebo. These dramatic results led him to conclude that either homeopathic medicine worked beyond a shadow of a doubt, or the double-blind, placebocontrolled trial, the gold standard of proof on which modem pharmacology is built, is essentially invalid.42 Throughout the range of healing arts and sciences, numerous examples of positive treatment outcomes occur,even though the mechanism cannot be explained. In functional medicine, the value of understanding mechanisms is in improving human function and patient outcome.

Prevention, Early Detection, and Functional Medicine ”Prevention” has become a welcome and popular concept in recent years in the practice of medicine. A distinction must be made, however, between true prevention and “early detection.” Although periodic mammography has been heralded as a form of preventive medicine, for example, it is clearly in the realm of early detection. Prevention assumes an understanding of factors that give rise to breast cancer and recommendatiodadoption of habits or patterns that prevent disease occurrence. Both prevention and early detection are included in the practice of functional medicine, but the patient’s individuality remains paramount. Functional medicine practitioners work to prevent a specific disorder by managing risk factors, but they also strive to raise the individual’s functional capacity within his or her unique life circumstances.

Approach to the Patient Functional medicine is always patient centered, but it is not the only discipline that fits this description. Naturopathic medicine has helped pioneer a patientcentered medical approach, not only by making the whole person the center of its practice, but also by incorporating highly patient-centered traditions into its repertoire, including traditional Chinese medicine, Ayurvedic

medicine, homeopathy, chiropractic, and physical therapy, including manipulation and massage. The focus on the patient is important, however, because as methods of data management become more sophisticated, the tendency is to think in terms of probability instead of thinking in terms of the individual patient. Probability is useful in understanding the broad context of health and disease, but clinical practice is filled with so many exceptions that relying on statistics is difficult.

Laboratory and Instrumental Diagnosis from a Functional Perspective In assessing a patient’s health, the functional medicine practitioner uses tools that help him or her understand how the patient functioned before he or she developed the pathology. These tools also help the practitioner understand function in the existence of pathology and assist in predicting preventive measures. Serum glucose measurement is a traditional assessment of a fixed analyte at a fixed point in time. Although this measurement yields useful information, it does not reveal how serum glucose responds under varying dietary conditions. The glucose challenge test, on the other hand, is a functional test that assesses glucose status over time. Similarly,although a resting electrocardiogram (ECG) provides useful information, it does not indicate how the heart would respond to a physical challenge. The stress ECG shows how the heart responds to exertion. Assessment of magnesium is a third example. Magnesium is an intracellular element, which means that most of the body’s magnesium stores are contained within cells, and only a small amount circulates in blood. A measurement of serum magnesium levels, therefore, does not reflect total body magnesium or the functional status of magnesium. Red cell magnesium is a better indicator of status, although it is a measurement of a fixed analyte at a fixed point in time and has limitations as well. Magnesium loading and subsequently assessing retention by measuring urinary excretion provides a means to assess the functional magnesium status and the unique needs of a particular patient. For functional medicine practitioners, tools that view the body under challenge conditions give a more accurate assessment of body function. This is especially true when one wishes to examine the body’s response to exogenous substances. Some individuals experience an adverse reaction to any given drug, and these reactions are regarded as atypical and unavoidable. From a different perspective, however, the reactions are not atypical and unavoidable; they are typical and avoidable for that person, and he or she would typically be expected to have an adverse reaction on ingestion of this drug. This understanding comes from developments in understanding the body’s detoxification mechanisms. When a drug or medication is ingested, it is metabolized

Functional Medicine in Natural Medicine

by the body and prepared for excretion. The process of detoxification and preparation for excretion takes place in two distinct biochemical phases, known as phases 1 and 2. In the biotransformation of a drug or chemical, the agent is progressively converted to a more watersoluble, excretable substance. In phase 1,which generally occurs first, a family of isozymes known as cytochrome P450 (cP450) converts the drug or substance into a reactive intermediate, which, although it may be excreted in its present form, is typically further acted on by phase 2 processes. In phase 2, conjugating substances are attached to the phase 1product to facilitate its excretion.Phase 2 reactions typically take place through glucuronidation, amino acid conjugation, glutathione conjugation, acetylation, and methylation.” The phase 2 process, which depends strongly on adequacy of specific nutrients, must be capable of transforming all of the phase 1-generated reactive molecules into excretable compounds. If this process is incomplete, toxic intermediates can build up. Acetaminophen is a typical drug that undergoes conversion for excretion through these two pathways. A common over-the-counter and prescription pain-relieving drug, acetaminophen is a useful model because more than 70,000 incidents of acetaminophen overdose were reported to U.S. poison control centers in 1994.44 Acetaminophen normally undergoes phase 2 transformation through the sulfation and glucuronidation pathways, with a small amount being metabolized through glutathione conjugation after conversion in phase 1.45 When the drug is not efficiently converted for excretion, the metabolites that build up can have negative metabolic consequences. Accumulations of one extremely toxic metabolite, NAPQI, may cause liver and nervous system damage. An individual with an adequately functioning detoxification ability that facilitates efficient phase 2 conversion of acetaminophen is less likely to have a negative experience than one whose ineffective conversion pathways allow toxic intermediates to accumulate. If an individual ingests acetaminophen on a regular basis, the sulfur-bearing nutrients glutathione, methionine, and cysteine can be depleted rapidly, with accompanying liver cell damage.& Therefore adverse acetaminophen reactions may result from alterations in detoxification pathways. The acetaminophen challenge test effectively assesses function of these pathways. After the individual has consumed a challenge substance, measurements of acetaminophen metabolites in urine

can determine the efficiency of the various conversion processes and provide information about the individual’s unique susceptibility. It may be that alterations in the detoxification pathways of many individuals who have ”atypical” drug reactions are making them predictably susceptible to certain kinds of substances. If practitioners can gather this information about them, they may be able to predict their response to drugs, as well as chemicals, foods, and plants. Practitioners may be able to understand the functional derangement that underlies the pathology that can result from interaction with the environment. And they may be able to use diet and nutrition to help individuals restore function in these pathways.

Pattern Recognition The next step in the evolution of functional assessment is to consider human physiology as a dynamic process involving the interrelationship of multiple systems. Functional assessment of only one pathway or one series of pathways may yield useful information, but it still provides a limited view. Functional testing will no doubt evolve to assess multiple analytes and use sophisticated pattern recognition methods. Pattern recognition is not new. For centuries, traditional Chinese medicine has dealt with ”patterns of disharmony.” The clinician trained in this discipline learns to recognize the pattern and assign it to a specific diagnostic category. In homeopathic medicine, it was pattern recognition that led to the extensive muferiu medicu. In psychotherapy, an evaluation of the patient’s life events and stories is conducted in an effort to understand the patterns that produce disharmony. In all these examples, the mechanisms are unimportant; the pattern leads to treatment decisions.

SUMMARY Pattern recognition, depth of action, total load, energetics, information, and patient-centered decisions all describe the early stages of development of the evolving functional approach to assessment and treatment. They also characterize a functional approach with a strong focus on the integrative use of treatment modalities based on recognition of underlying purpose in the transformations practitioners view as they work with individual patients. This is also the integrative paradigm that unites naturopathy with functional medicine.

1. Urdang L, Flexner SB. Random House dictionary of the English language. New York Random House, 1968:535. 2.Peters FE. Greek philosophical terms. New York New York University Press, 196761-62. 3.Peters FE. Greek philosophical terms. New York: New York University Press,1967152-155. 4. Young R. Mind, brain and adaptation in the nineteenth century. Oxford, UK:Clarendon Press,19709-53. 5. Young R. Mind, brain and adaptation in the nineteenth century. Oxford, UK:Clarendon Press,197043. 6. Allison N, ed. Illustrated encyclopedia of body-mind disciplines. New Yorum, NY Rosen Publishing Group, 1998. 7. Anderson R. Wehess medicine. Lynnwood, WA: American Health Press, 19876. 8. American Holistic Medical Association. Raleigh, NC: Available online at http:/7www.doubleclickd/com/about-ahma.htm1. 9. Fuller RB. Synergetics: explorations in the geometry of thinking. New York Macmillan Publishing, 1975:58. 10. Weiner LH, Mayer LF, eds. Oral tolerance: mechanisms and applications. Ann N Y Acad Sci 1996;778:xiii-xvii:6-7. 11. Raloff J. Eyes possess their own biological clocks. Sci News 1996;149245. 12. Tamarkin L, Bond CJ, Baird J, et al. Melatonin: a coordinating signal for mammalian reproduction? Science 1985;227714-720. 13. Portrnann A. Animal forms and patterns: a study of the appearance of animals. New York schocken Books, 1967;17:34. 14. Portmann A. Animal forms and patterns: a study of the appearance of animals. New York Schocken Books, 1967;17196. 15. Bernard C. An introduction to the study of experimental medicine (1865).Gmne HC, transl. New York Dover Publications, 1957. 16. Bemard C. An introduction to the study of experimental medicine (1865).Greene HC, transl.New York Dover Publications, 195767. 17. Bemard C. An introduction to the study of experimental medicine (1865).Greene HC, transl. New York Dover Publications, 195776. 18. Karjalainen J, Martin JM, Knip M, et al. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 1992;327(5):302-307. 19. National Academy of Sciences. Biologic markers in immunotoxicology. Washington, DC:National Academy Press, 199255. 20. Nobuyuki H, E t s w Y, Satoshi K, et al. A functionalpolymorphism in the RANTES gene promoter is associated with the development of late-onset asthma. Am J Respir Crit Care Med 2002; 166:686-690. 21. Berdanier CD, Hargrove JL. Nutrition and gene expression. Boca Raton, n:CRC Press, 1993. 22. McKeon R. Introduction to Aristotle. New York: Modem Library, 1947123. 23. Block KI. The role of self in healthy cancer survivorship: a view from the frontlines of treating cancer. Adv Mind Body J 1997. 24. Monod J. Chance and necessity. New York Vintage, 1971:21. 25. Monod J. Chance and necessity. New York Vintage, 1971:145.

26. Jonas H. The phenomenon of life: toward a philosophical biology. New York: Delta, 1971:46-47. 27. Foundation for Preventive Medicine. New York Available online at

http://wuw. prpuentiwemed.org. 28. Alberts B, Bray D, Lewis J, et al. Molecular biology of the cell. New York: Garland Publishing, 198362. 29.Zong-xiang Z. Recent advances in the electrical specificity of meridians and acupuncture points. Am J Acupunct 1981;9(3):203-215. 30.Cook TM. Homeopathic medicine today. New Canaan, CT: Keats Publishing, 1989~21-30. 31. DeMeyer WE. Technique of the neurological examination, ed 4. New York McGraw-Hill, 1994512-513. 32. Rea WJ. Chemical sensitivity, vol 4. Boca Raton, FL: CRC Press, 19961177-1178. 33. Hoover S. Meniere’s migraine and allergy. In Claussen CF, Kirtan MV, W i t t e r K, eds. Vertigo, nausea, tinnitus, and hypoacusia in metabolic disorders. New York: Elsevier Science Publishers, Biomedical Dvision, 1988:293-300. 34. Awang DVC. Feverfew. Can Pharm J 1989;122:266-270. 35. Rea WJ. Chemical sensitivity, vol 4. Boca Raton, FL: CRC Press, 1996:1177. 36. Anneren G, Magnusson CGM, Nordvall SL. Increase in serum concentrationsof IgG2 and IgG4 have been observed with selenium supplementation in children with Down syndrome. Arch Dis Child 1990;65:1353-1355. 37. Nsouli TM. Role of food allergy in serous otitis media. Ann Allergy 1994;73(3):215-219. 38. Peters EM. Vitamin C supplementation reduces the incidence of post-race symptoms of upper respiratory tract infection. Am J Clin Nutr 1993;57. 39. Rea WJ. Chemical sensitivity, vol 4. Boca Raton, n:CRC Press, 1996 preface. 40. Brown B. Supermind: the ultimate energy. New York Harper & Row, 1980:275. 41. Paul FA, Buser BR. Manipulative treatment applications for the emergency department patient. J Am Osteopath Assoc 1996;96(7):

403-409. 42. Reilly DT. Is evidence for homeopathy reproducible? Lancet 1994;344:1601-06. 43. Murray R, Granner D, Mayes P, Rodwell V. Harper’s biochemistry. Norwalk, CT: Appleton & Lange, 1990. 44.Anil D, Sorrell MD. Acetaminophen overdose: need to consider intravenous preparation of N-acetylcysteine in the United States. Am J Gastroenterol1996;91(7):1476. 45. Pate1M, Tang B, Kalow W. Variability of acetaminophen metabolism in Caucasians and Orientals. Pharmacogenetics 1992;238-45. 46.Willson RA, Hall T. The concentration and temporal relationships of acetaminophen-inducedchanges in intracellular and extracellular total glutathione freshly isolated hepatocytes from untreated and 3-methylcholanthrene pretreated Sprague-Dawley and Fischer rats. Pharmacol Toxic01 1991;69:205-212.

A Hierarchy of Healing: The Therapeutic Order The Unifying Theory of Naturopathic Medicine Jared Zeff, ND, LAC

Pamela Snider, ND Stephen P.Myers, ND, BMed, PhD CHAPTER CONTENTS A Brief History of Naturopathic Medicine 27

Original Philosophy and Theory 28 Modern Naturopathic Clinical Theory: The Process of Development 29

A Theory of Naturopathic Medicine 31

2. Stimulate the Self-Healing Mechanisms 36

3. Support Weakened or Damaged Systems ororgans 36 4. Address Structural Integrity 37 5. Address Pathology: Use Specific Natural Substances, Modalities, or Interventions 37 6. Address Pathology: Use Specific Pharmacologic or Synthetic Substances 38 7. Suppress Pathology 38

Illness as Process 32 Theory in Naturopathic Medicine 38 The Determinants of Health 34 Therapeutic Order 34 1. Establish the Conditions for Health 34

A BRIEF HISTORY OF NATUROPATHIC MEDICINE Benedict Lust "invented" naturopathy in 1902. Naturopathic medicine has deep roots, some of its therapies emerging from the mists of prehistory, but the modern naturopathic profession originated with Lust, and it grew under his tireless efforts. He crisscrossed the United States lecturing and lobbying for legislation to license naturopathy, testifying for naturopaths indicted for practicing medicine without a license and traveling to many events and conferences to help build the profession. He also wrote extensively to foster and popularize the profession, and through his efforts the naturopathic profession grew By the 1940s naturopathic medicine had developed a number of 4year medical schools and had achieved licensure in about one third of the United States, the District of Columbia, four Canadian provinces, and a number of other countries?** By 1957, however, there was only one naturopathic college left. By 1965 only eight states still licensed naturopathic physicians, and by 1979 there were only six. A survey conducted in 1980 demonstrated only about 175 naturopathic practitioners still licensed and practicing in the

United States and Canada.5 In 1951 the number was approximately 3000.6 The decline of naturopathic medicine after a rapid rise was due to several factors. By the 1930s a significant tension was developing within the profession regarding naturopathic practice; the development of unified standards; and the role of experimental, reductionist science as an element of professional d e v e l ~ p m e n t . This ~,~ tension split the profession of naturopathic physicians from within after the death of Lust in the late 1940s, at a time when the profession was subject to both s i m c a n t external forces and internal leadership challenges. Many naturopathic doctors questioned the capacity for the reductionist scientific paradigm to research naturopathic medicine objectively in its full scope. This perception created mistrust of science and of research. Science was also frequently used as a bludgeon against naturopathic medicine, and the biases inherent in what had become the dominant paradigm of scientific reductionism made a culture of scientific progress in the profession challenging. The discovery of effective antibiotics elevated the standard medical profession to dominant and unquestioned stature by a culture that had turned to mechanistic 27

science as an ultimate authority. The dawning of the atomic age reinforced a fundamental place for science in a society increasingly dominated by scientific discovery. In this culture, standard medicine, with its growing political and economic strength, was able to force the near elimination of naturopathic medicine through the repeal or sunsetting of licensure acts.’Jr9 In 1956, as the last doctor of naturopathy (ND)program ended (at the Western States College of Chiropractic), several doctors in the Northwest created the National College of Naturopathic Medicine in Portland, OR, to keep the profession alive. But that school was nearly invisible, the last vestige of a dying profession, and attracted rarely as many as 10 new students a year. The profession was considered dead by its historic adversaries. The culture of America, dominated by standard medicine since the 1940s, began to change by the late 1960s. The promise of science and antibiotics was beginning to seem less perfect. Chronic disease was increasing in prevalence as acute infection was less predominant, and standard medicine had no ”penicillin” for chronic diseases. In the late 1970s, family medicine proposing a biopsychosocial model of care emerged within conventional medicine in response to the perception then of a growing crisis in standard medicine. The publication of Engel’s “The Need for a New Medical Model”loin April 1977 signaled this trend. Elements of the culture were rebelling against plastics and cheap synthetics, seeking more natural solutions. The publication of Rachael Carson’s Silent Spring, an indictment of chemical pesticides and environmental damage, marked a turning point in cultural thinking. In Silent Spring (1962) Carson challenged the practices of agricultural scientists and the government and called for a change in the way humankind viewed the natural world.” New evidence of the dangers of radiation, synthetic pesticides, and herbicides, as well as environmental degradation from industrial pollution, were creating a new ethic. Organic farming, natural fibers, and other similar possibilities were starting to capture attention. A few began seeking natural alternatives in medicine. By the late 1960s and early 1970s, enrollments at National College of Naturopathic Medicine began to reach into the 20s. In 1975 National College enrolled a class of 63 students. The 1974 class had numbered 23.12 The profession was experiencing a resurgence. In 1978, with increasing enrollment interest at National College, Joseph E. Pizzorno, ND, LM, and his colleagues (Les Griffith, ND, LM; Bill Mitchell, ND; and Sheila Quinn) created the John Bastyr College of Naturopathic Medicine in Seattle,WA. With the creation of Bastyr, named after the eminent naturopathic physician Dr.JohnBartholomew Bastyr (1912-1995),the profession entered a new phase. Not only did this new college

double the profession’s capacity to produce new doctors, it also firmly placed the profession upon the ground of scientific research and validation. ”Science-based natural medicine” was a major driving force behind the creation and mission of Bastyr. Both Drs. Bastyr and Pizzorno had significant influence and leadership in achieving this focus. One of Bastyr’s important legacies was to establish a foundation and a model for reconciling the perceived conflict between science and the deeply established healing practices of naturopathic medicine. Kirchfeld and Boyle described his landmark contribution as follows: Although naturopathic colleges in the early 1900s did include basic sciences training, it was not until Dr.John Bastyr (1912-1995) and his firm,efficient and professional leadership that science and research-based training in natural medicine was inspired to reach its fullest potential. Dr. Bastyr, whose vision was one of “naturopathy’s empirical successes documented and proven by scientific methods,” was himself “the prototype of the modem naturopathic doctor, who culls the latest findings from the scientific literature, applies them in ways consistent with naturopathic principles and verifies the resultswith appropriatestudies.“Bastyr also saw a tremendous expansion in both allopathic and naturopathic medical knowledge, and he played a major role in making sure the best of both were integrated into naturopathic medical ed~cation.3,’~ Bastyr met Lust on two occasions and was closely tied to the nature cure tradition of Kneipp through his mother and Dr. Elizabeth Peters. He effortlessly reconciled the empirical tradition of naturopathy with the latest scientific studies, and helped create a new and truly original form of clinical care naturopathic medicine. He spent the twentieth century preparing the nature cure of the nineteenth century for entry into the twenty-first century.’J3 “Today’s debates concerning the philosophical range in the profession are no longer about science. They tend to center on challenges to “green allopathy’’ vs the importance of implementing the full range of healing practices derived from nature cure, along with natural substances. Professional consensus appears strong that the fullrange of naturopathic healing practices must be retained, strengthened and engaged in the process of education and scientific research and discovery in the twenty-first century.14-16

ORIGINAL PHILOSOPHY AND THEORY Through the initial 50-year period of professional growth and development (1896-1945), naturopathic medicine had no clear and concise statement of identity. The profession was whatever Lust said it was. He defined “naturopathy” or ”nature cure“ as both a way of life and a concept of healing that used various

A Hierarchy of Healing: The Therapeutic Order natural means of treating human infirmities and disease states. The “natural means” were integrated into naturopathic medicine by Lust and others based on the emerging naturopathic theory of healing and disease etiology. The earliest therapies associated with the term involved a combination of American hygienics and AustroGermanic nature cure and hydrotherapy. Leaders in this field included Lindlahr, Trall, Kellogg, Holbrook, Tilden, Graham, Kuhne, McFadden, Rikli, and others who wrote foundationalnaturopathic medicine treatises or developed naturopathic clinical theory, philosophy, and texts, enhancing, agreeing with, and diverging from Lust’s original Naturopathic medicine was defined most formally by the various licensure statutes, but these definitions were legal and scope-of-practice definitions, often in conflict with each other, reflecting different standards of practice in different jurisdictions. In 1965 the U.S. Department of Labor’s Dictionary of Occupational Titlesz6 presented the most formal and widespread definition, perhaps, but it reflected one of the internally competing views of the profession, primarily the nature cure perspective: Diagnoses, treats and cares for patients using a system of practice that bases treatment of physiological function and abnormal conditions on natural laws governing the human body. Utilizes physiological, psychological and mechanical. methods such as air, water, light, heat, earth, phytotherapy, food and herbs therapy, psychotherapy, electrotherapy,physiotherapy, minor and orificial therapy, mechanotherapy,naturopathic corrections and manipulations, and natural methods or modalities together with natural medicines, natural processed food and herbs and natural remedies. Excludes major surgery, therapeutic use of x-ray and radium, and the use of drugs, except those assimilable substances containing elements or compounds which are components of body tissues and physiologically compatible to body processes for the maintenance of life.26

This definition did not list drugs or surgery within the scope of modalities available to the profession. It defined the profession by therapeutic modality and was more limited than most of the statutes under which naturopathic physicians practiced, even in 1975 when there were only eight licensing authorities still a~tive.2~ The bulk of professional theory was found in Lust’s magazines: Herald of Health and The Naturopath. These publications displayed the prodigious writings of Lust but did not contain a comprehensive and definitive statement of either philosophy or clinical theory. Lust often stated that all natural therapies fell under the purview of naturopathy. Several other texts were also used as somewhat definitive by various aspects of the

profession at different times. These texts included Henry Lindlahr, MD’s seven-volume Natural Therapeutics, published in the early 1900s.Lindlahr’s Nature Cure (1913) is considered a seminal work in naturopathic theory, laying the groundwork for a systematicapproach to naturopathic treatment and diagnosis. Lindlahr ultimately presented the most coherent naturopathic theory extant, summarized in his Catechism of Naturopathy, which presented a five-part therapeutic progression: 1.“Return to Nature,” which meant attend to the basics of diet, dress, exercise, rest, etc. 2. Elementary remedies-water, air, light, electricity 3. Chemical remedies-botanicals, homeopathy, etc. 4.Mechanical remedies-manipulations, massage, etc. 5. Mental/spiritual remedies-prayer, positive thinking, doing good works, etc.= In the 1950s Spitler wrote Basic Naturopathy, a and Wendel, Standardized N ~ t u r o p a t h yThese .~~ texts presented the somewhat opposing perspectives of the more science-based, or “green allopathic,” and the nature cure camps. Kuts-Cheraux’s Naturopathic Materia Medica, written in the 1950s, was produced to satisfy a statutory demand by the Arizona legislaturebut persisted as one of the few extant guides. Practitioners have relied on a number of earlier texts, many of which arose from the German hydrotherapy pra~titioners~l-~ or the Eclectic school of medicine (a refinement and expansion of the earlier ‘Thomsonian” system of medicine)3741and predated the formal American naturopathic profession (1896). But by the late 1950s, publications diminished. The profession was generally considered on its last gasp, an anachronism of the preantibiotic era.

MODERN NATUROPATHIC CLINICAL THEORY THE PROCESS OF DEVELOPMENT ”Medical philosophy comprises the underlying premises on which a health care system is based. Once a system is acknowledged, it is subject to debate. In Naturopathic medicine, the philosophical debates are a valuable, ongoing process which helps the understanding of health and disease evolve in an orderly and truth revealingfashion.” -Randall Bradley, ND.42

After the profession’s decline in the 1950s and 1960s, a rebirth was experienced, more grounded in medical sciences and fueled by a young generation with few teachers. The profession’s roots were neglected out of ignorance, for the most part, along with a youthful arrogance. By the early-1980s it was apparent that attempts

to regenerate the progress made by Lust would require the creation of a unified professional organization and all which that entailed: accreditation for schools, national standards in education and licensure, clinical research, and the articulation of a coherent definition of the profession for legislative purposes, as well as for its own internal development. These accomplishments would be necessary to be able to demonstrate the uniqueness and validity of the profession, guide its educational process, and jusbfy its status as a separate and distinct medical profession. In 1987the newly formed (1985)American Association of Naturopathic Physicians (AANP) began this task under the leadership of James Sensenig, ND, (president) and Cathy Rogers, ND, (vice president) appointing a committee to head the creation of a new definition of naturopathic medicine. The ”Select Committee on the Definition of Naturopathic Medicine” succeeded in a %year project that culminated in the unanimous adoption by A A ” s House of Delegates of a comprehensive, consensus definition of naturopathic medicine in 1989 at the a n n d convention held at Rippling River, OR.M5The unique aspect of this definition was its basis in definitive principles, rather than therapeutic modalities, as the defining characteristicsof the profession. In passing this resolution, the House of Delegates (HOD) also asserted that the principles would continue to evolve with the progress of knowledge and should be formally reexamined by the profession as needed, perhaps every 5 years.In September 1996 the AANP HOD passed a resolution to review three proposed principles of practice that had been recommended as additions to the AANP definition of naturopathic medicine originally passed by the HOD in 1989. These three new proposed principles were rejected, and the AANP HOD reconfirmed the 1989 AANP definition unanimously in 1999. The results of a profession-wide survey conducted from 1996-1998 on these three new proposed principles demonstrated that while there was lively input, the profession agreed strongly that the original definition was accurate and should remain intact. The HOD recommended that the discussion be moved to the academic community involved in clinical theory, research, and practice for pursuit through scholarly dial0gue.4~-~~ This formed the basis for further efforts to articulate a clinical theory. AANP members had stated in 1987-1989 during the definition process: “These principles are the skeleton, the cure of naturopathic theory. There will be more growth from this f~undation.”~~ By 1997 this growth in modern clinical theory was evident. The first statement of such a theory was published in the AANP’s Iournal of Naturopathic Medicine in 1997 in an article titled “The Process of Healing, a Unifying Theory of Naturopathic Medicine.” This article contained three fundamental concepts that were presented as an

organizing theory for the many therapeutic systems and modalities used within the profession and was based on the principles articulated in the consensus AANP definition of naturopathic medicine. The first of these is the characterization of disease as a process rather than a pathologic entity. The second is the focus on the determinants of health rather than on pathology. The third is the concept of a therapeutic hierarchy? The article, ”The Process of Healing: A Urufylng Theory of Naturopathic Medicine” signaled the emergence of a growing dialogue amongst physicians, faculty, leaders and scholars of naturopathic philosophy concerning theory in naturopathic medicine. The hope and dialogue sparked by this article was the natural next step of a profession redefining itself both in the light of today’s advances in health care, and with respect to the foundations of philosophy at the traditional heart of naturopathic medicine. This dialogue naturally followed the discussionsof the definition process and created a vehicle for emerging models and concepts to be built on the bones of the principles. The genome of traditional naturopathic philosophy had been carried in the hearts and minds of a new generation of naturopathic physicians into the twenty-first century-these modern naturopathic physicians began to gather to redefine and reurufy the soul of the medicine and articulate the code of the naturopathic genome. This new dialogue was formally launched in 1996, when the AANP Convention opened with the plenary session: “Towards a Ururylng Theory of Naturopathic Medicine” with four naturopathic physicians presenting facets of emerging modem naturopathic theory. The session closed with an open microphone. The impassioned and powerful comments of the naturopathic profession throughout the United States and Canada engaged in the vital process of deepening and clarifymg its urufying theory. Dr. Zeff presented “The Process of Healing: The Hierarchy of Therapeutics”; Dr.Mitchell presented “The Physics of Adjacency, Intention Naturopathic Medicine and Gaia”; Dr.Sensenig presented “Back to the Future: Reintroducing Vitalism as a New Paradigm”; and Dr. Snider announced the Integration Project, inviting the profession to engage in it by ”sharing a beautiful and inspiring anguish-the labor pains of naturopathic theory in the twenty-first century. We know what we have done, and we know there is much more. . . . The foundation is laid. We are ready now [for integrati~n].”~~ Days later, in September 1996, the Co&ortium of Naturopathic Medical Colleges (now American Association of Naturopathic Medical Colleges [AANMC]) formally adopted and launched the Integration Project: an initiative to integrate naturopathic theory and philosophy throughout all divisions of all naturopathic college curricula, from basic sciences to clinical training. A key element of the project engaged the further development

A Hierarchy of Healing: The Therapeutic Order

and refinement of naturopathic theory. The project has been cochaired by Drs. Snider and Zeff since 1996. Steering members from all colleges have participated and ~ o n t r i b u t e d .Methods ~~ include professional and scholarly research, expert teams, symposiums, and training. The proposed result is the fostering of systematic inquiry among academicians, clinicians, and researchers concerning the underlying theory of naturopathic medicine and to bring the fruits of this work and inquiry into the classroom and into scientific research.% The Integration Project has sustained both formal and informal dialogue since its inception in 1996, which continues today. The work has engaged faculty and scholars of naturopathic philosophy in the United States, Canada, and Australia. It also engaged institutional leaders and practicing doctors and faculty in all areas of the profession. Why? Naturopathic philosophy is deeply felt as the "commons" of naturopathic medicine: a place where the profession meets; one that is owned by all naturopathic physicians; and reflects, holds, and deepens the heart of naturopathic medicine. Naturopathic philosophy is the foundationand heart of naturopathic medicine. It remains valid by evolving with the progress of knowledge, the progress of science, and the progress of the human spirit. Because naturopathicphilosophy engages the felt mission of nature doctors, it is vital that the profession periodically gathers to renew and revitalize progress regarding its u"lfymg foundations. The Integration Project sparked a wide range of activities in all six ND colleges, resulting in all-college retreats to share tools, retreats for training of non-ND faculty in naturopathic philosophy, integration of basic sciences curriculum, expert teams revision of core competencies across departments ranging from nutrition to case management and counseling, development of clinical tools and seminars for clinic faculty, creation of new courses, and the integration of important research questions derived from naturopathic philosophy into research studies and initiatives?' North American core competencies for naturopathic philosophy and clinical theory were developed by faculty representing all accredited ND colleges in a landmark AANMC retreat in 2000. The AANMC's Dean's Council formally adopted these competencies in 2000 and recommended that they be integrated throughout curricula in all ND colleges. These national core competencies included the hierarchy of therapeutics, or the therapeutic 0rder.%3~ Finally, many meetings with scholars and teachers of naturopathic theory and other faculty and leadersformal and informal-have resulted in the further development and refinement of the hierarchy of therapeutics developed by Dr. Zeff in 1997. Drs. Snider and Zeff and naturopathic theory faculty have worked closely with other naturopathic faculty from AANMC colleges in a series of revisions. Drs. Snider and Zeff collaborated in

1999 to develop the hierarchy of therapeutics into the therapeutic order. The therapeutic order has been subsequently explored and refined also through a series of faculty retreats and meetings, as well as experience with students. A key fkding of the clinic faculty at Bastyr University was the emphasis on the principle "holism: treat the whole person" and respect for the patient's own unique healing order and his or her values as a context for applying the therapeutic order to clinical decision maknig@ . -' The therapeutic order, or hierarchy of healing, is now incorporated into ND college curricula throughout the United States, Canada, Australia, and New Zealand. For example, an important international outgrowth of the profession's development of theory is the adoption of the unified "Working Definition of Naturopathic Nutrition" in June 2003 by the Australian naturopathic profession (Box 3-1). The 3-year project under the coordination of Professor Stephen Myers, ND, BMed, PhD, brought together nutrition faculty from naturopathic medicine colleges throughout Australia. The project was cohosted by the Naturopathy and Nutrition panel, an independent group of naturopaths and nutrition educators whose mission is to foster and support the development of the science, teaching, and practice of naturopathic nutrition, and the School of Natural and Complementary Medicine at Southern Cross University. The definition evolved over two retreats attended by more than 40 faculty members involved in teaching nutrition as part of naturopathic medicine education. It commenced as a general agreement within the group that there was a real and distinct difference between conventional nutrition and naturopathic nutrition. General agreement was that the distinction between the two had to date been poorly defined and had been the source of dissonance between the naturopathic and science faculty within the colleges. The obvious next step was to define that difference to ensure that nutrition curriculum within naturopathic medicine colleges reflected the core elements of naturopathic nutrition. At the second retreat held in June 2003, the working definition was adopted with a recommendation that it be widely circulated within the naturopathic medicine profession to commence a dialog aimed at both appropriate revision and broad adoption. This process created a much-needed consensus definition on naturopathic nutrition. This definition is based on the AANP defining principles and incorporates the therapeutic order theory.

A THEORY OF NATUROPATHIC MEDICINE Standard medicine, or biomedicine, has a simple and elegant paradigm. Simply stated, it would be "the diagnosis and treatment of disease." In practice, this statement

Philosophy of Natural Medicine

Preamble Naturopathic medicine is a distinct system of primary health carart, science, philosophy and practice of diagnosis, and treatment and prevention of illness. Naturopathic medicine is distinguished by the principles that underlie and determine its practice. These principles include the healing power of nature (vis medicatfix naturae), identification and treatment of the causes (tole causam), the promise to first do no harm (primum non nocere), doctor as teacher (docere), treatment of the whole person, and emphasis on prevention.These principles give rise to a practice that emphasizes the individual and empowers him or her to greater responsibility in personal health care and maintenance. Definition

Naturopathicnutrition is the practice of nutrition in the context of naturopathic medicine. Naturopathic nutrition integrates both scientific nutrition and the principles of naturopathic medicine into a distinct approach to nutritional practice. Core components of naturopathicnutrition are: A respect for the traditional and empirical naturopathic approach to nutritional knowledge The value of food as medicine An understanding that whole foods are greater than the sum of their parts and recognition that they have vitality (properties beyond physiochemical constituents) Individuals have unique interactions with their nutritional environments Practice In the context of the definition, and with respect to the therapeutic order, the practice of nafuropathic nutrition may include the appropriate use of the following: Behavioral and lifestyle counseling Diet therapy (including health maintenance, therapeutic diets, and dietary modification) Food selection, preparation, and medicinal cooking Therapeutic application of foods with specific functions Traditional approaches to detoxification Therapeutic fasting strategies Nutritional supplementation Data from Snider P, Payne S. Making naturopathic curriculum more naturopathic: agendas, minutes, 1999-2001. Clinic faculty task force on integration. Faculty development retreat, Bastyr University, 1999.

contains several assumptions. One assumption is that illness can be understood in terms of discrete diseases (i.e., human suffering can be divided into identifiable entities, such as measles or cancer [in its specific types], or all the other catalog of illnesses to which we are subject). Next is that “cure” is the elimination of the disease entity. Third, this is accomplished by the evidencebased application of pharmaceuticals, surgeries, or similar treatments to eliminate, palliate, or suppress the entity and its symptomatic expressions. These are so obvious that they are not commonly considered. They form the background thinking in medical decision making: idenhfy and treat the disease.

The elegance of this model, and the science behind it, has taken medicine to its highest point in history as a reliable vehicle to ease human suffering, and its application has saved countless lives. The understanding of the physician, at least about the nahm of pathology, has never been as complete. But illness has a near infinite capacity to baffle the physician. New diseases arise, such as human immunodeficiency virus/acquired immune deficiency syndrome, and shifts occur in disease focus, such as the shift between 1900 and 2000 from acute infection to chronic illness as the predominant cause of death. Beyond these obvious changes, even with the current depth of understanding, standard medicine physicians continue to experience a depth of ignorance. So, even representing a n apex of human achievement as it does, modem medicine is not without its weaknesses. Its greatest weakness is probably its inability to cure chronic illness as easily as it once dealt with thingslike infectious pneumonia with penicillin, or even tuberculosis with streptomycin. To compound that problem is the growing prevalence of antibiotic-resistant infections. Part of the reason for the failures within modem medical science is the mechanistic basis of it, with its fundamental ignorance of and disrespect for the wholeness of the individual, the natural laws of physiology governing health and healing, and especially for all things spiritual. Inherent in the dictum-diugnoseand treat the diseuse-is the general neglect of the larger understanding that disease is a process conducted by and within an intelligent organism “whose genome(s) is (are) developed and expressed in the natural world.”’ The uniqueness of naturopathic medicine is not in its therapeutic modalities, ”natural” alternativesto the drugs and surgeries of standard medicine. It is in the clinical theory that govern the selection and application of these modalities, captured in the unifying definition adopted in 1989and expressed more specifically in the continuing articulation of clinical theory. That is, it is the way the naturopath thinks about illness and healing. The first element of this theory is based upon the first defining principle: vis rnedicutrix naturae. It is based on the understanding that disease can be seen as a process, as well as an entity. One can analyze the process of illness and derive some understanding. But to do this,one needs to examine the assumptions underlying this concept. The governing assumptions of standard medicine are principally that diseases are entities and that drugs and surgery can eliminate these entities from the suffering person. These are not the governing assumptions of naturopathic medicine.

ILLNESS AS PROCESS Naturopathic medicine can be characterized by a different model than “idenhfy and treat the disease.”

A Hierarchy of Healing:The Therapeutic Order

“The restoration of health’’ would be a better characterization. In fact, naturopathic physicians adopted the following ultrashort definition of naturopathic medicine in 1989 in an AANP position paper: ”Naturopathic physicians treat disease by restoring health.” Immediately one can see a difference: Standard medicine is disease based; naturopathic medicine is health based. Although naturopathic medical students study pathology with the same intensity and depth as standard medical students, as well as its concomitant (diagnosis), the naturopathic physician applies that information in a different context. In standard medicine, pathology and diagnosis are the basis for the discernment of the disease ”entity” that afflicts the patient, the first of the two steps of idenwing and destroying the entity of affliction. In naturopathic medicine, however, disease is seen much more as a process than as an entity. Rather than viewing the ill patient as suffering from a ”disease,” the naturopath views the ill person as functioning within a process of disturbance and recovery, in the context of nature and natural systems. Various factors disturb normal health. If the physician can idenidy these disturbances and moderate them (or at least some of them), the illness and its effects abate, at least to some extent, if not totally. As disturbances are removed, the body can improve in function, and in doing so the health naturally improves. The natural tendency of the body is to maintain itself in as normal a state of health as is possible. The role of the physician is to facilitate this self-healing process. The obvious first task of the naturopathic physician, therefore, is to determine what is disturbing the health so that these causative elements may be ameliorated. Disease is the process whereby the intelligent body reacts to disturbing elements. It employs such processes as inflammation and fever to help restore its health. In general, one can graph this process simply: healthy state + disturbing factors + disturbance of function + reaction + discharge of the products of reaction + resolution

One can see this most easily in the common cold. Within standard medical understanding, the common cold is caused by a virus, from among a family of pathologic viruses, which infects the person. The immune system responds, developing appropriate antibodies, which eventually neutralize the virus. There is no ”cure” yet discovered, except time. Medications are used to ameliorate the symptomatic experience: aspirin or acetaminophen for fever, antihistamines to dry the mucus discharge, etc. These measures are not cures: They reduce the symptomatic expression of the ”cold” but often lengthen the process. In naturopathic medicine, the cold is seen not as a disease entity but as a fundamental process whereby the body restores itself.

If colds were caused solely by a virus, then everyone who came in contact with the virus would get the cold. Obviously, this does not happen. Susceptibility factors include immune competence, fatigue, vitality, and other resistance factors. The virus enters a milieu in which all these factors affect the process. Once the virus enters the system, if it overcomes some resistance factors, one begins to see disturbance of function. One does not feel quite right. One may begin to get a sore throat, the first inflammatory reaction, occurring at the point of entry of the virus into the body. The immune factors may overcome the virus at this point or may be insufficient or suppressed. All of this is mutable to some extent and is affected by nutrition, fatigue, an increase in immune tonics, vitamin C, etc. But the ”cold” may proceed into a general state of fatigue and inflammation, possibly fever, etc., followed by mucus discharge, cough, and so forth, as the body processes the virus and its effects, eventually overcoming it and eliminating the results. This model is not understood so much to be a separate disease entity but a general andfundamental process of disturbance and recovery within the living body. It is a method whereby the body restores itself after a sufficient amount of disturbance accumulates within the system. This is why the cold has no ”cure.” It is the cure for what is ailing the body. Chronic illness arises, in general, when any or all of three factors occur: (1) The disturbing factors persist, such as a chronically improper diet, which continues to burden the body cumulatively, as the digestive processes slowly weaken under the stress of that improper diet; (2) The reactive potential is blocked or suppressed, usually by drugs, which interferes with the capacity of the body to process and remove its disturbances; or (3) The vitality of the system is insufficient to mount a significant and sufficient reaction. As these three factors prevent a sufficient reactive purge of disturbances, the body slides into a chronic, weaker reactive state or episodes of intermittent reaction, perceived as persistent and chronic illness. Ultimately, as function is sufficiently disturbed, structures or functions are damaged and chronic inflammation becomes ulceration or scar tissue formation. Atrophy, paralysis, or even tumor formation may occur. All of this is the body manifestly doing the best it can for itself in the presence of persistent disturbing factors and with respect to the limitations and range of vitality influenced by the constitution, psycho-emotional/spiritual state, and genotype of the person and his or her surrounding environment. The reversal of this condition is rarely accomplished by ”drugging” the pathologic state, which usually results in the control of symptoms and persistence of the illness, hopefully controlled in its more dangerous

aspects by the presence of the drug or performance of the surgery. Reversal is more likely accomplished by identifymg and ameliorating the disturbance, and as necessary, strengthening or supporting the reactive potential. The first step in this process is to identdy and reduce disturbing factors.

THE DETERMINANTS OF HEALTH In order to reduce the disturbance, one must identdy the disturbance. In standard medicine, the first step is to identdy the pathology, which is then treated. In naturopathic medicine, one must come to understand what is disturbing the health. To do this, the physician needs to understand what determines health in the first place. The physician can then evaluate the patient in these terms and come to understand what is disturbing the natural state of health. Such a list could be created by any doctor, certainly any naturopathic physician. The authors propose the list in Box 3-2. The naturopathic physician evaluates the patient with these areas in mind, looking for aspects of disturbance, first in the spirit, and most generally in diet, digestion, and stress in its various aspects. In this evaluation the naturopathic physician brings to bear a body of knowledge somewhat unique to naturopathic medicine, to evaluate not solely in terms of pathologic entity but in terms of normal function and prepathologic functional disturbance. Locating areas of abnormal function or

In order to understand what disturbs health, one must understand what determines health. Therefore doctors of naturopathy study the determinants of health. A determinant of health becomes a disturbance when it is absent or present but distorted. 1. Inborn

Genetic makeup (genotype) Intrauterine/congenital Maternal exposures Drugs Toxins Viruses Psychoemotional Maternal nutrition Maternal lifestyle Constitution: determines susceptibility 2. Hygienic FactorsRistyle Factors: How We Live

Environment, Lifestyle, Psychoemotional, and Spiritual Health Spiritual life Self-assessment Relationship to larger universe Exposure to Nature Fresh air

disturbance, the physician acts or recommends ways to ameliorate the disturbance. As disturbing factors are reduced in the system, the natural tendency of the system to improve and optimize its function directs the system back toward normalcy. This is the removal of the obstacles to cure, which allows the action of the vis rnedicutrix nuturue, the vital force, the healing power of .nature. This is the first step in the hierarchy of healing and what naturopathic physicians may call the overarching clinical theory of naturopathic medicine: the therapeutic order.

THERAPEUTIC ORDER The therapeutic order is a natural hierarchy of therapeutic intervention, based on or dictated by observations of the nature of the healing process, from ancient times through the present.61 It is a natural ordering of the modalities of naturopathic medicine and their application. The concept is somewhat plastic in that one must evaluate the unique needs, and even the unique healing requirebut in general ments, of the specificpatient or the nature of healing dictates a general approach to treatment. In general, this order is listed in Box 3-3.

1. Establish the Conditions for Health Identify and Remove Disturbing Factors If one understands health to be the natural state and “disturbance” the original culprit, then identifymg and

Clean water Light Diet, Nutrition, and Digestion Unadulterated food Toxemia Rest and Exercise Rest Exercise Socio-economicFactors Culture Loving and being loved Meaningful work Community Stress (Physical, Emotional) Trauma (physicaVemotiona1) Illnesses: pathobiography Medical interventions (or lack of) Surgeries Suppressions Physical and emotional exposures, stresses, and trauma Toxic and harmful substances Addictions

From Zeff J, Snyder I?Course syllabus: NM51 71, Naturopathic clinical theory. Seattle: Bastyr University, 1997-2005.

A Hierarchy of Healing: The Therapeutic Order

1. Establish the conditions for health Identify and remove disturbing factors Institute a more healthful regimen 2. Stimulate the healing power of nature (vis medicatfix nafufae):the self-healing processes 3. Address weakened or damaged systems or organs Strengthen the immune system Decrease toxicity Normalize inflammatory function Optimize metabolic function Balance regulatory systems Enhance regeneration Harmonize with your life forces5 4. Correct structural integrity 5. Address pathology: Use specific natural substances, modalities, or interventions 6. Address pathology: Use specific pharmacologicor synthetic substances 7.Suppress or surgically remove pathology ~~

From Zeff J. Snyder P.Course syllabus: NM51 71. Naturopathic clinical theory. Seattle: Bastyr University, 1997-2005. The actual therapeutic order may change, depending on the individual patient's needs for safe and effective care. The needs of the patient are primary in determining the appropriate approach to therapy.

reducing disturbance is the obvious first step, unless there is immediate danger to life or limb, in which case acting to preserve life or limb is paramount. In most chronic disease, neither life nor limb is immediately threatened. This understanding dictates the first thing the physician must attend to: the identificationand amelioration of those factors disturbing health, especially factors that most disturb health (inappropriate diet, excessive stress, and spiritual disharmony). To understand what disturbs health, one must understand what determines health. The naturopathic physician evaluates a patient with reference to the determinants of health to discover wherein the patient's health is disturbed. In this step, the physician is essentially "removing the obstacles to cure, and allowing the vis rnedicutrix naturue to do its work." Among these many possibilities, in general, the most significant are diet, digestion, stress, and what might be called "spiritual integrity." Humans are spiritual beings. They are spirits that reside within bodies. Though the general purview of the physician is the body, that instrument cannot be separated from the spirit, which animates it. If the spirit is disturbed, the body cannot be fundamentally healthy. Hahnemann, the brilliant founder of homeopathy, instructs physicians thus. Disturbance in the spirit permeates the body and eventuates in physical manifestation. Physicians are responsible for perceiving such disturbances and addressing them. At colleges of naturopathic medicine in Australia and North America, faculty work with naturopathic medicine students to develop their ability to perceive the spiritual nature of an individual as those factors that give rise to an individual's

"will to live," their "joie de vivre," and their core beliefs and values. This is a foundational skill in addressing spirituality and health. Using this definition, both atheists and agnostics can be seen to have a spiritual aspect. This definition also removes spirituality from religiosity in a way that does not denigrate any individual religious belief a patient may hold, allowing the naturopathic clinician to explore this aspect of the individual. Perceived in this way, it is also easier to understand that many individuals within society are experiencing a "spiritual crisis." One of the oldest concepts in naturopathic medicine is the concept of toxemia. Toxemia is the generation and accumulation of metabolic wastes and exogenous toxins within the body. These toxins may be the results of maldigestive processes, non-end product metabolites, environmental xenobiotics, colon bacteria metabolites, etc. These toxins become irritants within the body, resulting in inflammation of tissues and interference with biochemical processes. The maldigestive and dysbiotic origin of these toxins is the product of inappropriate diet, broad spectrum antibiotics, and the effects of excessive stress on digestion. Eating a diet that cannot be easily digested or is out of appropriate nutrient balance for the individual results in the creation of metabolic toxins in the intestines. Stress, resulting in the excessive secretion of cortisol and adrenalin, results in the decrease of blood flow to the digestive process, which decreases the efficient functioning of digestion and increases the tendency toward maldigestion, dysbiosis, and toxemia. Physicians can now easily measure the degree of toxemia in various ways (e.g., urinary indican or phenol). Spiritual disharmony, inappropriate diet, digestive disturbance, stress, and toxemia are primary causes of chronic illness and must be addressed if healing is to occur. Beyond these, other disturbing factors must be discerned and addressed, whichever pertain to the individual patient.

Institute a Healthier Regimen As a corollary of the first, once physicians have determined major contributingfactors to illness, they construct a healthier regimen for the patient. Some disturbing factors can be eliminated, like inappropriate dietary elements. Others are a matter of different choices or living differently. The basics to consider are: appropriate diet, appropriate rest and exercise, stress moderation, a healthy environment, and a good spiritual connection. If this model is correct, these measures alone should result in enhanced health. The problem arises in knowing how to do these things. What is an appropriate diet? This is an area of considerable controversy. Physicians think about diet in many different ways. The goal of dietary improvement is to reduce the symptomatic consequences of the patient's diet and provide optimal nutrition to the patient. The point here, regardless of

how this is done, is that it is central and essential for fundamental health improvement. If the diet is not correct, if digestion is not appropriate, if nutrition is not adequate, the patient cannot maximally improve. If the diet and digestion are appropriate, the basis for improvement in other areas is enhanced. The same is true with these other fundamental elements, to which Lindlahr referred in the first element of his catechism, ”return to nature”: exercise, rest, dress, etc.28These have been expanded in the ”determinants of health.” They create the basis for improvement. What thisreally means is to change the ”terrain,” the conditions in which the disease has formed-not only to change but to improve the conditions so that there is less basis for the disease. Hahnemann addresses this on the first page of his Orgunon ofMedicine. He identified four tasks for the physician: to understand the true nature of illness, “what is to be cured”; to understand the healing potential of medicines; to understand obstacles to recovery and how to remove them; and to understand the elements that derange health and how to correct them so that recovery may be permanent.@ Changing and improving the terrain in which the disease developed is the obvious first step in bringing about improvement. This sets up the basis for the following elements to have the most beneficial effects.

Many naturopathic modalities can be used to stimulate the overall vital force. More specific approaches to stimulation, though general in effect, are applied differently to each patient and have a less general effect than those previously mentioned. Homeopathy and acupuncture are primary methods of such stimulation. They add little to the system: They are not gross chemical treatments. They work with what is there, stimulating a reaction, stimulating function, correcting disturbed patterns. Each method helps move the system out of its disturbed state and, with the reduction of encumbrance, helps move it toward health. Finally, exposure to the patterns, rhythms, and forces of nature is a traditional part of naturopathic medicine and the tradition of nature doctors throughout the world. As Pizzorno and Snider wrote: “We are natural organisms, our genomes developed and expressed in the natural world. The patterns and processes inherent in nature are inherent in us. We exist as part of complex patterns of matter, energy, and spirit.”’ The natural processes of these patterns and the drive toward health inherent in them is a natural ally for the physician. Exposure to appropriate rhythms, patterns, and forces of nature strengthens vitality and stimulates the healing power of nature.

2. Stimulate the Self-Healing Mechanisms

3. Support Weakened or Damaged Systems or Organs

A certain percentage of patients improve sufficiently simply by removing disturbing factors and establishing a healthier regimen. Most require more work. Once the patient is prepared, once the terrain is beginning to clear of disturbing factors, then one begins to apply stimulation to the self-healing mechanisms. The basis of this approach is the underlying recognition of the vis rnedicufrix nufurue, the tendency of the body to be self-healing, the wisdom and intelligence within the system that constantly tends toward the healthiest expression of function, and the healing “forces” in the natural environment (air, water, light, etc.). The body heals itself. The physician can help create the circumstances to promote this. Then, as necessary, the physician stimulates the system. One of the best ways to do this is through constitutional hydrotherapy, as developed by Otis G. Carroll, ND, early in the past century. This procedure is simple, involving the placement of hot and then cold towels on the trunk and back, in specific sequence (depending on the patient), usually accompanied by a sine wave stimulation of the digestive tract. This is a dynamic treatment, simple, inexpensive, and universally applicable. It helps recover digestive function, stimulates toxin elimination, ”cleans the blood,” enhances immune function, and has several other effects. It moves the system along toward a healthier state.” Exercise often achieves similar results.

Some systems or functions require more than stimulation to improve. Some organs are weakened or damaged (e.g., adrenal fatigue after prolonged stress), and some systems are blocked or congested (e.g., the hepatic detoxification pathways) and require extra help. This is where naturopathic physicians use their vast natural medicinary. Botanical medicines can affect any system or organ, enhancing its function, improving its circulation, providing specific nutrition, stimulating repair. Glandular substances can be applied to a similar purpose. And then there are the growing number of evidence-based “nutraceuticals,” biological compounds that enhance metabolic pathways and provide substance for metabolic function. Naturopathic physicians can also apply specific homeopathic medications, usually in the lower potencies, which act nutritively and can stimulate specific organs or functions. This method can be used to stimulate detoxificationof specific substancesfrom the body in general or of specific organ systems or tissues. Dr.Pizzorno’s work in Total Wellness and the work of “functional medicine” leader Jeffrey Bland, PhD, exemplify the clinical strategies applied at this level of the therapeutic order. These strategies are used to restore optimal function to an entire physiologic system (immune, cardiovascular, detoxification, life force, endocrine, etc.).65

A Hierarchy of Healing: The Therapeutic Order One can use specific exercises to stimulate or enhance organ health. Some systems of Yoga and Qi Gong are organ specific.And specific applications of hydrotherapy and other physiotherapy systems can be applied to enhance the function of organs or tissues. These methods, combined with an appropriate diet and a healthier regimen, along with constitutional hydrotherapy, appropriate homeopathy, and acupuncture, usually bring most health problems back to normal, without negative consequence, rapidly, efficiently, and permanently.

4. Address Structural Integrity Many structural problems result from stress of some kind on internal systems. For example, midback misalignment or discomfort is often found associated with a history of underlying stress on the digestive organs, the ennervation of which originates at those spinal segments. One can manipulate that vertebra back into proper alignment or massage contracted musculature, but until one corrects the underlying functional disturbance, there will be a tendency to repeated structural misalignment. In some circumstances the singular problem may be simply structural disintegrity. One may have fallen or been hit in some fashion and simply need the neck manipulated back into proper alignment and the surrounding soft tissue relaxed. There may be no diet error or other disturbance aside from the original injury, and correction requires only simple manipulation or therapeutic massage. This is an example of the flexibility of the “therapeutic order” concept. In this case, first-order therapeutics is to manipulate the cervical spine or to relax chronically contracted muscles. Usually, however, the problem of structure is part of the larger problem, and such intervention becomes a fourth-order therapeutic. Reintegrating structure can occur in many ways, one of which is the method of ”bone cracking” known to the ancient Greeks and Chinese and probably all other ancient healing cultures. But there are nonforce manipulative systems that include many modalities of therapeutic massage. Some systems of exercise are designed to reintegrate and maintain normal structural relationships. Any of these might be appropriate to a specific patient. By approaching the problem in the context of the therapeutic order, one can expect structural corrections to be required only occasionally and for the results to be more or less permanent.

5. Address Pathology: Use Specific Natural Substances, Modalities, or Interventions Having gone through the first four steps of this therapeutic hierarchy, most patients improve. The improvement is based on the sound footing of the underlying correction

or removal of fundamental causative elements. It is also based on the intrinsic nature of the body to heal itself by using the least possibleforce. Most pathology improves or disappears under these circumstances. Sometimes it is necessary to address pathology. This may be the case because the particular pathology may be threatening to life or limb. Acting on this threat is imperative. It can be done often with naturopathic means, directed specifically against the pathology. Biochemical or genetic individuality also can demand an emphasis at this level of intervention. One of the major conflicts in naturopathic medicine is that some practitioners find it expedient to diagnose and treat pathology (the standard medical model) rather than pursue a naturopathic model of practice. This approach tends to be less satisfymg and less productive of the most elegant outcomes and the long-term continued health of the patient. It also reduces the capacity of the physician to treat, such as in cases where there is no evidencebased treatment for the pathology in question, or where there is no clear diagnosis (i.e., no distinct pathology to treat). This approach is increasingly referred to as ”green allopathy.” But the vast body of knowledge that naturopathic education presents in this arena makes such an approach seductive, especially in a culture that more or less expects, supports, reinforces, and pays for an “allopathic” approach to diagnosis and treatment. It is easy to do this. The culture is accustomed to this model and often expects to encounter this in the naturopathic physician’s office. In some states, such as Oregon, where the naturopathic formulary includes most antibiotics and many pharmaceutic drugs, one can practice almost without distinction from a medical doctor. The typical naturopathic formulary is often sufficient to prescribe on a strictly pathologic basis. The problem with this is that it is generally not as effective, especially in the treatment of chronic disease. The value of naturopathic medicine in our culture is not that naturopathic physicians can function almost like medical doctors, with a ”natural” formulary instead of drugs. It is that they offer a fundamentally different approach, one based on the restoration of health rather than the treatment of pathology. Given all of this, it still may be useful to directly address the pathologic entity or its etiology. When treating an antibiotic-resistant infection, for example, it may be useful to apply botanical medicines with specific antibiotic properties along with immune tonics, and the more fundamental steps of this therapeutic hierarchy. In difficult cases, such as many cancers, using agents that have specific, pathology-based therapeutics may be an essential element of comprehensive treatment. The naturopathic formulary provides a vast and increasing number of such options. One advantage of such treatment is that, in general, when applied by a knowledgeable

Philosophy of Natural Medicine

practitioner, it rarely adds more burden or toxicity to the system. Naturopathic pathology-based treatments still follow the dictum ”do no harm.”

6. Address Pathology: Use Specific Pharmacologic or Synthetic Substances About 800,000 medical doctors and osteopathic physicians in the United States are well trained in the science of pathologic-based treatment, using pharmaceuticals, surgery, etc. There are times when such an approach is necessary to preserve life, limb, or function. Although some naturopathic physicians, by training and by statute, may prescribe pharmaceutics or even perform surgeries, naturopathic physicians may also refer patients in need of such services to appropriate medical doctors or osteopaths, depending on licensed formulary. In a growing number of states, NDs can legally provide an expanding range of prescription drugs. Although this is an important tool for the naturopathic primary care giver, this privilege requires enhanced responsibility for the ND to prescribe those substances only as needed-and to thoroughly rely on applying the least force appropriate to effect recovery and protect patient safety. Naturopathic physicians are well trained in this regard and respect the necessity and utility of standard medical practice in appropriate situations.Some disagreement exists regarding which situationsmay be appropriate. The AANP has developed position papers to resolve some of these questions. In general, while recognizing the necessity of such treatment, most naturopathic physicians also recognize that such treatment often carries consequences that must also be addressed.

7. Suppress Pathology Sometimes it is necessary, for the preservation of life or limb, to suppress pathology. Medical doctors are especially trained in this art and have powerful and effective tools with which to do this. Unfortunately, suppression, because it does not fundamentally remove or address essential causative factors (such as dietary error) often results in the development of other, often-deeper disturbance or pathology. Since much pathologic expression is the result of the actual self-healing mechanisms, such as inflammation, suppressive measures are, in general, anti-vis rnedicutrix nuturue. The result of suppression is that the fundamental disturbing factors are still at play within the person, still disrupting function to some extent, while the suppression reduces the symptomatic expression and resolution of disturbance. One simple example of this is the use of steroidal antiinflammatory and antihistaminic drugs in the treatment of acute asthma. This usually effectively opens the airways. But prolonged use weakens the patient. If the

treatment persists, the patient becomes immune compromised and osteoporotic and can develop psychologic disorders. These symptoms are part of the long-term effects of prednisone. It may necessarily maintain breathing, but the long-term cost to the organism is expensive. Suppression, although it may be life saving, often has serious consequences. With standard medical methods of care, cure of chronic illness is often elusive. This is the benefit of the naturopathicapproach: by taking a nonsuppressive course of action, based on sound physiologic principles, one can often restore health without recourse to the potential damage of suppression. Naturopathic physicians, while recognizing the occasionalnecessity of suppressive approaches, in general avoid suppression, which is a primary way in which physicians can inflict harm, even with the best of intentions.

THEORY IN NATU ROPATHIC MEDICINE This therapeutic hierarchy is based on the observation of the nature of healing and the inherent order of the healing process. It is part of a unifying theory of naturopathic medicine, an outgrowth of the principles which underlie naturopathic thinking. It provides the physician with instructions that order the many therapeutic modalities used by the practice. The consensus definition of naturopathic medicine, adopted by the AANP in 1989, is a statement of identity, distinguishingnaturopathic medicine from other systems of medical thought. Contained within it is a set of instructions regarding the practice of the medicine. The three concepts discussed here-”disease as process,” “the determinants of health,” and “the therapeutic order”-are an articulation of these instructions. They are presented as a clinical theory of naturopathic medicine. They are abstracted, as is the definition, from the observationby nature doctors throughout time and across many traditions of the nature of health and of disease and of the nature of healing. They provide the physician with instructions. These instructions include a procedure for thinking about human illness in such a way that one can approach its cure in an ordered and elegant fashion by understanding its process as an expression of the vis rnedicutrix naturue. It provides the framework for truly evaluating the patient as a whole being: spiritual, mental/emotional, and physical, rather than as a category of pathology. And it provides the physician a system for organizing and efficiently integrating the vast therapeutic array provided in naturopathic medicine. Ultimately, it satisfies Hahnemann’s observation of’the ideal role of medicine, that ”the highest ideal of cure is rapid, gentle and permanent restoration of the health . . . in the shortest, most reliable and most harmless way, upon easily understood principles.”63As in any system

A Hierarchy of Healing: The Therapeutic Order of medicine, it is understood that medicine evolves with understanding. The roots of the observations that form this theory are traceable through the mid- and earlytwentieth century, to the traditional theory of nineteenth-century European nature cure, and to the roots and theories of traditional world medicines. Hippocrates' writings on the vis medicutrix nuturue form a foundation that historically underpin the development of this t h e ~ t - y . ~ , ~ ~ Finally, it is observable across many traditional world medicines that various healing orders are described.

Such structures hold implications for public and community health priorities and suggest the reprioritization of health care priorities and financing. Implications for public policy and the growing national disease debt invite exploration. Although this presentation is not comprehensive, the attempt has been made to demonstrate these roots, at least in some of their major articulations. The work presented here is a continuation of this historical process, which ultimately is driven by the true mission of the physician: to ease suffering and to preserve life.

1. Pizzomo J, Snider P. Naturopathic medicine. In Micozzi MS, ed. The fundamentals of complementary and alternative medicine. New York Churchill Livingstone, 2001. 2.Cody G. The history of naturopathic medicine. In Pizzorno J, Murray M, eds. Textbook of natural medicine. New York Churchill Livingstone, 1999. 3. Kirchfeld F, Boyle W. The nature doctors: pioneers in naturopathic medicine. Portland, OR Medicina Biologica, 1994. 4.Schramm A, ed. Yearbook of the International Society of Naturopathic Physicians and Emerson University Research Council. April 1945. 5. Tribe W. Personal communication, 1980. National College Professional survey. 6. Wendel P. Standardized naturopathy. Brooklyn, Ny: Paul Wendel, 1951. 7. Kirchfeld F, Boyle W. Nature doctors. East Palestine, O H Buckeye Naturopathic Press, 1994:202-208,258-260. 8. Freibott G. Report submitted to Lanso Cavasos, secretary of education, U.S. Department of Education, 1990. 9. Coulter H. Divided legacy: a history of the schism in medical thought. Washington DC:Wehawken Book Company, 1973. 10.Engel GL. The need for a new medical model a challenge for biomedicine. Science 1977;196129-136. 11. Lear L. Rachel Carson biography. Available online at h t t p : / / m . ruchelcarson.org/index.cfm?fuseuction=bio[accessed 20 June 20041. 12. Enrollment records. National College of Naturopathic Medicine. [accessed June 20,20041 13. Kirchfeld F, Boyle W. The nature doctors: pioneers in naturopathic medicine. Portland, OR Medicina Biologica 1994;310-312. 14.The future of naturopathic medical education-primary care integrative natural medicine: the healing power of nature. In Cronin M, ed. Best of naturopathic medicine: anthology 1996 celebrating 100 years of naturopathic medicine. Tempe, Az: Southwest College of Naturopathic Medicine Publications, 1996. 15. Snider P. Integration project survey results: report to the AANMC dean's council: 1999. Database: Snider l', Monwai M. 16. Standish L, Calabrese C, Snider l', et al. Naturopathic medical research agenda: report to NCCAM: Draft 5,2004. 17. Tilden JH. Toxemia explained: an antidote to fear, frenzy, and the popular mad chasing after so-called cures: the true interpretation of the cause of disease, how to cure is an obvious sequence. Rev. ed. Denver: FJ Wolf, 1926. 18. Trall R. The true healing art. New York Fowler & Wells, 1880. 19. Graham S. Greatest health discovery: natural hygiene & its evolution past, present & future.Chicago: Natural Hygiene Press, 1860. 20. Kellogg J. Rational hydrotherapy, ed 2. Philadelphia: FA Davis Co, 1903.

21. Kuhne L. Neo-naturopathy: the new science of healing or the doctrine of the unity of diseases. Butler, NJ: Benedict Lust, 1917. 22. Kuhne L. The science of facial expression: the new system of diagnosis, based on original researches and discoveries. Butler, NJ: Lust, 1917. 23. McFadden B. MacFadden's encyclopedia of physical culture, 5 volumes. New York Physical Culture Publishing, 1920. 24. Rikli A. Die Grunderhren der Naturheilkunde einschliesslich "Dia atmospharische Kure," "Es werde Licht" und "Abschiedsworte" (The Fundamental Doctrines of Nature Cure including "the Atmospheric Cure," "Let There Be Light" and "Words of Farewell"), ed 9. Wolfsberg: G. Rikli, 1911. 25. Tilden JH. Impaired health: its cause and cure-a repudiation of the conventional treatment of disease, ed 2. Denver: Tilden, 1921. 26. Dictionary of Occupational Titles, vol 1, ed 3. The United States Department of Labor, 1965. 27. Schram A. Acts and laws. Yearbook of the International Society of Naturopathic Physicians & Emerson University Research Council, 1948. 28.Lindlahr H. Nature cure: philosophy and practice based on the unity of disease and cure. Chicago: Nature Cure Publishing, 1913. 29. Spitler HR. Basic naturopathy, a textbook. New York American Naturopathic Association, 1948. 30. Wendel P. Standardized naturopathy. Brooklyn: Published by the author, 1951. 31. Kneipp S. Thus shalt thou live. Kempten, Bavaria: Koesel, 1889. 32.Kneipp S. My water cure. UK: Thorsons, 1979. Reprint of 1891 edition. 33. Kneipp S. My will. Kempten, Bavaria: Koesel, 1894. 34. Trall RT. Hydropathic encyclopedia: a system of hydropathy and hygiene. New York Fowlers & Wells, 1851. 35. Rausse JH. Der Geist der Graffenberger Wasserkur. Zeitz: Schieferdecker, 1838. 36. Rikli A. Die Thermodiatetik oder das tagliche thermoelectrische Licht und Luftbad in Verbindung mit naturfemasser Diat als zukunftige Heilmethode. Vienna: Braumueller, 1869. 37. Thomson S. A brief sketch of the causes and treatment of disease. Boston: EG House, 1821. 38. Beach W. A treatise on anatomy, physiology and health. New York Author, 1847. 39. Ellingwood F. American materia medica, therapeutics, and pharmacognosy. Evanston: Ellingwood's Therapeutist, 1919. 40. Felter H. The eclectic materia medica, pharmacology, and therapeutics. Cincinnati: John K Sadder, 1922. 41. Boyle W. The herb doctors. East Palestine, OH: Buckeye Naturopathic Press, 1988.

Philosophy of Natural Medicine 42. Bradley R. philosophy of naturopathic medicine. In Pizzorno J,

Murray M, eds.Textbook of natural medicine. New York Churchill Livingstone, 1985. 43. AANP House of Delegates Resolution. Rippling River, OR: 1989. 44.Select Committee on the Definition of Naturopathic Medicine, Snider F‘, Zeff J, cochairs. Definition of naturopathic medicine: AANP position paper. Rippling River, OR 1989. 45.Select Committee on the Definition of Naturopathic Medicine, AANP 1987-1989. Report submitted to AANP in 1988, final recommendation submitted to AANP house of delegates, September, 1989. 46.Snider P, Zeff J. Personal letters and communications, 1987-1989. 47.Zeff J. Convention theme: “what is a naturopathic physician?” AANP Q News 19883:1,11. 48. Snider F’, Zeff J. Definition of naturopathic medicine: first draft. AANP Q News 19889:6. 49. North American Association of Naturopathic Medical Colleges Integration Project Survey 1997-1999.P r e w report.October 26, 1999. Snider P, Zeff J, co-chairs. Mitchell M, Bastyr University Integration Project Student Task Force Chair. Monwai M, database and research assistant. 50. Snider F’, Zeff J. Integration project report on survey data and proposed principles of naturopathic medicine to the AANMC dean’s council, 1999. 51.The integration project update 2ooO: AANP house of delegates principles survey, presented by Mitchell M, IP student task force chair 1997-2000.Comments presented by Snider S, Zeff J, cochairs integration project 1996-2OOO. Monwai M, database manager. Saunders F, data analyst. 52. OKeefe M, Milliman B, Zeff J. Proposed new principles of naturopathic medicine: wehess, least force, relieve suffering. Submitted to the AANP house of delegates, 1996. 53. Resolution introduced in HOD regarding new principles: passed 2000 AANP convention, Seattle. The HOD recommended that the

discussion be moved to the academic community involved in clinical theory and practice for development. 54. Zeff J. The process of healing: a unifying theory of naturopathic medicine. J Naturopath Med 1997;l:lZ-126. 55. Snider P, Zeff J, Sensenig J, et al. Towards a unifying theory of naturopathic medicine. AANP plenary session. Portland, OR, 1996. 56. Snider P. Integration project: timeline, scope of work, goals, methods. Proposal adopted by CNMC 1996, readopted by AANMC 1997-1998. 57. CNME report from Bastyr University, 1999. Standard XI and appendices: curriculum. 58. AANMC dean’s council minutes and correspondence, 2OOO. 59. Snider P, Downey C, co-chairs. Invitation letter, supporting information, agenda, minutes, tools and materials. AANMC integration project retreat for naturopathic philosophy and clinical theory faculty, basic sciences chairs and clinic directors. August 20-21,2001. 60.Snider P, Payne S. Making naturopathic curriculum more naturopathic: agendas, minutes, 1999-2001. Clinic faculty task force on integration. Faculty development retreat, Bastyr University, 1999. 61. Hippocrates. The genuine works of Hippocrates. Adam F, trans. Baltimore: Williams & Wilkins, 1939. 62. Zeff J, Snyder P.Course syllabus: NM51 71, Naturopathic clinical theory. Seattle: Bastyr University, 1997-2005. 63. Hahnemann S. Organon of medicine. Philadelphia: Boericke & Tafel, 1922. 64. Boyle W, Saine A. Naturopathic hydrotherapy. East Palestine, O H Buckeye Naturopathic Press, 1988. 65. Pizzomo J. Total wellness. Rocklin, CA: Prima Publishing, 1996. 66. Snider P, Weeks J. Design principles for healthcare renewal 2002. Available online at wurw.thecoZZnboration.org [accessed June 4,20041. 67. Weeks J. Integrative medicine industry leadership summit 2001. Altem Ther Health Med 2002;8:S3-11.

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing George Wm. Cody, JD, MA CHAPTER CONTENTS Introduction 41 A Brief History of Early American Medicine with an Emphasis on Natural Healing 42 Medicine in America: 1800-1875 42 The American Influence 45 The Beginnings of “Scientific Medicine” 47 The New “Sects” 48

The Convergence with American Influences 55

Early Twentieth-Century Medicine 57 The Metamorphosis of Orthodox Medicine 57 The Halcyon Years of Naturopathy 58 The Emerging Dominance of American Medical Association Medicine 60 The Modern Rejuvenation 61

The Founding of Naturopathic Medicine 48 Benedict Lust 48 The Germanic Influence 53

INTRODUCTION Naturopathy, as a generally used term, began with the teachings and concepts of Benedict Lust. Naturopathy, or ”nature cure,” is both a way of life and a concept of healing that employs various natural means of treating human infirmities and disease states. The earliest mechanisms of healing associated with the term, as used by Lust, involved a combination of hygienics and hydropathy (hydrotherapy). The term itself was coined in 1895 by Dr. John Scheel of New York City to describe his method of health care. But earlier forerunners of these concepts had already existed in the history of natural healing, both in America and in the Austro-Germanic European core. Lust came to this country from Germany in 1892 as a disciple of Father Sebastian Kneipp, a Domenican priest, and as a missionary dispatched by Kneipp to bring hydrotherapy to America. Lust purchased the term ”naturopathy” from Scheel in 1902 to describe the eclectic compilation of doctrines of natural healing that he envisioned to be the future of natural medicine. In January 1902, Lust, who had been publishing the Kneipp Water Cure Monthly and its German language counterpart in New York since 1896, changed the name of the journal

to The Nuturopathic and Herald of Health and evoked the dawn of a new health care era with the following editorial: Naturopathy is a hybrid word. It is purposely so. No single tongue could distinguish a system whose origin, scope and purpose is universal-broad as the world, deep as love, high as heaven. Naturopathy was not born of a sudden or a happen-so. Its progenitors have for eons been projecting thoughts and ideas and ideals whose culminations are crystallized in the new Therapy. Connaro, doling out his few fixed ounces of food and drink each day in his determined exemplification of Dietotherapy; Priessnitz, agonizing, despised and dejected through the long years of Hydropathy’s travail; the Woerishofen priest, laboring lovingly in his little parish home for the thousands who journeyed Germany over for the Kneipp cure; Kuhne, living vicariously and dying a martyr for the sake of Serotherapy;A.T. Still, studying and struggling and enduring for his faith in Osteopathy; Bemarr Macfadden, fired by the will to make Physical Culture popular; Helen Willmans, threading the mazes of Mental science, and finally emerging triumphant; Orrison Sweet Maraden, throbbing in sympathy with human faults and failures, and longins to realize Success to all mankind-these and hosts of others have brought into being single systems whose focal features are perpetuated in Naturopathy.

41

Philosophy of Natural Medicine Jesus Christ-I say it reverently-knew the possibility of physical immortality. He believed in bodily beauty; He founded Mental Healing; He perfected Spirit-power. And Naturopathy will include ultimately the supreme forces that made the Man of Galilee omnipotent. The scope of Naturopathy is from the first kiss of the newfound lovers to the burying of the centenarian whose birth was the symbol of their perfected one-ness. It includes ideally every life-phase of the id, the embryo, the foetus, the birth, the babe, the child, the youth, the man, the lover, the husband, the father, the patriarch, the soul. We believe in strong, pure, beautiful bodies thrilling perpetually with the glorious power of radiating health. We want every man, woman and child in this great land to know and embody and feel the truths of right living that mean conscious mastery. We plead for the renouncing of poisons from the coffee, white flour,glucose, lad,and like venom of the American table to patent medicines, tobacco, liquor and the other inevitable recourse of perverted appetite. We long for the time when an eight-hour day may enable every worker to stop existing long enough to live; when the spirit of universal brotherhood shall animate business and society and the church; when every American may have a little cottage of his own, and a bit of ground where he may combine Aerotherapy, Heliotherapy, Geotherapy, Aristophagy and nature’s other forces with home and peace and happiness and things forbidden to flat-dwellers; when people may stop doing and thinking and being for others and be for themselves; when true love and divine marriage and prenatal culture and controlled parenthood may fill thisworld with germ-gods instead of humanized animals. In a word, Naturopathy stands for the reconciling, harmonizing and urufylng of nature, humanity and God. Fundamentally therapeutic because men need healing; elementally educational because men need teaching; ultimately inspirational because men need empowering, it encompasses the realm of human progress and destiny. Perhaps a word of appreciation is due Mr. John H. Scheel, who first used the term ”Naturopathic” in connection with his Sanitarium ”Badekur,” and who has courteously allowed us to share the name. It was chosen out of some 150 submitted, as most comprehensive and enduring. All our present plans are looking forward some five or ten or f&y years when Naturopathy shall be the greatest system in the world. Actually the present development of Naturopathy is pitifully inadequate, and we shall from time to time present plans and ask suggestions for the surpassing achievement of our worldwide purpose. Dietetics, Physical Culture and Hydropathy are the measures upon which Naturopathy is to build; mental culture is the means, and soul-selfhood is the motive. If the infinite immensity of plan, plea and purpose of this particular magazine and movement were told you, you would simply smile in your condescendingly superior way and straightway forget. Not having learned as yet what a brain and imagination and a will can do, you consider Naturopathy an ordinarily innocuous affair, with a lukewarm purpose back of it, and an ebbing future ahead of it. Such is the character of the average wishy-washy health movement and tumultuous wave of reform. Your incredulous smile would not discomfit us-we do not importune your belief, or your help, or your money. Wherein we

differ from the orthodox self-labeled reformer, who cries for sympathy and cringes for shekels. We need money most persistently-a million dollars could be used to advantage in a single branch of the work already definitely planned and awaiting materialization; and we need co-operation in a hundred different ways. But these are not the things we expect or deem best. Criticism, fair, full and unsparing is the one thing of value you can give this paper. Let me explain. Change is the keynote of this January issue-in form, title, make-up. If it please you, your subscription and a word to your still-benighted friends is ample appreciation. But if you don’t like it, say so. Tell us wherein the paper is inefficient or redundant or ill-advised, how it will more nearly fit into your personal needs, what we can do to make it the broadest, deepest, truest, most inspiring of the mighty host of printed powers. The most salient letter of less than 300 words will be printed in full, and we shall ask to present the writer with a subscription-receipt for life. By to-morrow you will probably have forgotten this request; by the day after you will have dropped back into your old ways of criminal eating and foolish drinking and sagged standing and congested sitting and narrow thinking and deadly fearing-until the next progress paper of New Thought or Mental Science or Dietetics or Physical Culture prods you into momentary activity. Between now and December we shall tell you just how to preserve the right attitude, physical and mental, without a single external aid; and how, every moment of every day, to tingle and pulsate and leap with the boundless ecstasy of manhood consciously nearing perfection.

A BRIEF HISTORY OF EARLY AMERICAN MEDICINE WITH AN EMPHASIS ON NATURAL HEALING To understand the evolutionary history of naturopathic medicine in this country, it is necessary to view the internal development of the profession against the historical, social, and cultural backdrop of American social history.

Medicine in America: 1800-1875 In the America of 1800, although a professional medical class existed, medicine was primarily domestically oriented. An individual who fell ill was commonly nursed by a friend or family member who relied upon William Buchan’s Domestic Medicine (1769), John Wesley‘s Primitive Physic (1747, or John G m ’ s DomesficMedicine (1830).’

Professional Medicine Professional medicine transferred from England and Scotland to America in prerevolutionary days. However, eighteenth- and early nineteenth-century America considered the concept of creating a small, elite, learned profession to run counter to the political and institutional concepts of early American dem0cracy.l The first medical school in the American colonies was opened in 1765 a t what was then the College of

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

Philadelphia (later the University of Pennsylvania), and the school came to be dominated by revolutionary leader and physician Benjamin Rush, a signatory to the Declaration of Independence. The proliferation of medical schools to train the new professional medical class began seriously after the war of 1812. Between 1810 and 1820, new schools were established in Baltimore, Lexington, Cincinnati, and even rural communities in Vermont and Western New York. Between 1820 and 1850 a substantial number of schools were established in the western rural states. By 1850 there were 42 medical schools recognized in the United States, although there were only three in all of France. Generally, these schools were started by a group of five to seven local physicians approaching a local college with the idea of establishing a medical school in conjunction with the college’s educational facilities. The schools were largely apprenticeship based, and the professors received their remuneration directly from fees paid by the students. The requirements for a Doctor of Medicine (MD) degree in late eighteenth- and early nineteenth-century America were roughly as follows: Knowledge of Latin, natural and experimental philosophy 3 years of serving an apprenticeship under practicing physicians Attending of two terms of lectures and passing of attendant examinations A thesis Graduating students had to be at least 21 years of age.’ The rise of any professional class is gradual and marked by difficulties, and varying concepts existed as to the demarcation of a “professional” physician. Contrasts included: graduates of medical school versus nongraduates, medical society members versus nonmembers, and licensed physicians versus unlicensed “doctors.” Licensing statutes came into existence between 1830 and 1850 but were soon repealed, as they were considered ”undemocratic” during the apex of Jacksonian democracy.’

Thomsonianism In 1822 the rise in popularity of Samuel Thomson and his publication of New Guide to Health helped to frustrate the creation of a professional medical class. Thomson’s work was a compilation of his personal view of medical theory and American Indian herbal and medical botanical lore. Thomson espoused the belief that disease had one general cause-“cold” influences on the human body-and that disease had therefore one general remedy-”heat.” Unlike the followers of Benjamin Rush and the American ”heroic” medical tradition who advocated blood-letting, leeching, and the substantial use of

mineral-based purgatives such as antimony and mercury, Thomson believed that minerals were sources of “cold” because they come from the ground and that vegetation, which grew toward the sun, represented “heat.”’ As noted in Griggs’ Green Pharmacy (the best history of herbal medicine to date), Thomson’s theory developed as follows? Instead, he elaborated a theory of his own, of the utmost simplicity: ”Alldiseases. . . are brought about by a decrease or derangement of the vital fluids by taking cold or the loss of animal warmth. . . the name of the complaint depends upon what part of the body has become so weak as to be affected. If the lungs, it is consumption, or the pleura, pleurisy; if the limbs, it is rheumatism, or the bowels, colic or cholera morbus . . . all these different diseases may be removed by a restoration of the vital energy, and removing the obstructions which the disease has generated . . .” Thus the great object of his treatment was always to raise and restore the body’s vital heat: “All . . . that medicine can do in the expulsion of disorder, is to kindle up the decaying spark, and restore its energy till it glows in all its wonted vigor.”

Thomson’s view was that individuals could be selftreating if they had a sincere understanding of his ”new guide to health philosophy and a copy of his book, New Guide to Health. The right to sell “family franchises” for use of the Thomsonian method of healing was the basis of a profound lay movement between 1822 and Thomson’s death in 1843. Thomson adamantly believed that no professional medical class should exist and that democratic medicine was best practiced by laypersons within a Thomsonian ”family” unit. By 1839 Thomson claimed to have sold some 100,000 of these family franchises called ”friendly botanic societies.” Although he professed to have solely the interests of the individual at heart, his system was sold at a profit under the protection of a patent he had obtained in 1813.

The Eclectic School of Medicine Some of the ”botanics” (professionalThomsonian doctors) wanted to separate themselves from the lay movement by creating requirements and standards for the practice of Thomsonian medicine. Thomson, however, was adamantly against a medical school founded on his views. Thus it was not until the decade after Thomson’s death that independent Thomsonians founded a medical college (in Cincinnati) and began to dominate the Thomsonian movement. These Thomsonian botanics were later absorbed into the medical sectarian movement known as the ”eclectic school,” which originated with the New Yorker Wooster Beach. Beach was another of medical history’s fascinating characters. From a well-established New England family, he started his medical studies at an early age, apprenticing under an old German herbal doctor, Jacob Xdd.

After Tidd died, Beach enrolled in the Barclay Street Medical University in New York. Griggs2 wrote the following: Beach’s burning ambition was to reform medical practice generally-not to alienate the entire profession by savage attacks from without-and he was convinced that he would be in a stronger position to do so if he were himself a diplomatized doctor. The faculty occasionally listened to criticism from within their own number: against onslaughts of “illiterate quacks” like Samuel Thornson, they simply closed ranks in complacent hostility.

After opening his own practice in New York, Beach set out to win over fellow members of the New York Medical Society (into which he had been wannly introduced by the screening committee) to his point of view that heroic medicine was inherently dangerous to mankind and should be reduced to the gentler theories of herbal medicine. He was summarily ostracized from the medical society. To Beach this was a bitter blow, but he soon founded his own school in New York, calling the clinic and educational facility “The United States Infirmary.” However, due to continued pressure from the medical society, he was unable to obtain charter authority to issue legitimate diplomas. He then located a financially ailing but legally chartered school, Worthington College, in Ohio. He opened a full-scale medical college; out of its classrooms he launched what became known as the eclectic school of medical theory. Griggs related the following? Beach had a new name for his practice: While explaining to a friend his notions of combining what was useful in the old practice with what was best in the new, the friend exclaimed, “You are an eclectic!” to which, according to legend, Beach replied, “You have given me the term which I have wanted: I am an eclectic!”

Cincinnati subsequently became the focal point of the eclectic movement, and the medical school remained until 1938 (the last eclectic school to exist in America).’ The philosophies of the sect helped to form the theoretical underpinnings of Lust’s naturopathic school of medicine. Despite his criticism of the early allopathic medical movement (although the followers of Rush were not as yet known by this term, reputed to have been coined by Samuel Hahnemann) for their “heroic” tendencies, Thomson’s medical theories were “heroic” in their own fashion. Although he did not advocate blood-letting, heavy metal poisoning, and leeching, botanic purgatives-particularly Lobelia inflllta (Indian tobacco)-were a substantial part of the therapy.

The Hygienic School of Thought One other forerunner of American naturopathy, also originating as a lay movement, grew into existence at

this time. This was the ”hygienic” school, which had its genesis in the popular teachings of Sylvester Graham and William Alcott. Graham began preaching the doctrines of temperance and hygiene in 1830. In 1839he published Lectures on the Science of Human Lqe, two hefty volumes that prescribed healthy dietary habits. He emphasized a moderate lifestyle, recommending an antiflesh diet and bran bread as an alternative to bolted or white bread. Alcott dominated the scene in Boston during this same period and, together with Graham, saw that the American hygienic movement-at least as a lay doctrine-was well e~tablished.~

Homeopathy By 1840 the profession of homeopathy had also been transplanted to America from Germany. Homeopathy, the creation of an early German physician, Samuel Hahnemann (1755-1843))had three central doctrines:

..

The “law of similars” (that like cures like) That the effect of a medication could be heightened by its administration in minute doses (the more diluted the dose, the greater the “dynamic” effect) That nearly all diseases were the result of a suppressed itch, or ”psora”

The view was that a patient’s natural symptomproducing disease would be displaced after homeopathic medication by a similar, but much weaker, artificial disease that the body’s immune system could easily overcome. Originally, most homeopaths in this country were converted orthodox medical men, or “allopaths.” The high rate of conversion made this particular medical sect the arch-enemy of the rising orthodox medical profession. (For a more detailed discussion of homeopathy, see Chapter 39.) The first homeopathic medical school was founded in 1850 in Cleveland; the last purely homeopathic medical school, based in Philadelphia, survived into the early 1930s.’

The Rise and Fall of the Sects Although these two nonallopathic sects were popular, they never comprised more than one fifth of the professional medical class in America. Homeopathy at its highest point reached roughly 15%, and the eclectic school roughly 5%. However, their very existence for many years kept the exclusive recognition desired by the orthodox profession from coming within its grasp. Homeopathy was distasteful to the more conventional medical men not only because it resulted in the conversion of a substantial number of their peers, but also because homeopaths generally also made a better income. The rejection of the eclectic school was more

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

fundamental: It had its roots in a lay movement that challenged the validity of a privileged professional medical class. The existence of three professional medical groupsthe orthodox school, the homeopaths, and the eclecticscombined with the Jacksonian view of democracy that prevailed in mid-nineteenth century America, resulted in the repeal of virtually all medical licensing statutes existing before 1850.But by the 1870s and 1880s, all three medical groups had begun to voice support for the restoration of medical licensing. Views differ as to what caused the homeopathic and eclectic schools to disappear from the medical scene in the 50 years following 1875. One view defines a sect as follows4: A sect consists of a number of physicians, together with their professional institutions, who utilize a distinctive set of medically invalid therapies which are rejected by other sects. . .

By this definition, the orthodox or allopathic school was just as sectarian as the homeopathic and eclectic schools. Rothstein’s view is that these two nineteenthcentury sects disappeared because, beginning in the 1870s, the orthodox school grasped the European idea of ”scientific medicine.” Based on the research of such men as Pasteur and Koch and the ”germ theory,” this approach supposedly proved to be the medically proper view of valid therapy and gained public recognition because of its truth. Another view is that the convergence of the needs of the three sects for professional medical recognition (which began in the 1870s and continued into the early 1900s)and the ”progressive era’’ led to a political alliance in which the majority orthodox school ultimately came to be dominant by sheer weight of numbers and internal political authority. Starr’ noted the following: Both the homeopaths and eclectics wanted to share in the legal privileges of the profession. Only afterward did they lose their popularity. When homeopathic and eclectic doctors were shunned and denounced by the regular profession, they thrived, but the more they gained an access to the privileges of regular physicians, the more their numbers declined. The turn of the century was both the point of acceptance and the moment of incipient disintegration. . .

In any event, this development was an integral part of the drive toward professional authority and autonomy established during the progressive era (1900-1917). It was acceptable to the homeopaths and the eclectics because they controlled medical schools that continued to teach and maintain their own professional authority and autonomy. However, it was after these professional goals were attained that the lesser schools of medical thought went into rapid decline.’

The American Influence From 1850 through 1900, the medical counterculture continued to establish itself in America. From its lay roots in the teachings of the hygienic movement grew professional medical recognition, albeit a small minority and “irregular” view, that hygiene and hydropathy were the basis of sound medical thought (much like the Thomsonian transition to botanic and eclectic medicine).

Trall The earliest physician who came to have a significant impact on the later growth of naturopathy as a philosophical movement was Russell Trall, MD. As noted in Whorton’s Crusaders for Fitness? he “passed like a meteor through the American hydropathic and hygienic movement”: The exemplar of the physical educator-hydropath was Russell Thatcher Trall. Still another physician who had lost his faith in regular therapy, Trall opened the second water cure establishment in America, in New York City in 1844. Immediately he combined the full Preissnitzian armamentarium of baths with regulation of diet, air, exercise and sleep. He would eventually open and or direct any number of other hydropathic institutions around the country, as well as edit the Water-Cure Journal, the Hydropathic R&, and a temperance journal. He authored several books, including popular sex manuals which perpetuated Graham-like concepts into the 1890’s, sold Graham crackers and physiology texts at his New York office, was a charter member (and officer) of the American Vegetarian Society, presided over a short-livedWorld Health Association, and so on. His crowning accomplishment was the Hygeian Home, a “model Health Institution [which] is beautifully situated on the Delaware River between Trenton and Philadelphia.”A drawing presents it as a palatial establishment with expansive grounds for walking and riding, facilities for rowing, sailing, and swimming, and even a grove for open-air ”dancing gymnastics.” It was the grandest of water cures, and lived beyond the Civil War period, which saw the demise of most hydropathic hospitals. True, Trall had to struggle to keep his head above water during the 1860’~~ but by the 1870’s he had a firm financial footing (being stabilized by tuition fees from the attached Hygeiotherapeutic College). With Trall’s death in 1877, however, the hydropathic phase of health reform passed.

As evident later in this chapter, this plethora of activity is similar to that engaged in by Benedict Lust between 1896 and his death in 1945, when he worked to establish naturopathic medicine. The Hygeian Home and later “Yungbom”establishmentsat Butler, NJ,and Tangerine, FL, were similar to European nature cure sanitariums, such as the ori@ Yungbom founded by Adolph just and the spa/sanitarium facilities of Preissnitz, Kneipp, and Just. Trall gave a famous address to the Smithsonian Institution in Washington, D.C., in 1862, under the sponsorship of the Washington Lecture Association. ”The true healing art: or hygienic vs drug medication,” a 2.5-hour

lecture purported to have received rapt attention, was devoted to Trall’s belief in the hygienic system and in hydropathy as the true healing art. The address was reprinted by Fowler and Wells (New York, 1880) with an introduction written by Trall, before his death in 1877. Trall also founded the first school of natural healing arts in this country to have a Cyear curriculum and the authorization to confer the degree of MD. It was founded in 1852 as a “hydropathic and physiological school” and was chartered by the New York State Legislature in 1857 under the name “New York HygioTherapeutic College,” with the legislature’s authorization to confer the MD degree. In 1862 Trall went to Europe to attend the International Temperance Convention. At this meeting of reformers, he took prominent part, specifically relating to the use of alcohol as a beverage and as a medicine. He eventually published more than 25 books on the subjects of physiology, hydropathy, hygiene, vegetarianism, and temperance, among many others. The most valuable and enduring of these was his Hydrqathic Encyclopedia, a volume of nearly 1000 pages that covered the theory and practice of hydropathy and the philosophy and treatment of diseases advanced by older schools of medicine. At the time of his death, according to the December 1877 Phrenological Journal cover article featuring a lengthy obituary of Trall, this encyclopedia had sold more than 40,000 copies since its original publication in 1851. For more than 15 years, Trall was editor of the WaterCure Journal (also published by Fowler and Wells). During this period, the journal went through several name changes including the Hygienic Teacher and The Herald of Health. When Lust originally opened the American School of Naturopathy, an English-language version of Kneipp’s Water-cure (or in German Meine Wasser-kurr)being unavailable, he used only the works and writings of Trall as his texts. By 1871 Trall had moved from New York to the Hygeian Home on the Delaware River. His water-cure establishment in New York became The New Hygienic Institute. One of its coproprietors was Martin Luther Holbrook, who later replaced Trall as the editor of The Herald ofHealth. Professor Whorton noted the following? But Holbrook‘s greatest service to the cause was as an editor. In 1866 he replaced Trall at the head of The Herald of Health, which had descended from the Water-Cure Journal and Herald ofR.$orms (1845-1861)by the way of the Hygienic Teacher and Water-Cure Journal (1862). Under Holbrook’s direction the periodical would pass through two more name changes (Journal ofHygiene Herald ofHealth, 1893-1897, and Omega, 18981900)before merging with Physical Culture.

Trall and Holbrook both advanced the idea that physicians should teach the maintenance of health

rather than simply provide a last resort in times of health crisis. Besides providing a strong editorial voice espousing vegetarianism, the evils of tobacco and drugs, and the value of bathing and exercise, dietetics and nutrition along with personal hygiene were strongly advanced by Holbrook and others of the hygienic movement during this era. Whorton described the idea as follows3: The orthodox hygenists of the progressive years were equally enthused by the recent progress of nutrition, of course, and exploited it for their own ends, but their utilization of science hardly stopped with dietetics. Medical bacteriology was another area of remarkable discovery, bacteriologists having provided, in the short space of the last quarter of the 19th century, an understanding, at long last, of the nature of infection. This new science’s implications for hygienic ideology were profound-when Holbrook locked horns with female fashion, for example, he did not attack the bulky, ground-length skirts stiU in style with the crude Grahamite objection that the skirt was too heavy. Rather he forced a gasp from his readers with an account of watching a smartly dressed lady unwittingly drag her skirt ”over some virulent, revolting looking sputum, which some unfortunate consumptive had expectorated.”

Holbrook expanded on the work of Graham, Alcott, and Trall and, working with an awareness of the European concepts developed by Preissnitz and Kneipp, laid further groundwork for the concepts later advanced by Lust, Lindlahr, and others3: For disease to result, the latter had to provide a suitable culture medium, had to be susceptible. As yet, most physicians were still so excited at having discovered the causative agents of infection that they were paying less than adequate notice to the host. Radical hygienists, however, were bent just as far in the other direction. They were inclined to see bacteria as merely impotent organisms that throve only in individuals whose hygienic carelessness had made their body compost heaps. Tuberculosis is contagious, Holbrook acknowledged, but “the degree of vital resistance is the real element of protection. When there is no preparation of the soil by heredity, predisposition or lowered health standard, the individual is amply guarded against the attack.” A theory favored by many others was that germs were the effect of disease rather than its cause; tissues corrupted by poor hygiene offered microbes, all harmless, an environment in which they could thrive.

In addition to introducing the works of Kneipp and his teachings to the American hygienic health care movement, Holbrook was a leader of the fight against vivisection and vaccination3: Vivisection and vaccination were but two of the practices of medicine criticized in the late 19th century. Therapy also continued to be an object of protest. Although the heroism of standard treatment had declined markedly since mid-century, a prescription was still the reward of any visit to the doctor, and drugless alternatives to healing were appearing in protest. Holbrook published frequent favorable commentaries on the revised water cure system of Germany‘s Kneipp. A combination

The History of Naturopathic Medicine, Part I:The Emergence of an American School of Healing of baths, herbal teas, and hardening exercises, the system had some vogue in the 1890’s before flowering into naturopathy. Holbrook’s journal also gave positive notices to osteopathy and “chiropathy” [chiropractic],commending them for not going to the “drugstore or ransack[ing] creation for remedies nor load[ing]the blood with poison.” But though bathing and musculoskeletal manipulation were natural and nonpoisonous, Holbrook preferred to give the body complete responsibility for healing itself. Rest and proper diet were the medicines of this doctor who billed himself as a “hygienic physician” and censured ordinary physicians for being engrossed with disease rather than health.

The Beginnings of “Scientific Medicine” While the hygienic movement was making its impact, the orthodox medical profession, in alliance with the homeopaths and eclectics, was making sigruficant advances. The orthodox profession, through the political efforts of the American Medical Association (AMA), had first tried to remove sectarian and irregular practitioners by segregating them from the medical profession altogether. It did so by formulating and publishing its first national medical code of ethics in 1847. (In 1846 the orthodox profession formed the AMA to represent their professional views.) The code condemned proprietary patents (even carrying over into a physician’s development of surgical or other medical implements, which led to its greatest criticism); encouraged the adoption of uniform rules for payment in geographic areas; condemned the practice of contract work; prohibited advertising and fee-sharing even among specialists and general practitioners; eliminated blacks and women; and, most significantly,prohibited any consultation or contact with irregulars or sectarian practitioners. The code stated the following? No one can be considered as a regular practitioner, or a fit associate in consultation, whose practice is based on an exclusive dogma, to the rejection of the accumulated experience of the profession, and of the aids actually furnished by anatomy, physiology,pathology, and organic chemistry. In the late 1870s and into the 1880s, the major sectsthe orthodox or allopathic school, the homeopaths, and the eclectics-began to find more reason to cooperate to obtain common professional goals. These included the enactment of new licensing laws and the creation of a “respectable” medical educational system. Also at this time, the concept of “scientificmedicine” was brought to America. (Although Starr differs from Rothstein about the cause of the death of the homeopathic and eclectic sectarian schools, he notes that Rothstein clearly documents the transition, during the nineteenth century, of medicine to a recognized professional class composed of both the minority sects and the orthodox school.) This transition from conflict between the major sects resulted in the erosion of the implementation of the code of ethics, the cooperation among the sects to revive

medical licensing standards, the admission of sectarian physicians to regular medical societies, and, ultimately, a structural reorganization of the AMA, which occurred between 1875 and 1903.l” Once the cooperation among the three medical views had begun, the medical class as dominated by the regular school came fully into power. And the homeopathic and eclectic schools of thought met their demise, which was finally brought about by two significant events: (1)the rapid creation of new medical educational standards between 1900 and 1910, culminating in the publication of the famous “Flexner Report” (1910), and (2) the effective infusion of millions of dollars into selected allopathic medical schools by the newly created capitalistic philanthropic foundations, principally the Carnegie and Rockefeller foundations.

The Foundations The impact of the monies from the Carnegie and Rockefeller foundations has been clearly documented6 and is described in detail, albeit for the advancement of a particular political point of view, in Brown’s Rockefeller Medicine Men. The impact of the monies from these foundations, as contributed to medical schools that met the AMA‘s view of medical education and philosophy, cannot be underestimated. As disThis process has been well cussed by Burrows,(rthis educational reform allowed the AMA to form a new alliance with legislators and push quickly for medical licensing designed to reward the educational and medical expertise of the new orthodox “scientific medicine” and the exclusion of all others.s

Medical Education in Transition Based on the rising example of scientific medicine and its necessary connection to research, the educational laboratory, and a more thorough scientific education as a preamble to medical practice, Harvard University (under the presidency of Charles Elliott) created a 4-year medical educational program in 1871. The primal modern medical educational curriculum was devised and set in motion more than 20 years later at Johns Hopkins University under the leadership of William Osler and William Welch, using the resources from the original endowment of the hospital and university from the estate of Johns H0pkins.l Other schools followed suit. By the time the AMA set up its Council on Medical Education in 1904, it was made up of five members from the faculties of schools modeled on the Johns Hopkins prototype. This committee set out to visit and rate each of the 160 medical schools then in operation in the country. The ratings used were class “ A (acceptable), class “B” (doubtful), and class ”C” (unacceptable).

Eighty-two schools received a class " A rating, led by Harvard, Rush (Chicago), Western Reserve, the University of California and, notably, Johns Hopkins. Forty-six schools received a class "B" rating, and tlurtytwo a class "C"rating. The class "C" schools were mostly in rural areas, and many of them proprietary in nature.

Flexner Report Subsequent to the AMA ratings, the Council on Medical Education applied to the Carnegie Foundation to commission an independent report to verify its work. Abraham Flexner, a young, energetic, and noted educator, was chosen for this task by the Carnegie Foundation and accompanied by the secretary (Nathan Colwell, MD) of the Council on Medical Education, who had participated in all of the committee site visits. Flexner visited each of the 162 US. medical schools then operating. The widely publicized Flexner Report put the nails in the coffins of all schools with class "C" ratings and many with class " B ratings. SigIuiicantly, the educational programs of all but one eclectic school (in Cincinnati)and one homeopathic school (in Philadelphia) were eliminated by 1918. The eclectic medical schools, in particular, were severely affected by the report. Griggs explained this effect as follows2: Of the eight Eclectic schools, the Report declared that none had "anythmg remotely resembling the laboratory equipment which is claimed in their catalogs."Three of them were underequipped; the rest "are without exception filthy and almost bare. They have at best grimy little laboratories. . . a few microscopes, some bottles containing discolored and unlabeled pathological material, in an incubator out of commission, and a horrid disseding room.''The Report found them more culpable than a regular school for these inadequacies: ". . . the Eclectics are drug-mad; yet, with the exception of the Cincinnati and New York schools, they are not equipped to teach the drugs or drug therapy which constitutestheir sole reason for existence."

The other regular schools that had conducted homeopathic or eclectic programs had by that time phased them out in the name of "scientific medicine."

Pharmaceutical Industry During this same time period, the AMA, through several of its efforts, began a significant alliance with the organized pharmaceutic industry of the United States, shaping it in a manner acceptable to the allopathic profe~sion.',',~

The New "Sects" The period from 1890-1905 saw the rise of three new medical sects and several other smaller "irregular" schools, which replaced those soon to pass away. In Missouri, Andrew Taylor Still, originally trained as an orthodox practitioner, founded the school of medical

thought known as "osteopathy" and in 1892 opened the American School of Osteopathy in Kirksville, MO. In 1895 Daniel David Palmer, originally a magnetic healer from Davenport, IA, performed the first spinal manipulation, which gave rise to the school he termed "chiropractic." He formally published his findings in 1910, after having founded a chiropractic school in Davenport, IA. And in 1902 Lust founded the American School of Naturopathy in New York. Although some of the following discussion are devoted to the schools of healing called osteopathy and chiropractic, only that portion of their histories related to the history of naturopathy is mentioned.1° (A full study of osteopathic medicine in America may be found in The D.0.sby Gevitz," and a reasonable sketch of chiropractic medicine may be found in Kapling's chapter in Al temative Medicine. lo) As noted by Starr,' these new sects, including Christian Science, formulated by Mary Baker Eddy (see SilbergerI2for further discussion), either rose or fell on their own without ever completely allying with orthodox medicine. Starr theorized that these sects arose late enough that the orthodox profession and its political action arm, the AMA, had no need to ally with them and would rather battle with them publicly. This made these sectarian views separate and distinct from the homeopathic and eclectic schools.

THE FOUNDING OF NATUROPATHIC MEDICINE Benedict Lust Lust came to the United States in 1892 at the age of 23. He had suffered from a debilitating condition in his late teens while growing up in Michelbach, Baden, Germany, and had been sent by his father to undergo the Kneipp cure at Woerishofen. He stayed there from mid-1890 to early 1892; not only was he "cured" of his condition, but he also became a protbgk of Kneipp. Dispatched by Kneipp to bring the principles of the Kneipp water cure to America, he emigrated to New York City. By making contact in New York with other German Americans who were also becoming aware of the Kneipp principles, Lust participated in the founding of the first "Kneipp Society," which was organized in Jersey City, NJ, in October 1896. Lust also attended the first organizational meeting (in mid-October 1896) of the Kneipp Society of Brooklyn. Subsequently, through Lust's organization and contacts, Kneipp Societies were founded in Boston; Chicago; Cleveland; Denver; Cincinnati; Philadelphia; Columbus; Buffalo and Rochester, NY; New Haven, CT; San Francisco; New Mexico; and Mineola on Long Island, NY. The members of these organizations were provided with copies of the Kneipp Blatter and a companion

English publication Lust began to put out called The Kneipp Water Cure Monthly. The first “sanatorium” using Kneipp’s principles was organized in this country shortly before Lust’s arrival. Charles Lautenvasser, an earlier student of Kneipp‘s who called himself a hydrophic physician and natural scientist, opened the Kneipp and Nature Cure Sanatorium in Newark, NJ, in 1891. In 1895 the Brooklyn Light and Water-Cure Institute was established in Brooklyn, NY,by L. Staden and his wife Carola, both graduates of Lindlahr’s Hygienic College in Dresden, Germany. According to their advertising, they specialized in natural healing, Kneipp water treatment, Kuhne’s and Preissnitz’s principles (including diet cure, electric light baths [both white and blue], electric vibration massage, Swedish massage and movements, and Thure-brandt massage). In 1895 Lust opened the Kneipp Water-Cure Institute in New York City, listing himself as the owner and Dr.William Steffens as the residing physician. At the same address (on 59th Street) in October of that year, Lust opened the first “Kneipp store.” In the originating November 1896 edition of The Kneipp Water Cure Monthly and Kneipp Blutter, he advertised his store and sanitarium as personally authorized by Kneipp. In the first part of 1896, just before his organizing of various Kneipp Societies around the New York area, Lust returned to Woerishofen to study further with Kneipp. Kneipp died in Germany, at Woerishofen, in June 1897. With his passing, Lust was no longer bound strictly to the principles of the Kneipp water cure. He had begun to associate earlier with other GermanAmerican physicians, principally Dr. Hugo R. Wendel (a German-trained Nutururzt), who began, in 1897, to practice in New York and New Jersey as a licensed osteopathic physician. In 1896 Lust entered the Universal Osteopathic College of New York, graduated in 1898, and became licensed as an osteopathic physician. In 1897 Lust became an American citizen. Once he was licensed to practice as a health care physician in his own right, Lust began the transition toward the concept of “naturopathy.” Between 1898 and 1902, when he adopted the term ”naturopath,” Lust acquired a chiropractic education and changed the name of his Kneipp store to Health Food Store (the original facility to use that name and concept in this country), specializing in providing organic foods and the materials necessary for drugless cures. He also began the New York School of Massage (listed as established in 1896) and the American School of Chiropractic, all within the same facility-Lust’s Kneipp Institute. Photographs of this facility taken between 1902 and 1907, when the facility moved to another location, show a five-story building listing “Benedict Lust-Naturopath, Publisher, Importer.”

He returned to Germany in 1907 to visit with Dr. Baumgarten, Kneipp’s medical successor at the Woerishofen facility, which was then run,in cooperation with Baumgarten, by the Reverend Prior Reily, the former secretary to Kneipp and his lay successor at Woerishofen. As directed by Kneipp, Reily had completed, after Kneipp’s death, Kneipp’s master work Dus grosse Kneipp-Buch. Lust maintained contact with the partnership of Reily and Baumgarten throughout the early part of the twentieth century. In 1902, when he purchased and began using the term naturopathy and calling himself a “naturopath,” Lust, in addition to his New York School of Massage and American School of Chiropractic, his various publications, and his operation of the Health Food Store, began to operate the American School of Naturopathy, all at the same 59th Street address. By 1907, Lust’s enterprises had grown sufficiently large that he moved them to a 55-room building. It housed the Naturopathic Institute, Clinic and Hospital; the American Schools of Naturopathy and Chiropractic; the now entitled Original Health Food Store; Lust’s publishing enterprises; and New York School of Massage. The operation remained in this four-story building, roughly twice the size of the original facility, from 1907 to 1915. From 1912 through 1914, Lust took a “sabbatical” from his operations to further his education. By this time he had founded his large estatelike sanitarium in Butler, NJ, known as “Yungborn” after the German sanitarium operation of Adolph Just. In 1912 he attended the Homeopathic Medical College in New York, which, in 1913, granted him a degree in homeopathic medicine and, in 1914, a degree in eclectic medicine. In early 1914, Lust traveled to Florida and obtained an MD’s license on the basis of his graduation from the Homeopathic Medical College. Thereafter he founded another “Yungborn” sanitarium facility in Tangerine, FL, and for the rest of his life, while continuing his publications, engaged in active lecturing. He also continued to maintain a practice in New York City and operated the sanitariums in Florida and New Jersey. His schools were operated by Hugo R. Wendel. From 1902, when he began to use the term naturopathy, until 1918, Lust replaced the Kneipp Societies with the Naturopathic Society of America. Then, in December 1919, the Naturopathic Society of America was formally dissolved due to its insolvency and Lust founded the American Naturopathic Association. Thereafter 18 states incorporated the association. In 1918, as part of his effort to replace the Naturopathic Society of America (an operation into which he invested a great deal of his funds and resources in an attempt to organize a naturopathic profession) and replace it with

the American Naturopathic Association, Lust published the first Universal Naturopathic Directory and Buyer’s Guide (a ”yearbook of drugless therapy”). Although a completely new version was never actually published, in spite of Lust’s announced intention to make this volume an annual publication, annual supplements were published in either The Naturopath and Heruld of Health or its companion publication, with which The Naturopath at one time merged, Nature’s Path (which commenced publication in 1925). The Naturopath and Herald ofHeulth, sometimes printed with the two phrases reversed, was published from 1902 through 1927, and from 1934 until after Lust’s death in 1945. This volume documents the merging of the German and American influences that influenced Lust in his development of the practice of naturopathy,The voluminous tome, which ran to 1416 pages, is dedicated to: The memory of all those noble pioneers and discoverers who have died in the faith of Naturopathy, and to their courageous successors in the art of drugless healing, all of whom have suffered persecution for saving human lives that medical autocracy could not save, this work is respectfully dedicated by its editor Benedict Lust, N.D., M.D., “The Yungbom,” Butler, New Jersey, U.S.A., April 1, 1918.

Lust’s introduction is reprinted here in its entirety to show the purpose of the directory and the status of the profession in the early 1900s: Introduction To the Naturopathic Profession, the Professors of Natural Healing in all its branches, the Professors of Scientific Diet, Hydrotherapy, Heliotherapy, Electrotherapy, Neuropathy, Osteopathy, Chiropractic, Naprapathy, Magnetopathy, Phytotherapy, Exercise, Swedish Movements, Curative Gymnastics,Physical and Mental Culture, Balneopathy, and all forms of Drugless Healing, the Faculties of all Drugless Colleges, Institutions, Schools, and all Professors of Hygiene and Sanitation; Manufacturers of Naturopathic Supplies; Publishers of Health Literature, and Natural Healing Societies, GREETINGS: I have the honor to present to your consideration and goodwill, this Volume, No. 1, Year 1918-1919, of the Universal Naturopathic Directory, Year Book of Drugless Healing, and Buyers’ Guide. For twenty-two years past, the need of a directory for Drugless Therapy has been felt. The medical world is in a condition of intense evolution at the present time. It is evolving from the Drugging School of Therapy to the Drugless School. People by the million have lost confidence in the virtues of Allopathy and are turning with joyful confidence to the Professions of Natural Healing until it has been estimated that there are at least forty thousand practitioners of Naturopathic healing in the United States. The motto that IN UNITY THERE IS STRENGTH is the foundation of the present enterprise. Hitherto, the drugless profession has lacked that prestige in the eyes of the public, which comes from the continuous

existence of a big institution, duly organized and wielding the immense authority which is derived no less from organization and history than from the virtues of the principles that are held and practiced by such institutions. The public at large instantaneously respects an institution that is thoroughly organized and has its root earthed in history. The time has fully arrived when the drugless profession should no longer exist in the form of isolated units, not knowing one another and caring but little for such knowledge. Our profession has been, as it were, as sheep without a shepherd, but the various individuals that constitute this movement so pregnant with benefits to humanity, are now collected for the first time into a Directory and Year-Book of Drugless Healing, which alone will give immense weight and dignity to the standing of the individuals mentioned therein. Not only will the book add to the prestige of the practitioner in the eyes of his patients, but when the scattered members of our profession in every State desire to obtain legislative action on behalf of their profession and themselves, the appeal of such a work as our directory will, in the eyes of legislators, gain for them a much more respectful hearing than could otherwise be obtained. Now, for the first time, the drugless practitioner finds himself one of a vast army of professional men and women who are employing the most healthful forces of nature to rejuvenate and regenerate the world. But the book itself throws a powerful light upon every phase of drugless healing and annihilates time and distance in investigating WHO IS WHO in the realm of Drugless Therapy. A most sincere effort has been made to obtain the name and address of every adherent of the Rational School of Medicine who practices his profession within the United States, Canada and the British Isles. It is impossible at this stage of Naturopathic history, which is still largely in the making, to obtain the name and address of every such practitioner. There were some who, even when appealed to, refused to respond to our invitation, not understanding the object of our work. Many of even the most intelligent members have refused to advertise their professional cards in our pages. But we can only attribute these drawbacks to the fact that every new institution that has suddenly dawned upon human intelligencewill find that a certain proportion of people who do not understand the nature of the enterprise because the brain cells that would appreciate the benefits that are sought to be conferred upon them, are undeveloped, but a goodly proportion of our Naturopaths have gladly responded to the invitation to advertise their specialty in our columns. These, of course, constitute the brightest and most successful of our practitioners and their examples in this respect should be followed by every practitioner whose card does not appear in this book. We take it for granted that every one of the forty thousand practitioners of Naturopathy is in favor of the enterprise represented by this Directory. This work is a tool of his trade and not to possess this book is a serious handicap in the race for success. Here will be found an Index of by far the larger number of Naturopaths in the country arranged in Alphabetic, Geographic and Naturopathic sections. Besides this, there is a classified Buyers’ Guide that gives immediate information regarding where you can find special supplies, or a certain

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing apparatus, or a certain book or magazine, its name, and where it is published. The list of Institutions with the curriculum of each will be found exceedingly useful. Natural healing, that has drifted so long, and, by reason of a lack of organization, has been made for so many years the football of official medicine, to be kicked by any one who thought fit to do so, has now arrived at such a pitch of power that it has shaken the old system of bureaucratic medicine to its foundations. The professors of the irrational theories of life, health and disease, that are looking for victims to be inoculated with dangerous drugs and animalized vaccines and serums, have begun to fear the growth of this young giant of medical healing that demands medical freedom, social justice and equal rights for the new healing system that exists alone for the betterment and uplifting of humanity. I want every Professor of Drugless Therapy to become my friend and co-worker in the great cause to which we are committed, and those whose names are not recorded in this book should send them to me without delay. It will be of far greater interest and value to themselves to have their professional card included amongst those who advertise with us than the few dollars that such advertisement costs. It will be noted that there are quite a number of Drugless Healers belonging to foreign countries (particularly those of the Western Hemisphere) represented in this Directory. The profession of medicine is not confined to any race, country, clime or religion. It is a universal profession and demands universal recognition. It will be a great honor to the Directory, as well as to the Naturopathic profession at large to have every Naturopathic practitioner, from the Arctic Circle to the furthest limits of Patagonia, represented in the pages of this immense and most helpful work. I expect that the Directory for the year 1920 will be larger and even more important than the present Directory and that it will contain the names of thousands of practitioners that are not included in the present work. The publication of this Directory will aid in abolishing whatever evils of sectarianism, narrow-mindednessand lack of loyalty to the cause to which we are devoted, that may exist. That it will promote a fraternal spirit among all exponents of natural healing, and create an increase of their prestige and power to resist the encroachments of official medicine on their constitutional rights of liberty and the pursuit of happiness, by favorably influencing Legislators, Law courts, City Councils and Boards of Health everywhere, is the sincere belief of the editor and publisher. Having introduced the volume, Lust leads off with his article entitled ”The principles, aim and program of the nature cure system.”Again, thisrelatively brief article is reproduced here in its entirety, so that one can see the merging of influences: The principles, aim and program of the nature cure system Since the earliest ages, Medical Science has been of all sciences the most unscientific. Its professors, with few exceptions, have sought to cure disease by the magic of pills and potions and poisons that attacked the ailment with the idea of suppressing the symptoms instead of attacking the real cause of the ailment. Medical science has always believed in the superstition that the use of chemical substances which are harmful and

destructive to human life will prove an efficient substitute for the violation of laws, and in this way encourages the belief that a man may go the limit in self indulgences that weaken and destroy his physical system, and then hope to be absolved from his physical ailmentsby swallowinga few pills, or submitting to an injection of a serum or vaccine, that are supposed to act as vicarious redeemers of the physical organism and counteract life-long practices that are poisonous and wholly destructive to the patient’s well-being. From the earliest ages to the present time, the priests of medicine have discovered that it is ten times easier to obtain ten dollars from a man by acting upon his superstition, than it is to extract one dollar from him,by appealing to reason and common sense. Having this key to a gold mine within their grasp, we find official medicine i n d u l p g at all times in the most blatant, outrageous, freakish and unscientific methods of curing disease, because the methods were in harmony with the medical prestige of the physician. Away back in pre-historic times, disease was regarded as a demon to be exorcized from its victim, and the medicine man of his tribe belabored the body of his patient with a bag in which rattled bones and feathers, and no doubt in extreme cases the tremendous faith in this process of cure that was engendered in the mind of the patient really cured some ailments for which mental science and not the bag of bones and feathers should be given credit. Coming down to the middle ages, the Witches’ Broth-one ingredient of which was the blood of a child murderer drawn in the dark of the moon-was sworn to, by official medicine, as a remedy for every disease. In a later period, the “docteur a la mode,” between his taking pinches of snuff from a gold snuff box, would order the patient bled as a remedy for what he denominated spirits, vapors, megrims, or miasms. Following this pseudo-scientific diagnosis and method of cure, came the drugging phase in which symptoms of disease were unmercifully attacked by all kinds of drugs, alkalis, acids and poisons which were supposed, that by suffocating the symptoms of disease, by smothering their destructive energy, to thus enhance the vitality of the individual. All these cures have had their inception, their period of extensive application, and their certain desuetude. The contemporary fashion of healing disease is that of serums, inoculations and vaccines, which, instead of being an improvement on the fake medicines of former ages are of no value in the cure of disease, but on the contrary introduce lesions into the human body of the most distressing and deadly import. The policy of expediency is at the basis of medical drug healing. It is along the lines of self-indulgence, indifference, ignorance and lack of self-control that drug medicine lives, moves and has its being. The sleeping swineries of mankind are wholly exploited by a system of medical treatment, founded on poisonous and revolting products, whose chemical composition and whose mode of attacking disease, are equally unknown to their originators, and this is called “Scientific medicine.“ Like the alchemist of old who circulated the false belief that he could transmute the baser metals into gold, in like manner the vivisector claims that he can coin the agony of animals into

Philosophy of Natural Medicine cures for human disease. He insists on cursing animals that he may bless mankind with such curses. TOunderstand how revolting these products are, let us just refer to the vaccine matter which is supposed to be an efficient preventive of smallpox. Who would be fool enough to swallow the putrid pus and corruption scraped from the foulest sores of smallpox that has been implanted in the body of a calf? Even if any one would be fool enough to drink so atrocious a substance, its danger might be neutralized by the digestive juices of the intestinal tract. But it is a far greater danger to the organism when inoculated into the blood and tissues direct, where no digestive substances can possibly neutralize its poison. The natural system for curing disease is based on a return to nature in regulating the diet, breathing, exercising, bathing and the employment of various forces to eliminate the poisonous products in the system, and so raise the vitality of the patient to a proper standard of health. official medicine has in all ages simply attacked the symptoms of disease without paying any attention to the causes thereof, but natural healing is concerned far more with removing the causes of disease, than merely curing its symptoms. This is the glory of this new school of medicine that it cures by removing the causes of the ailment, and is the only rational method of practicing medicine. It begins its cures by avoiding the uses of drugs and hence is styled the system of drugless healing. It came first into vogue in Germany and its most famous exponents in that country were Priessnitz, Schroth, Kuhne, Kneipp, Rickli, Lahmann, Just, Ehret, Engelhardt, and others. In Sweden, Ling and others developed various systems of mechano-therapy and curative gymnastics. In America, Palmer invented Chiropractic; McCormick, Ophthalmology.Still originated Osteopathy; Weltmer, suggestive Therapeutics. Lindlahr combined the essentials of various natural methods, while Kellogg, Tiden, Schultz, Trall, Lust, Lahn, Arnold, Struch, Havard, Davis, Jackson, Walters, Deininger, Tyrell, Collins and others, have each of them spent a lifetime in studying and putting into practice the best ideas of drugless healing and have greatly enlarged and enriched the new school of medicine. Life Maltreated by Allopathy The prime object of natural healing is to give the principle of life the line of least resistance, that it may enable man to possess the most abundant health. What is life? The finite mind of man fails to comprehend the nature of this mysterious principle. The philosopher says "Life is the sum of the forces that resist death," but that definition only increases its obscurity. Life is a most precious endowment of protoplasm, of the various combinations of oxygen, hydrogen, carbon and nitrogen, and other purely mineral substances in forming organic tissues. As Othello says, referring to Desdemona's life, which he compares to the light of a candle"If I quench thee thou flaming minister, I can thy former light restore Should I repent me; but once put out THY light, I know not whence is that Promethean heat That can thy light relume."

The spark of life flickers in the sockets of millions and is about to go out. What system of medicine will most surely restore that flickering spark to a steady, burning flame? Will [it be] the system that employs poisonous vaccines, serums and inoculations, whose medical value has to be supported by the most mendacious statements, and whose practitioners are far more intent on their emoluments and fame, than they are in the practice of humanity? The Allopathic system, which includes nine tenths of all medical practitioners, is known by its fruits, but it is an appalling fact that infant mortality, insanity, heart disease, arteriosclerosis, cancer, debility, impoverished constitutions, degeneracy, idiocy and inefficiencyhave enormously increased, particularly during the last twenty-five years, that is, during the regime of inoculations, serums and vaccines. Naturopathy, on the other hand, so far as it has been developed, and so far as official medicine will allow it to act, leaves no such trail of disease, disaster and death behind it. Natural healing is emancipation from medical superstition, ignorance and tyranny. It is the true Elixir of Life. The Allopaths have endeavored to cure sick humanity on the basis of the highly erroneous idea that man can change the laws of nature that govern our being, and cure the cause of disease by simply ignoring it. To cure disease by poisoning its symptoms is medical manslaughter. Dr. Schwenninger of Germany says: "We are suffering under the curse of the past mistakes of our profession. For thousands of years medical doctors have been educating the public into the false belief that poisonous drugs can give health. This belief has become in the public mind such a deepseated superstition, that those of us who know better and who would like to adopt more sensible, natural methods of cure, can do so only at the peril of losing practice and reputation. "The average medical man is at his best but a devoted bigot to this vain school-craft, which we call the Medical Art and which alone in this age of science has made no perceptible progress since the days of its earliest teachers. They call it recognized science! Recognized ignorance! The science of to-day is the ignorance of to-morrow. Every year some bold guess lights up as truth to which but the year before the schoolmen of science were as blind as moles." And Dr.O.W. Holmes, Professor of Anatomy in Harvard University, states: "The disgrace of medicine has been that colossal system of self-deception, in obedience to which mines have been emptied of their cankering minerals, entrails of animals taxed for their impurities, the poison bags of reptiles drained of their venom, and all the inconceivable abominations thus obtained thrust down the throats of human beings, suffering from some fault of organization, nourishment, or vital stimulation." And these misguided drug doctors are not only not ashamed of their work, but they have induced subservient legislators to pass laws that perpetuate the age-long scandal of allopathic importance, and the degenerative influence of the poisons, and to actually make it a crime on the part of nature doctors to cure a man of his ailment. The brazen effrontery of these medical despots has no limits. They boast of making the State legislators their catspaw in arresting, fining and imprisoning the professors of natural healing for saving human life.

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing Legislators have no right to sit in judgment over the claims of rival schools of healing. They see tens of thousands of sick people go down to their graves by being denied the cures that the employers of nature’s forces alone can give them. It is their business to provide for the various schools of medicine a fair field and no favor. A citizen has an inalienable right to liberty in the pursuit of happiness. Yet the real saviors of mankind are persecuted by the medical oligarchy which is responsible for compulsory vaccination, compulsory medical inspection of public school children, and the demands for State and Federal departments of health, all for the ostensible good of the people, but in reality for the gain of the Medical Trust.

The Naturopaths The Naturopaths are desirous of freedom for all schools of medicine. They are responsible practitioners who are willing to be examined by an impartial council, appointed by and acting for the State, who will testify to the life and character of every drugless physician before he is entitled to practice medicine. Not one invidious discriminationshould be made between the different schools of medicine. The state should see to it that each school should have a full opportunity to do its best for the up-lifting of its citizens.

The Program of Naturopathic Cure 1.ELIMINATION OF EVIL HABITS, or the weeds of life, such as overeating, alcoholic drinks, drugs, the use of tea, coffee and cocoa that contain poisons, meat eating, improper hours of living, waste of vital forces, lowered vitality, sexual and social aberrations, worry, etc. 2. CORRECTIVE HABITS. Correct breathing, correct exercise, right mental attitude. Moderation in the pursuit of health and wealth. 3. NEW PRINCIPLES OF LIVING. Proper fasting, selection of food, hydropathy, light and air baths, mud baths, osteopathy, chiropractic and other forms of mechano-therapy, mineral salts obtained in organic form, electropathy, heliopathy, steam or Turkish baths, sitz baths, etc. Natural healing is the most desirable factor in the regeneration of the race. It is a return to nature in methods of living and treatment. It makes use of the elementary forces of nature, of chemical selection of foods that will constitute a correct medical dietary. The diet of civilized man is devitalized, is poor in essential organic salts. The fact that foods are cooked in so many ways and are salted, spiced, sweetened and otherwise made attractive to the palate, induces people to over-eat, and over eating does more harm than under feeding. High protein food and lazy habits are the cause of cancer, Bright’s disease, rheumatism and the poisons of auto-intoxication. There is really but one healing force in existence and that is Nature herself, which means the inherent restorative power of the organism to overcome disease. Now the question is, can this power be appropriated and guided more readily by extrinsic or intrinsic methods? That is to say, is it more amenable to combat disease by irritating drugs, vaccines and serums employed by superstitious modems, or by the bland intrinsic congenial forces of Natural Therapeutics, that are employed by this new school of medicine, that is Naturopathy, which is the only orthodox school of medicine?

Are not these natural forces much more orthodox than the artificial resources of the druggist? The practical application of these natural agencies, duly suited to the individual case, are true signs that the art of healing has been elaborated by the aid of absolutely harmless, congenial treatments, under whose ministration the death rate is but five per cent of persons treated as compared with fifty per cent under the present allopathic methods.

The Germanic Influence The philosophical origins of naturopathy were clearly Germanic. The most significant influences, except those of Russell Trall and the Osteopathic concepts of A.T. Still (at this time strictly the correction of spinal lesions by adjustment), and the chiropractic principles of D.D. Palmer, were all Germanic. (This is well documented in the January 1902 editorial of Water Cure Monthly.) The specific influences on which Lust drew for his work, in order of their chronological contributions to the system of naturopathy, are the following: 1. Vincent Preissnitz (1799-1851) 2. J o h m Schroth (1798-1856) 3. Father Sebastian Kneipp (1821-1897) 4. Amold Rickli (1823-1926) 5. Louis Kuhne (c. 1823-1907) 6. Henry Lahman (no dates known) 7. F.E. Bilz (1823-1903) 8. Adolph Just (?-1939).

Also of note were Theodor Hahn and T. Meltzer, who, in the 1860s, were well known for their work in the movement called, in German, Nuturutz or ”naturism.” In photographs accompanyinghis article “The principles, aim and program of the nature cure system,” Lust described each of these thinkers as follows: 1. VINCENT PREISSNITZ, of Graefenberg, Silesia. Founder of Hydropathy. Born October 4,1799. A pioneer Naturopath, prosecuted by the medical authorities of his day, and convicted of using witchcraft, because he cured his patients by the use of water, air, diet and exercise. He took his patients back to Nature-to the woods, the streams, the open fieldstreated them with Nature’s own forces and fed them on natural foods. His fame spread over the whole of Europe, and even to America. His cured patients were numbered by the thousands. The Preissnitz compress or bandage is in the medical literature. Preissnitz is no more, but his spirit lives in every true Naturopath. 2. J O H A ” SCHROTH, a layperson, not described in Lust’s directory but often talked of in later works and prominently mentioned for his curative theories in Bilz’s master work, The Natural Method of Healing. Schroth smashed his right knee in an accident with a horse and it remained stiff in spite of repeated medical treatment. At last, a priest told schroth that

Preissnitz’s methods might help, and Schroth decided to give them a try. In order to avoid frequent changing of the packs that were directed by Preissnitz, he placed several packs on top of one another, wrapping the whole portion with a woolen cloth. He left this pack on the injured knee for several hours and produced a moist heat which he theorized to cause the poisonous toxins to dissolve and be swept away. These packs are still used as part of the ”Schroth cure” and have reportedly become famous for their blood-cleansing effect. (From an article in the March 1937 Naturopath and Herald of Health by Dr.T.M. Schippel.) As noted by Bilz, the Schroth cure, called by Bilz “the regenerative treatment,” was developed for treatment of chronic diseases through the use of an extreme diet following total fasting by withdrawing of all food and drink and then the use of totally dry grain products and the eventual reintroduction of fluids. 3.FATHER SEBASTIAN KNEIPP, of course, is much described and the photos include one of Kneipp lecturing to the multitudes at Wandelhale at Woerishofen, attending Pope Leo XIII in 1893, noting this is the only consultation on health care matters that Kneipp ever consented to outside of Woerishofen, though many famous and aristocratic individuals desired his counsel, and a picture of Kneipp with the Archdukes Joseph and Francis Ferdinand of Austria walking barefoot in new-fallen snow for purposes of hardening the constitution. It was noted that the older Archduke was cured by Kneipp of Bright’s disease in 1892, and it noted that the Archduke Joseph, in appreciation of this cure, donated a public park in the town of Woerishofen at a cost of $150,000 florens. The Archduke Francis Ferdinand, the son of Archduke Joseph, was the individual whose murder precipitated World War I. There is a further picture of Kneipp surrounded by “Doctors” from different parts of the world while he gave consultation to numerous patients. 4.ARNOLD RICKLI, founder of the light and light and air cures (atmospheric cure). Dr. Rickli was one of the foremost exponents of natural living and healing. In 1848, he established at Veldes, Krain, Austria, the first institution of light and air cure or as it was called in Europe the ”atmospheric cure.” In a limited way (rather very late) his ideas have been adopted by the medical profession in America for the cure of consumption. He was an ardent disciple of the vegetarian diet and exemplified the principles of natural living in his own life. The enclosed photo shows him at the age of 97, when he was still active and healthy. He has since passed on, but his work still lives as a testimonial of his untiring efforts. He was the founder and for over 50 years the President of the National Austrian Vegetarian Association.

5. LOUIS KUHNE wrote, in 1891, The New Science of Healing, the greatest work of basic principles in natural healing. In the tradition of Natural Healing and prevention, Kuhne has been described as one who ”. . . advocated sun, steam baths, a vegetarian diet, and whole-wheat bread . . . in these relatively early days.” His renowned work constitutes the only true scientific philosophy for the application of all Drugless Methods. He was the first to give to the world the comprehensible idea of pathology and the first to proclaim the doctrine of the ”unity of cure.’’ His book Facial Expression gives the means of diagnosing a patient’s pathological condition and determining the amount and location of the systemic encumbrance. He is the founder and first Master of Naturopathy. 6. DR. H. LAHMAN. When the University of Leipzig expelled H. Lahman for his spreading medical sedition among the students, it added a staunch advocate to natural healing. Dr.Lahman finished his medical education in Switzerland and returned to Germany to refute in practice the false ideas of medical science. He later founded the largest Nature Cure institution in the world at Weisser Hirsch, near Dresden, Saxony.He was a strong believer in the “Light and Air” cure and constructed the first appliances for the administration of electric light treatment and baths. He was the author of several books on Diet, Nature Cure and Heliotherapy. As noted in Other Healers, Other Cures: “Heinrich Lahmann came along to stress no salt on foods and no water with meals . . . ”* His works on diet are authoritative and his “nutritive salts theory” forms the basis of rational dietetic treatment. This work has but recently come to light in America, and progressive dietitians are forsaking their old, worn-out, high protein, chemical and caloric theories for the “organic salts theory.” Carque, Lindlahr, McCann, and other wide awake food scientists have adopted it as a basis for their work. Dr. Lahman was a medical nihilist. He denounced medicine as unscientific and entirely experimental in its practice and lived to prove the saneness of his ideas as evidenced by his thousands of cured patients. 7. PROFESSOR F.E. BILZ. That real physicians are born, not made, is well illustrated in the case of Dr. Bilz, who achieved his first success in healing as a lay practitioner. As a mark of gratitude, a wealthy patient presented him with land and a castle in which to found a Nature Cure sanitarium. . . . The Bilz institution at Dresden-Rdebeul, Germany, became world renowned and was long considered the center of the Nature Cure movement. Professor Bilz is the author of the first Naturopathic encyclopedia, The Natural Method of Healing, which has been translated into a dozen

‘See Kruger.16

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing languages, and in German alone has run into 150 editions. He has written many works on Nature Cure and Natural Life, among them being The Future State, in which he predicted the present World War, and advocated a federation of nations as the only logical solution of international problems. 8. ADOLPH JUST, famous author of Return to Nature and founder of original ”Yungborn” in Germany. Both Adolph Just’s Return to Nature and Louis Kuhne’s The Natural Science ofHealing were translated into English by Lust and released through his publication house.

The Convergence with American Influences The Universal Naturopathic Directory was truly eclectic in its compilation and composition. Besides the Lust article noted previously, the volume included: ”How I became acquainted with nature cure” by Henry Lindlahr, MD, ND (which has been reproduced in large part in the introduction to volume 1 of Lindlahr13); “The nature cure” by Carl Strueh, MD, ND; ”Naturopathy” by Harry E. Brook, ND; “The present position of naturopathy and allied therapeutic measures in the British Isles” by J. Allen Pattreiouex, ND; “Why all drugless methods?” by Per Nelson; and “Efficiency in drugless healing” by Edward Earle Purinton (a reprint of the 1917 publication, referred to earlier, which was composed of a series of articles published in The Herald of Health and Naturopath between August 1914 and February 1916). The volume also contained Louis Kuhne’s ”Neonaturopathy (the new science of healing)” in the first publication of the translation by Lust, and articles on electrotherapy, neuropathy, dietology, chiropractic, mechanotherapy, osteopathy, phytotherapy, apyrtropher, physical culture, optometry, hydrotherapy, orthopedics, pathology, natural healing and living, astroscopy, phrenology, and physiology-all of which were specially commissioned for the directory from practitioners and authors considered expert in these subjects. The volume also included the directory of drugless physicians in alphabetical order, geographically arranged and itemized by profession; biographical notes on American contributors of note; the naturopathic book catalog; a guide to natural healing and natural life books and periodicals; a classified list of medical works; a series of book reviews; a buyer’s guide for naturopathic supplies; and, in addition to extensive indexes, a “parting word“ by Lust. In addition, the volume contained numerous advertisements for naturopathic schools, sanitariums, and individual practices, and it closed with the following note: This, then, completes Volume 1 of the Naturopathic Directory, Drugless Yearbook and Buyer’s Guide for the years 1918 and 1919.

Into it, has been placed the conscientious labor of many willing hearts, hands and minds. It is their contribution to the noble cause of natural healing. It will stand as a monument to their endeavors, as well as a memorial to the great souls, the fathers of natural healing, who have passed on. Let this, then, herald a new era-the era wherein man shall recognize the omniscience of Nature, and shall profit through conforming to her laws.

In the biographical section, it becomes apparent that Lust owed a great deal of the feeling of camaraderie in the nature cure movement to some varied American practitioners. The most prominent of these have had their biographical sections as contained in the 1918 directory. Two of them deserve specific note and attention: Palmer and Still. Lust met A.T. Still in 1915 in Kirksville, MO, shortly before Still‘s death. From their meetings, Lust noted later in the Naturopath and Herald of Health (June 1937) that Still believed that osteopathy by “compromising with medicine . . . is doomed as the school that could have incorporated all the natural and biological healing arts . . .” Lust wanted naturopathy to fill this void. Lust also had lengthy acquaintance with B.J. Palmer (the son of D.D. Palmer, the founder of chiropractic), who, following in his father’s footsteps, put Davenport, IA, and the Palmer Chiropractic College on the map. Lust also became connected with Henry Lindlahr, MD, ND, of Chicago (as noted in the autobiographical sketch contained in the directory14and reprinted in volume 1 of Lindlahr13). Lindlahr was a rising businessman in Chicago with all the bad habits of the “gay nineties” era. In his 30s he became chronically ill. He had gone to the orthodox practitioners of his day and received no relief. Then he was exposed to Schroth’s works, and in following them began to feel somewhat better. Subsequently, he liquidated all his assets and went to a German sanitarium to be cured and to learn nature cure. He returned to Chicago and enrolled in the Homeopathic/Eclectic College of Illinois. In 1903 he opened a sanitarium, which included a residential sanitarium, located in Elmhurst, IL, a “transient” clinic (office)on State Street in Chicago, and ”Lindlahr’s Health Food Store.” Shortly thereafter he founded the Lindlahr College of Natural Therapeutics, which included hospital internships at the sanitarium. The institution became one of the leading naturopathic colleges of the day. In 1908 he began to publish Nature Cure Magazine and began publishing his series of Philosophy of Natural Therapeutics, with volume 1 (“Philosophy”) in 1918. This was followed by volume 2 (“Practice”) in 1919, volume 3 (“Dietetics”; republished with revisions as it had originally been published in 1914), and, in 1923, volume 6 (“Iridiagnosis”).The intended volumes 4 and 5 were in

Philosophy of Natural Medicine

production at the time of Lindlahr’s death in 1927. As described in Other Healers, Other Cures: Henry Lindlahr, another American, is remembered for his conviction that disease did not represent an invasion of molecules, but the body’s way of healing something. In other words, he viewed symptoms as a positive physiological response-proof that the body is fighting whatever’s wrong. Accordingly, a fever is a ”healthy” sign and one should be let alone, unless it is dangerously high, of course.

The impact of all these gentlemen on the development of naturopathy in America, under Lust‘s guidance, was profound. From these beginnings, the naturopathic movement gathered strength and continued to grow through the 1920s and 1930s, having a major impact on natural healing and natural lifestyle in the United States. Along the way, Lust was greatly influenced by the writings of John H. Tilden, MD (largely published between 1915 and 1925). Tiden was originally a practicing physician in Denver who became disenchanted with orthodox medicine and began to rely heavily on dietetics and nutrition, formulating his theories of ”auto-intoxication” (the effect of fecal matter remaining too long in the digestive process) and ”toxemia.” Lust was also greatly influenced by Elmer Lee, MD, who became a practicing naturopath in about 1910 and whose movement was called the “hygienic system,” following the earlier works of Russell Trall. Lee published Health Culture for many years. In addition to John Tiden, MD, and Elmer Lee, MD, another medical doctor, John Harvey Kellogg, MD, who turned to more nutritionally based natural healing concepts, was greatly respected by Lust. Kellogg was renowned through his connection with the Battle Creek Sanitarium. The sanitarium itself was originally founded in the 1860s as a Seventh Day Adventist institution designed to perpetuate the Grahamite philosophies of Sylvester Graham and William Alcott. The sanitarium was on the verge of being closed, however, due to economic failure, when in 1876 Kellogg, a new and more dynamic physician-in-chief, was appointed. Kellogg, born in 1852, was a ”sickly child” who, at the age of 14, ran across the works of Graham and converted to vegetarianism. At the age of 20 he studied for a term at Trall’s Hygio-Therapeutic College and then earned a medical degree at New York’s Bellevue Medical School. He maintained an affiliation with the regular schools of medicine during his lifetime, due more to his practice of surgery than his beliefs in the area of health care.3 Kellogg designated his concepts, which were basically the hygienic system of healthful living, ”biologic living.” Principally, Kellogg defended vegetarianism, attacked sexual misconduct and the evils of alcohol, and was a prolific writer through the late nineteenth century

and early twentieth century. He produced a popular periodical, Good Health, which continued in existence until 1955. When Kellogg died in 1943 at the age of 91, he had had more than 300,000 patients through the Battle Creek Sanitarium (which he had had renamed from Western Health Reform Institute shortly after his appointment in 1876), including many celebrities, and the “Sad’ became nationally well known. Kellogg, along with Tilden and Elie Metchnikoff (director of the prestigious Pasteur Institute and winner of the 1908 Nobel Prize for a contribution to immunology), wrote prolifically on the theory of “auto-intoxication.” Kellogg, in particular, felt that humans, in the process of digesting meat, produced various intestinal self-poisons that contributed to “auto-intoxication.” As a result, Kellogg became a near fanatic on the subject of helping humans return to a more healthy, natural state by returning to the naturally designed usage of the colon. He felt that the average modem colon was devitalized by the combination of sedentary living, the custom of sitting rather than squatting to defecate, and the modem civilized habit of ignoring ”nature’s call” out of an undue concern for politeness. Further, Kellogg concentrated on the fact that the modem diet had insufficient bulk and roughage to stimulate the bowels to proper action. Kellogg was also extremely interested in hydrotherapy. In the 1890s, he established a laboratory at the San to study the clinical applications of hydrotherapy. This led, in 1902, to his writing Rational Hydrotherapy. The preface espoused a philosophy of dmgless healing that came to be one of the bases of the hydrotherapy school of medical thought in America. Tiden, as mentioned, was of a similar mind. Indeed, he must have been to have provided natural health care literature with his 200-plus page dissertation entitled “constipation,” with a whole chapter devoted to the evils of not responding when nature called. This belief in the “evils“ drawing away from the natural condition of the colon was extremely important to Kellogg’s work? Because of Lust’s interest, Kellogg’s The Nau Dietetics (1921) became one of the bibles of naturopathic literature.15 Lust was also influenced by the works of Sidney Weltrner, the father of “suggestive therapeutics.” The theory behind Professor Weltmer’s work was that whether it was the mind or the body that first lost its grip on health, the two were inseparably related. When the problem originated in the body, the mind nonetheless lost its ability and desire to overcome the disease because the patient “felt sick” and consequently slid further into the diseased state. Alternatively, if the mind first lost its ability and desire to ”be healthy” and some physical infirmity followed, the patient was susceptible to being overcome by disease.

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

Weltmer’s work dealt specifically with the psychologic process of desiring to be healthy. Lust enthusiastically backed Weltmer’s work and had him appear on the programs at various annual conventions of the American Naturopathic Association (which commenced after its founding in 1919). Lust was also personal friends with and a deep admirer of Bernarr MacFadden. MacFadden was the founder of the ”physical culture” school of health and healing, also known as ”physcultopathy.” This school of healing gave birth across the country to gymnasiums at which exercise programs, designed to allow the individual man or woman to maintain the most perfect state of health and human condition possible, were developed and taught? Other Healers, Other Cures described it as followd6: The next Naturopathic star, after Kellogg, was Bernarr MacFadden, the physical culturist who built a magazine-publishing empire (hisfirst magazine was Physical Culture founded in 1898).MacFadden proselytizesfor exerciseand fresh vegetables, hardly eccentric notions. But his flamboyant efforts to publicize them and his occasionalcrack-pot ideas (likefreezing the unemployed, then thawing them out when the Depression was over) alienated many people. Still, he was his own best advertisement. He fathered nine children by four wives and was parachuting from planes in his 80s. One of MacFadden‘s admirers was that arch-foe of the medical profession, George Bernard Shaw, the longevous eccentric in his own right. . . Lust was also interested in, and helped to publicize, “zone therapy,” originated by Joe Shelby Riley DC,a chiropractor based in Washington, D.C., and one of the early practitioners of “broad chiropractic.” Zone therapy was an early forerunner of acupressure as it related ”. . . pressures and manipulations of the fingers and tongue, and percussion on the spinal column, according to the relation of the fingers to certain zones of the body. . . .”I4 Several other American drugless healers contributed to a broad range of “-opathies” that Lust merged into his growing view of naturopathy as the eclectic compilation of methods of natural healing. The Universal Directory also contained a complete list of osteopaths and chiropractors as drugless healers within the realm of Lust’s view of naturopathic theory. His other sigruficant compatriots at the time of the publication of the directory were Carl Stueh, described by Lust as “one of the first medical men in this country who gave up medicine and operation for natural healing”; F.W. Cohgs, MD, DO, DC, an early graduate of the American school of Naturopathy (1907) who went on to graduate from the New Jersey College of Osteopathy (1909) and the Palmer School of Chiropractic (1912); another “broad chiropractor,” Anthony Matijaca, MD, ND, DO, the naturopathic resident expert in electrotherapy and an associate editor of the Herald and Health Naturopath (the inverted name of the Lust journal at the time of the directory); and Carl Schultz, ND, DO, MD, president and general manager of the

Naturopathic Institute and Sanatorium of California, essentially the second school in the country to pursue the education of physicians under the name of ”naturopathy.”

EARLY TWENTIETH-CENTURY MEDICINE The Metamorphosis of Orthodox Medicine In many ways, naturopathy’s formative years, as well as its halcyon days, were from 1900-1917.In many jurisdictions, modern licensing laws, crafted during this time, were not yet in effect, so varied views of health care could be openly practiced. By 1920, however, the American world of medicine had undergone a sharp transition, culminating 4 decades of change. A look at the structure of early medical care in the United States, even as practiced and dominated by the orthodox school, is instructive, when one notes the changes occurring between 1875 and 1920. In 1875 the following was generally true of American medical practice: The practice, even in urban areas, sent the doctor to the patient; the “house call” was the norm. There was little modem licensing regulation. Hospitals were charitable institutions where persons too poor to otherwise receive health care were usually sent when ill. The AMA, although formed in 1846, and generally representative of the professional goals of the regular or orthodox school of medicine, had scarcely begun to make any political inroads at all. Medical schools required little or no college education for entrance and were largely apprenticeship based and proprietary in nature, having changed little throughout the century. *Although some doctors had begun to specialize, to do so was far from the norm. The major recognized specialties were surgery, obstetrics, and gynecology. Many different types of doctors existed, and society’s recognition of the profession neither recognized specific expertise nor necessarily rewarded professionals in medical practice well. Although the orthodox school made up roughly 80% of the professional medical practitioners, the homeopaths and the eclectics were visible and respected in their own communities for their abilities and expertise, and much of the public relied on other “irregular” practitioners. By comparison, in 1920, total metamorphosis of medicine as a profession had occurred:

By 1920, practices had become office oriented and clinic oriented. Modern licensing principles had become fully developed, and physicians and surgeons were licensed in

all jurisdictions. Most other health care providers had some licensing restrictions placed on them if they were recognized at all. 0 Due largely to the introduction into surgery of the practice of antiseptic techniques and aseptic procedures, and a correspondent decline in operative mortality, institutional care in the hospital became increasingly accepted. Also, clinical pathology and diagnostic laboratory procedures had become well developed, and the hospital had become a major training and clinical research facility that was generally more acceptable to the patient. The AMA was approaching the peak of its political power, having exercised, through its Council on Medical Education and its Council of Pharmacy and Chemistry, major effects on medical schools and the pharmaceutic industry. The transition to research- and education-based medical schools, instead of practitioner apprenticeships and proprietary education, had become complete. AU recognized medical schools had a Pyear curriculum, with an undergraduated e w or substantial undergraduate study required as a prerequisite. In addition, most schools, in conjunction with most licensing statutes, required a year’s internship. Specialization was becoming well developed, and the number of specialty groups had increased considerably. This would continue through the 1930s and into the early 1940s. Professional authority and autonomy had undergone a substantial transition; and the allopathic physician was now recognized as the medical expert. By 1922, the last eclectic school was on the verge of closure, and in the early 1930s the last of the homeopathic schools in the United States was also on the verge of closure. The influence of these sects on orthodox medicine had dwindled to almost nothing. Natwopaths and other alternative health care practitioners had adopted the areas of expertise previously considered the temtory of homeopaths and eclectics.

The Halcyon Years of Naturopathy In 1924 Morris Fishbein succeeded George Simmons as editor of the journal of the American Medical Association (JAMA).Fishbein had joined the editorial staff of j A M A under Simmons immediately following his graduation from Chicago’s Rush Medical School in 1913. Campion pointed out the following7: Over the years Fishbein not only established himself as the &ted editor of the most widely read medical journal in the United States; he also learned how to extend his editorial position, how to project his opinions nationwide. He became, as the saying went in those years, a “personality.“ TIME referred to him as “the nation’s most ubiquitous, the most widely maligned, and perhaps most influential medico.”

In addition to his development of JAMA as an editorial and personal voice, Fishbein also continually railed against ”quackery.” Lust, among others, including MacFadden, became Fishbein’s epitome of quackery. When MacFadden became a wealthy man, after his publishing company included popular magazines like True Confessions and True Detective, he began campaigning for the 1936 Republican presidential nomination. In response, a physician submitted, under the initials“K.G.,” a tonguein-cheek listing of the cabinet that would exist under MacFadden, including the newly created ”Secretary of Aviation” for Lust. Lust was a popular figure by thistime who conducted such a busy lecture scheduleand practice, alternating between the “Yungborns” in Butler, NJ, and Tangerine, FL, that he had become almost as well known as an airline traveler. Lust devoted a complete editorial in Nature’s Path to a response. While Fishbein had j A M A as a personal editorial outlet, Lust had his own publications. Commencing with the Naturopath and Herald of Health in 1902 (which changed its name to Herald of Health and Naturopath in 1918), Lust continually published this and other monthly journals. In 1919 it became the official journal of the American Naturopathic Association, mailed to all members. Each edition contained the editorial column ”Dr.Lust Speaking.” In the early 1920s the “health fad” movement was reaching its peak in terms of public awareness and interest. As described, somewhat wistfully, in his June 1937 column, Lust announced the approach of the 41st Congress of Natural Healing under his guidance: The progress of our movement could be observed in our wonderful congresses, in 1914 Butler, N.J., 1915 Atlantic City, 1916 in Chicago, 1917 Cleveland, 1918 New York, 1919 Philadelphia, 1920 and 1921 again New York, and 1922 in Washington, D.C., where we had the full support and backing of the Congress of the United States. President Harding received the president and the delegates of our convention and we were the guests of the City of Washington. Through the strenuous efforts of Dr. T.M. Schippel, Hon. Congresswoman Catherine Langley of Kentucky, and eight years of hard work financed and sustained by Dr. Schippel and her powerful friends in Congress, Naturopathy was fully legalized as a healing art in the District of Columbia and the definition was placed on record and the law affirmed and amended by another act which has been fully published over and over again in the official journal of the A.N.A., Nuturoputh. In 1923 in Chicago, with the help and financing of the great and never-to-be forgotten Dr.Henry Lindlahr, we had a great convention. Not only were all the Naturopaths there but even to an extent our congress was recognized and acknowledged as official and of great importance by the medical people, particularly by the Health Commissioner of Chicago. We held a banquet, and there were discussions covering all platforms of the healing art. It was the first congress in the United States where medicine and Naturopathy in all its branches such as

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

the general old-time Nature Cure, Hydrotherapy and Diet, Osteopathy, Naprapathy, Chiropractic, Neuropathy and Physiotherapy were represented on the same platform. The speakers represented every modem school of healing and the movement at that time was in the direction of an entirely recognized and independent school of healing. There were two camps, official medicine and official Naturopathy, the medical camp having all that is good and bad in medicine and surgery and all the other schools of healing that had sold their birthright and trusted to the allurement of organized medicine, such as Homeopaths, Eclectics, Physio-medics, and the Osteopaths to a large extent. The Osteopaths were always in the wrong camp when they went on mixed boards and Dr.Andrew Taylor Still, the father of Osteopathy, told me in 1915 that by compromising with medicine Osteopathy is doomed as the school that could have incorporated all of the natural and biological healing arts. The year following we had the great congress in Los Angeles which has never been duplicated. We had to meet in two hotels because the crowds ran over 10,000. The glorious banquet will never be forgotten and the congress celebrated and demonstrated that the initial and first intent of the A.N.A. to teach the public Natural Living and Nature Cure was realized. We will never forget the glorious week in Los Angeles where the authoritiesand the whole city joined us. The success of that congress was largely due to the talent of Dr. Fred Hirsch, the successor to Prof. Arnold Ehret and the noble and generous Naturopaths of the A.N.A. of Cal. There was never a second congress like that. Then we had the great congresses of New York in 1925, Indianapolis 1926, Philadelphia 1927, Minneapolis 1928, Portland, Oregon 1929, New York 1930, Milwaukee 1931, Washington, D.C., 1932, Chicago 1933, Denver 1934, San Diego 1935, and Omaha 1936.

In 1925 Lust began to try to reach more of the general populace through the lay publication Nature’s Path. The Naturopath and Nature‘s Path were later merged because the self-supportingadvertising and subscription monies were more available by publication to the general populace than to the members of the association (The Naturopath, 1902-1927; Nature’s Path, 1925-1927; merged 1927-1933; separated 1934-1938; Nature‘s Path, 1939-?). In January 1934 Lust commenced republication under the title Naturopath and Heruld of Health in addition to Nature’s Path. Each volume opened with his column, which was different for each publication. Both publications were issued continuing through 1938, when the Nature‘s Path again became the sole publication until Lust‘s death in 1945. After the Universal Directory, Lust continued to write volumes on naturopathic principles, although he was more of a synthesizer, organizer, lecturer, and essayist than a lasting scientific author of naturopathic articles. His most enduring contributions remain his early translations of Kuhne’s and Just’s works. During the 1920s and up until 1937, Lust’s brand of “quackery“ as labeled by Fishbein, was in its most

popular phase. Although the institutional markings of the orthodox school had gained ascendancy, before 1937 it had no real solutions to the problems of human disease. Instructive in this regard is Louis Thomas’s interesting work The Youngest Science. Thomas compares his education and internship as a physician to his father’s life as a physician. His father believed that bedside manner was more important than any actual medication offered by the physician. Indeed, his father went into general surgery so that he could offer some service to his patients that actually made some change in their condition. Thomas points out that the major growth of “scientific medicine” until 1937 advanced diagnosis rather than offering any hope of cure. During this time, Lust’s naturopathic medicine, as well as both chiropractic and osteopathic medicine, continued to be on the outside looking in. Practitioners of all three groups were continually prosecuted for practicing medicine without a license, although they often won their cases by establishing before juries that their practices were, even according to the testimony of medical men, not the same at all. Additionally, because the orthodox practitioners could offer little or no actual hope of cure for many diseases, the “health food and natural health” movement was generally popular. During the 1920s, Gaylord Hauser, later to become the health food guru of the Hollywood set, came to Lust as a seriously ill young man. Lust, through application of the nature cure, removed Hauser’s afflictions and was rewarded by Hauser’s lifelong devotion. His regular columns in Nature’s Path became widely read among the Hollywood set. As noted in Other Healers, Other Cures? The last big name in Naturopathy was Gaylord Hauser, a Viennese-Born food scientist (as one of his early books identified him) turned to Naturopathy in his later years. He is best remembered for advising the eating of living foods, not dead foods, and for escorting Greta Garbo around. In addition to fresh fruits and vegetables, Hauser’s ”Wonder Foods” were skinned milk, brewers yeast, wheat germ, yogurt, and black strap molasses. In 1937, however, all thisbegan to change. The change came, as both Thomas and Campion note in their works, with the era of “miracle medicine.” Lust recognized this and his editorializing became, if anythmg, even more strident. From the introduction of sulfa drugs in 1937 to the Salk vaccine‘s release in 1955, the American public became used to annual developments of miracle vaccines and antibiotics. Lust died in September 1945 at the Yungbom facility in Butler, NJ, preparing to attend the 49th Annual Congress of his American Naturopathic Association. In August 1945, for the official program of that congress

held in October 1945 just after his death, he dictated the following remarks What is the present condition of Naturopathy? What is its future? I can give my opinion in a very few words. For fifty years I have been in the thick of the fight to bring to the American people the Nature Cure. During that period I have had an opportunity to judge what Naturopathy has done, and can accomplish and the type of men and women, past and present, who make up the Naturopathic ranks. Let us take the present situation first. What is Naturopathy accomplishing? The answer to that is: “Everything.” Naturopathy holds the key for the prevention, alleviation and cure of every ailment, to man and beast alike. It has never failed in the hands of a competent Naturopath. Whatever the body can “catch”-that same body, with proper handling, can eliminate. And that takes in cancer, tumors, arthritis, cataract and the whole gamut of “incurable medical” disease and ailments. During my years of practice I, personally, have seen every type of human ailment and so-called serious ”disease” give way to the simple, proven Naturopathic methods. I make no exception to that statement. Now let us see the type of men and women who are the Naturopaths of today. Many of them are fine, upstanding individuals, believing fully in the effectiveness of their chosen profession-willing to give their all for the sake of alleviating human suffering and ready to fight for their rights to the last ditch. More power to them! But there are others who claim to be Naturopaths who are woeful misfits. Yes, and there are outright fakers and cheats masking as Naturopaths. That is the fate of any scienceany profession-which the unjust laws have placed beyond the pale. Where there is no official recognition and regulation, you will find the plotters, the thieves, the charlatans operating on the same basis as the conscientious practitioners. And these riff-raff opportunists bring the whole art into disrepute. Frankly such conditions cannot be remedied until suitable safeguards are erected by law, or by the profession itself, around the practice of Naturopathy. That will come in time. Now let us look at the future. What do we see? The gradual recognition of this true healing art-not only because of the efforts of the present conscientious practitioners but because of the bungling, asinine mistakes of orthodox m e d i c i n e Naturopathy’s greatest enemy. The fiasco of the sulpha drugs as emphasized disastrously in our armed forces is just one straw in the wind. The murderous Schick test-that deadly “prevention” of diphtheria-is another. All these medical crimes are steadily piling up. They are slowly, but inevitably, creating a public distrust in all things medical. This increasing lack of confidence in the infallibility of Modem Medicine will eventually make itself felt to such an extent that the man on the street will turn upon these self-constituted oppressors and not only demand but force a change. I may not be here to witness this revolution but I believe with all my soul that it is coming. Yes, the future of Naturopathy is indeed bright. It merely requires that each and every true Naturopath carry o n - c a n y on-to the best of his and her abilities. May God bless you all.

The naturopathic journals of the 1920s and 1930s are instructive. Much of the dietary advice focused on poor

eating habits, including the lack of fiber in the diet and an overrelianceupon red meat as a protein source. More than half a century later in the 1980s, the pronouncements of the orthodox profession, the National Institute of Health and the National Cancer Institute finally became aware of the validity of the early assertions of the naturopaths that such dietary habits would lead to degenerative diseases, including cancers associated with the digestive tract and the colon. The December 1928 volume of Nature’s Path was the first American publication of the works of Herman J. DeWolff,a Dutch epidemiologistwho was one of the first individuals to assert, based on studies of the incidence of cancer in the Netherlands, that there was a correlation between exposure to petrochemicals and various types of cancerous conditions. He saw a connection between chemical fertilizers and their usage in some soils (principally clay) that led to their remaining in vegetables after they had arrived at the market and were purchased for consumption. Again, it was 50 years later before orthodox medicine began to see the wisdom of such assertions.

The Emerging Dominance of American Medical Association Medicine The introduction of ”miracle medicine,” the impact of World War I1 on health care, and the death of Lust in 1945 all combined to cause the decline of naturopathic medicine and natural healing in the United States. (During the war, the necessity for crisis surgical intervention techniques for battlefront wounds encouraged use of morphine and sulfa drugs and penicillin for diseases not previously encountered by American citizens. This resulted in rapid development of high-technology approaches to medicine and highly visible successes.) The effects of these events on osteopathy and chiropractic, however, were completely different. In the early days of osteopathy, there was a sigruficant split between the strict drugless systems advocated by A.T. Still and the beliefs of many MDs who converted to osteopathy because of its therapeutic value. The latter group did not want to abandon all of the techniques they had previously learned and all of the drugs they had previously used when those therapy techniques were sometimes effective. Ultimately, most schools of Osteopathy, commencing with the school based in Los Angeles, converted to more of an imitation of modern orthodox medicine. These developments led to more of an accommodation between the California osteopaths and the members of the California Medical Association. (This developing cooperation between the California Osteopathic and Medical Association was one of the major issues leading to the downfall, in 1949, of Fishbein’s editorial voice in ]M.) Thus osteopathy found a place in professional medicine, at the cost of its drugless healing roots and therapies?

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing

The effect on chiropractic of the postwar years was somewhat different. Because of educational recognition under the G.I. Bill, the number of chiropractors in the country grew substantially, and their impact on the populace grew accordingly. The sect eventually grew powerful enough in terms of numbers and economic clout that it could pose a legal challenge to the orthodox monopoly of the AMA. However, in the immediate postwar years, the AMA gained tremendous political clout. Combined with the American Legion and the National Board of Realtors,” these three groups posed a powerful political triumvirate before the U.S.Congress. These years, called the years of the ”great fear” in Caute’s book by that name,18 were the years during which to be unorthodox was to be “un-American.” Across the country, courts began to take the view that naturopaths were not truly doctors, as they espoused doctrines from ”the dark ages of medicine” (something American medicine had apparently come out of in 1937) and that drugless healers were intended by law to operate without “drugs” (which became defined as anythmga person would ingest or apply externally for any remedial medical purpose). In this regard, the Washington State Supreme Court case of Kelly v. CuwoZl* and the Arizona State Supreme Court case of Kuts-Chuux v. Wilson document how sigruficant limitations were placed on naturopaths under the guise of calling them ”druglesshealers.” In the state of Tennessee, as a reaction to the 1939 publication of the book Buck to Eden by herbalist Jethro Kloss, court action initiated by the Tennessee State Medical Association led first to the publishers being forbidden to advertise the book for any therapeutic purpose. They were allowed only to acknowledge that it was in stock. The Tennessee State Legislature then declared that the practice of naturopathy in the state of Tennessee would be considered a gross misdemeanor, punishable by up to 1 year in jail. Although it was under considerable public pressure in those years, the American Naturopathic Association undertook some of its most scholarly work, coordinating all the systems of naturopathy under commission. This resulted in the publication of a basic textbook on naturopathy (BasicNuturuputky published in 1948 by the ANA19) and a sigruficant work compiling all the known theories of botanical medicine (as commissioned by the ANA’s successor after its 1950 name change to the American Naturopathic Physicians and Surgeons Association), the Nuturue Medicinu published in 19533O Naturopathic medicine began splintering when Lust‘s ANA was succeeded by six different organizations in the mid-1950s. T h e defendant was Otis G. Canoll of Spokane,WA. He and his brother, Robert V. Carroll, Sr., of Seaffle were longtime associates of Benedict Lust. As members of Lust‘s Ameikan NaturopathiiAssociation, they had advanced naturopathy‘s presence in Washington state through the Washington State Naturopathic Association.

The primary organizations among these were the successor to the ANA, which underwent a name change in 1950 to the American Naturopathic Physician and Surgeon’s Association, and subsequently changed to the American Association of Naturopa thic Physicians (AANP) in 1956, and the International Society of Naturopathic Physicians formed under the leadership of M.T. Campenella of Florida shortly after Lust’s death, with its American offshoot, the National Association of Naturopathic Physicians. By 1955, the AANF, as it ultimately became known, had recogruzed only two schools of naturopathic medicine, the Central States College of Physiatrics in Eaton, OH, under the leadership of H. Riley Spitler, and Western States College of Chiropractic and Naturopathy located outside Portland, OR, under the leadership of R.A. Budden. Budden was a kdlahr graduate and among the group that took over control of the Lindlahr College after Lindlahr’s death in the 1920s. He moved west after World War 11when the northwestern states, including Oregon, became the last bastion of naturopathic medicine in thiscountry.

THE MODERN REJUVENATION After the counterculture years of the late 1960s and America’s disenchantment with organized institutional medicine, which began after the miracle era faded and it became apparent that orthodox medicine had its limitations,alternativemedicine began to gain new respect. Naturopathic medicine underwent an era of rejuvenation. As succinctly described in Cassedy’s Medicine in America: A Short this phenomenon, which is not limited to naturopathic medicine, is consistent with the modern, and continuing, ”search for health beyond orthodox medicine”: It should not have been surprising to anyone that certain organized therapeutic sects continue to exist in mid-twentieth century America as successful and conspicuous alternatives to regular medicine. This is not to say that they offer the same threats to the medical establishment or play the same roles as their nineteenth-century counterparts had, as complete therapeutic systems. But they do continue to hold a strong collective appeal for individuals who mistrust or are somehow disenchanted with mainline medicine. They have appealed also to antiauthoritarian sentiments that flourish throughout society. Moreover, as earlier, they satisfy various needs that regular medicine continues to neglect or ignore.

The same author, in describing the post-World War II decades and the changing fortunes of such healing theories as naturopathic medicine, observed as follows: The period also brought about the renewal or updating of certain previously widely used therapies and considerable experimentationwith others, some of them exotic. To an extent this trend represented the rediscovery by trained physicians, nurses, and other regular health professionals of certain values

Philosophy of Natural Medicine and older styles of therapy. The participation of such professionals proved to be an essential ingredient in the rebirth of several such therapies. However, the major reason for the new successes was the widespread active interest and involvement of America’s literate lay people in the search for more personal or humane forms of treatment. As another author, John Duffy,has observed in From Humors to Medical Scienct?: Since health is too closely related to cultural, social, and economic factors to be left exclusively to doctors, American lay people have always engaged in do-it-yourself medicine, resorted to ”irregulars and quacks,” and supported health movements. As a result of the current fad for physical fitness, our streets are beset by sweat-suited individuals of all ages doggedly jogging their way to health and long life. In addition, stores selling “natural” foods are flourishing, physical fitness salons have become a major business, and anti-smoking and weight-loss clinics and workshops are attracting thousands of individuals bent on leading cleaner and leaner lives. And those for whom physical activity in itself is not enough are seeking physical and mental well-being through faith healing, yoga, and a host of major and minor gurus. When neither mental effort nor physical exercise can solve medical problems, the sceptics of modem medicine can always turn to the irregulars. A recent estimate places a number of Americans who have relied on an irregular practitioner at some time in their lives at 60 million, and, aided by the high cost of orthodox medicine, irregular medical practice appears tobeontherise.. .

At the beginning of this period of rejuvenation, the profession’s educational institutions had dwindled to one, the National College of Naturopathic Medicine (which had branches in Seattle, WA, and Portland, OR), which was created after the death of R.A. Budden and the conversion of Western States College to a straight school of chiropractic. Kruger’s book Other Healers, Other CuresI6described it a s follows in 1974: Today, Naturopaths in seventeen states are licensed to diagnose, treat, and prescribe for any human disease through the use of air, light, heat, herbs, nutrition, electrotherapy, physiotherapy, manipulations, and minor surgery. At present, one can eam an D.N. [a misnomer, actually-N.D.] degree at the National College of Naturopathic Medicine in Seattle and Emporia, Kansas, [where, by contract, the first two years of the four year medical education were then taught], or the new North American Naturopathic Institute in North Arlington, New Jersey [there is also a school in Montreal]. The four-year curriculum covers many standard medical courses-anatomy, bacteriology, urology, pathology, physiology, X-ray reading etc.-but also includes botanical medicine, hydrotherapy, electrotherapy, and manipulative technique. . .

The public, by the late 1970s, was particularly ripe for another rejuvenation of naturopathy’s brand of “alternative” health care. As described in Murphy’s

Enter the Physician: The Transformation of Domestic

Medicine, 1760-1860, when discussing this cyclical rejuvenation in the mid-twentieth century23: Contemporary crusaders still stress prevention as the layperson’s primary duty, but a growing chorus is calling for every person to assume the newly proactive role in his or her own health care. This is essential, say the analysts, because both lay people and doctors have placed far too much faith in the power of medicine and technology to work miracles. For a host of different reasons and from a variety of different perspectives, health advocates are calling on each person to “accept a certain measure of responsibility for his or her own recovery from disease or disability.” What would this entail? There are probably as many answers to this question as there are respondents, but it is striking to note how many of the solutions would have been familiar to our ancestors who lived between 1760 and 1860.One reaming idea, for instance, is that each person knows his or her own constitution history the best, and therefore has a duty to communicate that knowledge to medical personnel. Another is a refurbished concept of vis medicatrix naturae, the belief that many diseases are self-limiting and therefore do not require much medical intervention-and certainly not the amount or the sort to which contemporary Americans are accustomed. Most significantly, today’s analysts are calling on professionals and non professionals to build and nurture a health-care partnership very much like that envisioned by nineteenth-century health publicists: a partnership based on mutual respect, clear understanding and faithful execution. In that scenario, both as it originally evolved and in its updated version, it is the doctor who directs treatment, but crucial to a successful outcome are the informed and responsible actions of the patients, other care givers, and the patient’s family and friends.

In 1978 the John Bastyr College of Naturopathic Medicine was formed in Seattle by Joseph E. Pizzorno, Jr, ND (founding president), Lester E. Griffith, ND, and William Mitchell, ND (all graduates of the National College of Naturopathic Medicine), who felt that it was necessary to have more institutions devoted to naturopathic care and the teaching of naturopathic therapeutics. During the late 1970s, other naturopathic doctors also recognized this need and naturopathic colleges were established in Arizona (the Arizona College of Naturopathic Medicine), Oregon (the American College of Naturopathic Medicine), and California (the Pacific College of Naturopathic Medicine). Unfortunately, none of these three survived. However, the current status of naturopathic medicine, a s represented by Bastyr University a n d National College of Naturopathic Medicine, and now joined by the Southwest College of Naturopathic Medicine and Health Sciences in Arizona and a program in naturopathic medicine at the University of Bridgeport in Connecticut, is that of growth and presumably a solid future. There are currently favorable commentaries on the state of naturopathic medicine and its continuing efforts to reinvest various diverse theories of ”natural healing” with modem vigor.

The History of Naturopathic M By 1902, he had founded the American School of Naturopathy In Other Healers, Unorthodox Medicine in America (edited by Norman Gevitz, the author of The D . O . ’ S )a~ ~ ~in New York City. The practice quickly spread across the United States volume written to provide “a scholarly perspective on (California was the first State to pass a law regulating natural unorthodox movements and practices that have arisen medicine, in 1919). in the United States” (from the editor’s preface), part Numerous schools offeringa variety of training cropped up of this effort is described by Author Martin Kauffman and disappeared. The movement peaked in America around (from the Department of History at Westfield State 1950 and nearly died out by the early 1960’s. The legal climate College), a modern expert on homeopathy: for naturopathy turned cold in many States, in the face of the powerful modern medical establishment. While naturopathy In addition to the revival of classical homeopathy, a major medicine is now legal (in several states), many naturopaths development in recent times has been the teaching of homeoppracticing in other states are old-timers, practicing under athy at naturopathic colleges on the West coast. In Seattle, John their original ”drugless therapy” licenses, issued before laws Bastyr, a Naturopath and Homeopath who had been practicing prohibiting new naturopathic practices went into effect. Today, for fifty years, readied the move in 1956 to establish the there are only two schools in naturopathic medicine in the national college of Naturopathic Medicine, which was later United States: the National College in Portland, Oregon, and moved to Portland, Oregon. The College’s four-year curricuJohn Bastyr College in Seattle, Washington. The American lum includes a required third-year course in homeopathy, with Association of Naturopathic Physicians is beginning to organhomeopathic electives being available to third and fourth year ize and unify the profession, with its own definition and students. philosophy of modem naturopathic medicine. In 1978, three naturopathic practitioners in Seattle founded Alaska, Arizona, Connecticut, Oregon, Washington, and the John Bastyr College of Naturopathic Medicine. During the Hawaii recognize naturopathy as a primary medicine with sixth quarter all students at that school are required to take specific licensing laws, as do the Canadian provinces of British 44 hours of course work in homeopathy, after which they may Columbia, Manitoba, Ontario, and Saskatchewan. In other elect another 66 hours and up to 238 hours of clinical homeostates, efforts are under way to gain licensure for naturopaths pathic instruction. The significance of the naturopathic schools (this description was circa 1989). to the resurgence of homeopathy is demonstrated by the fact The movement continues to grow, and so, the impact that “about one third of the graduating class specialized in homeopathic practice, a total of about 50 each year in all” of natural healing has come full circle. In a n era where (citing The American Homeopath). the statistical number of persons born who are expected to contract cancer, now recognized as a degenerative disease, has increased rather than declined, and the And, as described in the Encyclopedia of Alternative incidence of other degenerative diseases (arthritis, arteHealth Care by O l ~ e n ~ ~ : riosclerosis, atherosclerosis, etc.) has increased in direct Today in Germany, the nature care movement in herbal relation to the lengthening of life expectancies produced remedies tradition has matured into a well-established health by improved sanitation and nutrition (although specare practice, with about 5,000 professionals throughout the ciously claimed by AMA medicine to be the result of country.. . . their therapies), the early teachings of Lust, Lindlahr, One Kneipp practitioner, Benedict Lust, emigrated to a n d others appear to have more validity than ever. America to begin teaching and practicing naturopathy here.

1. Starr I? Social transformation of American medicine. New York Basic Books, 1983107. 2.Griggs 8. Green pharmacy. London: Jill, Norman, & Hobhouse, 1981:180-183, 251. 3. Whorton J. Crusaders for fitness. Princeton, NJ: Princeton Press, 1982138-147. 4. Rothstein W. American physicians in the 19th century. Baltimore: Johns Hopkins Press, 1972. 5. Haller J. American medicine in transition, 1850-1910. Urbana, E University of Illinois Press. 1981:234-279. 6. Rosen G. The structure of American medical practice. Philadelphia: University of Pennsylvania, 1983. 7. Campion F. AMA & US health policy since 1940. Chicago: AMA Publishers, 1984. 8. Burrows J. Organized medicine in the progressive era. Baltimore: Johns Hopkins Press, 1977~31-51. 9.Coulter H. Divided legacy, vol II. Washington, DC: Wehawken Books, 1973:402-423.

10. Salmon JW. Alternative medicines. New York Tavistock, 1984: 80-113. 11. Gevitz N. The D.O.’s.Baltimore: JohnsHopkins Press, 1982. 12. Silberger J. Mary Baker Eddy. Boston: Little Brown, 1980. 13. Lindlahr H. Philosophy of natural therapeutics, vol. I. Maidstone, England: Maidstone Osteopathic, 1918 (vol 2-Practice: 1919; vol &Dietetics: 1914; Reprints: CW Daniel Co, Essex, England, 1975,1981,1983). 14. Lust B. Universal directory of naturopathy. Butler, NJ: Lust, 1918. 15.Kellogg JH. New dietetics. Battle Creek, MI: Modem Medical Publications, 1923. 16. Kruger H. Other healers, other cures. A guide to alternative medicine. New York Bobbs-Merrill, 1974182-183. 17. Goulden J. The best years. New York Athenium, 1976. 18. Caute D. The great fear. New York Simon & Schuster, 1978. 19. Spitler HR. Basic naturopathy. Des Moines: ANA, 1948. 20. Kuts-Cheraux AW. Naturae medicina. Des Moines: ANPSA, 1953.

Philosophy of Natural Medicine 21. Cassedy JH. Medicine in America: a short history. Baltimore: Johns Hopkins University Press,1991:147-148. 22. Duy. J. From humors to medical science: a history of American medicine, ed 2. Urbana, E University of Illinois Press, 1993350. 23. Murphy LR. Enter the physician: the transformation of domestic medicine, 1760-1860. University of Alabama Press,1991:226-227.

24. Gevitz N. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Press, 1988:116-117. 25. Olsen KG. The encyclopedia of alternative health care. New York Pocket Books, 1989:209-210.

General

Thomas L. The youngest science. Boston: Viking, 1983. Whorton J. Crusaders for fitness.Princeton, NJ: Princeton Press, 1982. Wirt A. Health & healing. New York Houghton W i n , 1983. Wohl S. Medical industrial complex. New York Harmony, 1983.

B m t t S, Herbert V. The vitamin pushers: how the health food industry is selling America a bill of goods. New York Prometheus Books, 1994. Barrett S, Jarvis W. The health robbers: a close look at quackery in America. New York Prometheus Books, 1993. Berlinger H. A system of medicine: philanthropic foundations in the Flexner era. New York Tavistock Publishers, 1985. Breiger G. Medical America in the 19th century. Baltimore: Johns Hopkins Press, 1972. Brown ER. Rockefeller medicine men. Berkeley, CA: University of California Press,1978. Burrows J. Organized medicine in the progressiveera. Baltimore: Johns Hopkins Press, 1977. Campion F. AMA & U.S. health policy since 1940. Chicago: AMA Publishers, 1984. Cassedy JH. Medicine in America: a short history. Baltimore: Johns Hopkins University Press, 1991. Coulter H. Divided legacy, vol3. Washington, DC:Wehawken Books, 1973. Coward R. The whole truth:the myth of alternative health. London: Faber & Faber, 1989. Duy. J. The healers. Urbana, E University of Illinois Press, 1976. Duyr J. From humors to medical science: a history of American medicine, ed 2. Urbana, I L University of Illinois Press, 1993. Gevitz N. The D.O.’s.Baltimore: JohnsHopkins University Press, 1982. Gevitz, N. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Press, 1988. Dr Goodenough’s Home Cures & Herbal Remedies. New York Crown, 1982. Green H. Fit for America: health, fitness, sport & American society. New York Pantheon Books, 1986. Griggs B. Green pharmacy. London: Jill, Norman & Hobhouse, 1981. Haller J. American medicine in transition, 1850-1910. Urbana, E University of Illinois Press, 1981. Inglis B, West R. Alternativehealth guide. New York Knopf, 1983. Kruger H. Other healers, other cures: a guide to alternative medicine. New York Bobbs-Merrill, 1974. Ludmerer K. Learning to heal. New York: Basic Books, 1985. Manger LN. A history of medicine. New York Marcel Dekker, 1992. McKeown T. The role of medicine: dream, mirage, or nemesis? London: Nuffield Provinaal Hospitals Trust, 1976. Murphy LR. Enter the physician: the transformation of domestic medicine, 1760-1860. Tuscaloosa, AL University of Alabama Press,1991. Rosen G. The structure of American medical practice: 1875-1941. Philadelphia: University of Pennsylvania, 1983. Rosenberg C. The care of strangers: the rise of America‘s hospital system. New York: Basic Books, 1987. Rothstein W. American physicians in the 19th century. Baltimore: Johns Hopkins Press, 1972. Salmon JW. Alternative medicines. New York Tavistock, 1984. Serrentino J. How natural remedies work. Vancouver, B C Hartley & Marks, 1991. Silberger J. Mary Baker Eddy. Boston: Little Brown, 1980. Starr P. Social transformation of American medicine. New York Basic Books, 1983.

A Naturopathic Bibliography Abbot JK. Essentials of medical electricity. Philadelphia:WB Saunders, 1915. Altman N. The chiropractic alternative: how the chiropractic health care system can help keep you well. Los Angeles: JP Tarcher, 1948. Barber ED. Osteopathy complete. Kansas City: Private, 1896. Baruch S. An epitome of hydro-therapy. Philadelphia: WB Saunders, 1920. Benjamin H. Everybody’s guide to nature cure, ed 7. London: Thorsons, 1981. Bennet HC. The electro-therapeuticguide. Lima, O H National College of Electro-therapeutics, 1912. Bilz FE. The natural method of healing, vols 1 and 2. (English trans.) New York Bilz, International News, 1898. Dejarnette MB. Technic & practice of bloodless surgery. Nebraska City, NE: Private, 1939. Downing CH. Principles & practice of osteopathy. Kansas City: Williams, 1923. Filden JH. Impaired health (its cause & cure), ed 2. Denver: Private, 1921. Finkel H. Health via nature. New York: Barness Printing & Society for Public Health Education, 1925. Foster AL. Foster’s system of non-medicinal therapy. Chicago: National Publishing Association, 1919. Fuller RC. Alternative medicine and American religious life. New York Oxford University Press, 1989. Goetz EW. Manual of osteopathy. Cincinnati: Nature’s Cure, 1909. Gottsschalk FB. Practical electro-therapeutics.Hammond, IN: Frank Betz, 1904. Olsen KG. The encyclopedia of alternative health care. New York Pocket Books, 1989. Graham RL. Hydro-hygiene. New York: Thompson-Barlow, 1923. Inglis B. Natural medicine. London: William Collins, 1979. JohnsonAC. Principles & practice of drugless therapeutics. Los Angeles: Chiropractic Education Extension Bureau, 1946. Just A. Retum to MW. Lust B, trans. Butler, NJ. Lust Publications, 1922. Kellogg JH. New dietetics. Battle Creek, M I Modern Medical Publications, 1923. Kellogg JF. Rational hydrotherapy. Battle Creek, MI: Modem Medical Publications, 1901,1902. King FX. Rudolf Steiner and holistic medicine. York Beach, MA: Nicolas-Hays, 1987. Kuhne L. Neo-naturopathy (new science of healing). Lust B, trans. Butler, NJ: Lust Publications, 1918. Kuts-Cheraux AW. Naturae medicina. Des Moines: M A , 1953. Lust B. Universal directory of naturopathy. Butler, NJ: Lust Publications, 1918. Lindlahr H. Philosophy of natural therapeutics, vol 1. Maidstone, England: Maidstone Osteopathic, 1918. (vol 2-Practice: 1919;vol3Dietetics: 1914;Reprints: CW Daniel, Essex, England, 1975,1981,1983)

The History of Naturopathic Medicine, Part I: The Emergence of an American School of Healing MacFadden 8. Building of vital power. NJ: Physical Culture Publications, 1904. MacFadden 8.Power & beauty of superb womanhood. NJ: Physical Culture Publications, 1901. Murray CH. Practice of osteopathy. Elgin, E Private, 1909. Murray MT, Pizzorno JE. Encyclopedia of natural medicine. Rocklin, CA: Prima, 1998. Pizzomo JE.Total wellness. Rocklin, CA. Prima, 1996.

Richter JT. Nature-the healer. Los Angeles: Private, 1949. Spitler HR.Basic naturopathy. Lks Moines: ANA, 1948. Trall RT.Hydropathic encyclopedia (vols 1-3).New York SR Wells, 1880. Turner RN. Naturopathic medicine: treating the whole person. London: Thorsons, 1984. Weltmer E. Practice of suggestive therapeutics. Nevada, M O Weltmer Institute, 1913.

The History of Naturopathic Medicine, Part 11: Decline and Rejuvenation-Politics and Professionalization George Wm. Cody, JD Heidi B. Hascall, MA CHAPTER CONTENTS The Emergence 67 Naturopathy’s Period of Emergence-Education and Professional Presence 69

Developments Outside the United States 75 Canada 75 Elsewhere 75 Other Relevant Scholarship 75

The Long Decline 71 Conclusion 76 The Period of Rejuvenation 73 The Twenty-First Century Awaits

74

Since the earlier chapter, “The History of Naturopathic Medicine,” first appeared in 1985, naturopathic medicine has continued its rejuvenation, accompanied by a growing scholarly interest. This philosophy of health and healing was reported in the mid- to late-1970s to have reached extinction. Renewed interest has been inspired by, and within, diverse academic disciplines: medical history (Professor James Whorton, University of Washington), medical sociology (Walter I. Wardwell, University of Connecticut), and medical anthropology (Professor Hans A. Baer, University of Arkansas, Little Rock). Baer provided a useful analysis of the changing state of naturopathic medicine in a trilogy of writings on the subject.” He described naturopathy as passing through “three stages of development: (1)its emergence around the turn of the twentieth century; (2) its period of decline beginning in the late 1930s; and (3) its recent potential rej~venation.”~ Each stage of development can be examined in turn; new scholarship and historical information covering each stage has become available.

THE EMERGENCE Naturopathic medicine has evolved from a health philosophy first publicly labeled naturopathy in 1902 by German-born Benedict Lust.* Naturopathy as described

and advanced by Lust was an eclectic collection of “natural” treatment philosophies and modalities (see previous chapter) that from the 1920s to the 1950s rose and fell with chiropractic.32,48In The Great American Water-Cure Craze: A History of Hydropathy in the United States (1967),Weiss and Kemble described the life’s work of Benedict Lust in ”Chapter IX-The Father Kneipp Treatment.” At the time of Weiss and Kemble’s writing, little attention had been paid to Lust’s work in the 20 years since his death, which was described by the authors: Lust was the author of many books and magazine articles.

In his battle against the drug trust, he was arrested sixteen times. He died in Butler, New Jersey,September 5,1945.

Since the reemergence and rejuvenation of naturopathy as naturopathic medicine in the 1970s (discussed later),

‘See Chapter 4. In Nature Doctors (Pioneersin Natura/ Medicine), Kirchfeld and BoyleZ7noted “A conflicting and probably inaccurate vemion of the term’s evolution given by George Cody states that it was coined in 1895 by Dr. Scheel and purchased by Lust in 1902.”This was taken directly from the lead editorial of the first edition of Lust‘s Naturopatb and Herald of HeaM (January 1902). Lust’s great-niece, Anita Lust Boyd, privately published Lust‘s memoirs in 1997 as Yungborn: The Life and Times of Dr. Benedict Lust, Founder and Father of Nitturnpathy. The same explanation for the coining of the term ‘naturopathy” appears in the memoirs on pp. 77-78.

67

Whorton51conducted the first scholarly examination of the work and writings of Lust in Nature Cures: The History of Alternative Medicine in America. The first outside examinations of naturopathy were hostile ones, labeling it a "healing cult" tied to chiropractiS2and a type of "medical Discussion of Lust and naturopathy from the 1920s through the 1970s had been placed against the backdrop of these related, negative assessments in Louis Reed's32 work The Healing Cults (published under the often-praised and presumably objective sponsorship of the Committee on the Costs of Medical Care [CCMC]) and Morris Fishbein's unabashedly "quackery"-oriented writings.* New scholarship by Professor Jonathan Engel (Seton Hall University) has shown the clear imprint of the American Medical Association (AMA)-in the person of its theninfluential Journal of the American Medical Association Editor Fishbein-n this aspect of the work of the CCMC, which calls into question Reed's objectivity in assessing naturopathy and chir~practic.'~~ Whorton, instead of relying on these 1930s sources, undertakes a fresh examination of the actual writings and life's work of Lust in Nature Cures. His interest in naturopathy goes back to the mid-1980s. In Drugless Healing in the 1920s: the Therapeutic Cult of Sanipractic, W h o r t ~ described n~~ the history of a philosophy of drugless healing that Reed32had described as distinguished from naturopathy in name only. He also described the history of Washington's Drugless Healing Act of 1919 with all of its own peculiarities.$ This piece of history is more than just tangentially related to the ultimate rejuvenation of naturopathy as naturopathic medicine.As Whorton additionallydescribes, well-intentioned drugless healers in Washington state, among them John Bastyr, doctor of chiropractic (DC), 'As an example see Gardner and Martin's In the Name of Science, Chapter 16 "Medical Cults," (GP Putnam. 1952), later appearing as fads and Fallacies (in the Name of Science), (Dover Publications, 1957). +Engel, as part of his research, examined Fishbein's papers archived at the University of Chicago: 'In 1931, Louis Reed, a staff researcher for the CCMC, wrote to Fishbein to ask him to chedc the manuscript the committee was preparing on sectarian healers. 'If it is possible,' wrote Reed, 'I should like very much to have you read the section of this devoted to healing cults. so that I may have the benefit of your criticisms and suggestions.' Fishbein obliged the request (as he almost always did) and wrote back detailed comments on the section."13 T h e story of sanipractic is the story of John Lydon and his regional rivalry with naturopathy during naturopathy's period of emergence (1902-1930s) and naturopathy's period of decline from the late 1930s until the late 1960s. As described by Whorton, sanipractic did not survive long enough to see the rejuvenation and revival of naturopathy as naturopathic medicine and the adoption of Washington's Naturopathic Practice Act in 1988. Whorton viewed Lydon as a leader of the legislative drive to open the state to the 'irregular" practices that had been emerging in the Pacific Northwest under the banner of "drugless healing." These various philosophies opposed the use of 'pharmaceutic drugs and poisons," in the language of the 1919 Act. But the world of American drugless healing, which joined together a variety of irregulars that opposed the rising strength and burgeoning monopoly of the American Medical Association and conventional biomedicine, included some well-intentioned healers, some true visionaries, and healers of dubious credentials and intentions. Whorton clearly views Lydon as one of the latter.

doctor of naturopathy (ND), sought to escape the dubious legacy of being linked to Lydon's sanipracticby petitioning to be recognized as naturopaths in the late 1950s. This effort kept naturopathy alive in Washington just long enough for this school of healing to rejuvenate and reemerge as naturopathic medicine in the 1970s (as discussed later). In Inner Hygiene: Constipation and the Pursuit of Health in Modern Society, WhortonWoffered his first assessments of the work of Lust as it related to the emergence of naturopathy in the early twentieth century: Most of the drugless clan also identified themselves as practitioners of naturopathy, a system of practice that grew out of hydropathy, as well as German water-cure and nature-cure traditions. Organized in the late 1890s under the leadership of German immigrant Benedict Lust, naturopathy sought to cure the full scope of human ills with natural agents (herbs, water, air, sunlight, electricity, massage, and others), agents that supported and stimulated the body's own healing mechanisms.

In his extensive assessments of Lust's work and writings in Nature Cures: the History of Alternative Medicine in America, Morton51has attempted to put the philosophical development of naturopathy in a reasonable historical context: However much a dreamer Lust was in some respects, he was an insightful realist in others. He was correct in believing that simply giving nature support as it ran its course was the best one could do with many diseases in his day. He was correct in seeing self-abuse as the source of much physical, and emotional, suffering and attacked it with an ardor that MDs could not bring to the task until nearly a century later. Recent medical lamentations over the evils of smoking, sexual promiscuity, and other risky behaviors adopted in the thoughtless chase after pleasure have nothing on Lust's jeremiads. . . Lust was right in reprimanding allopaths for focusing so strongly on disease as to lose sight of the importance of promoting health. He was right in appreciating the need to "individualize" the treatment of each patient-and in seeing patient self-responsibility as part of that individualization.

How large a professional movement Lust inspired during this period of naturopathy's emergence was difficult to gauge at any point until a government survey was undertaken in 1965. But, as Morton described, naturopathy had an impact: Those were messages that had enough appeal, evidently, to allow naturopathy to expand steadily though the first decades of the century until by 1923Lust could estimate that there were nine thousand.naturopaths, a "vast army of professional men and women" working on all continents to "rejuvenate and regenerate the world." His figures undoubtedly inflated. An independent study [the work of the CCMC discussed later] put the number of naturopaths at "possibly 1500," allowing that if the "allied groups" that advocated drugless healing under other names [physiotherapy, sanipractic] were added on the total may reach 2500. Yet whatever their numbers, naturopaths had grown into a force not to be ignored.

The History of Naturopathic Medicine, Part II: Decline and Rejuvenation-Politics and Professionalization

While Lust’s claim of 9000 naturopaths worldwide is difficult to assess, 5000 practitioners may be a reasonable estimate of the reach of his naturopathy in the United States by the late 1920s and into the 1930s. As Whorton51 reported, ”without making the connection-the mixer orientation within Chiropractic was also becoming a growing presence. And, as will be discussed later in relation to Professor Wardwell’s work, this orientation was a philosophy that tended to merge Chiropractic and Naturopathy in education and practice.”* Whorton noted a ”1930 survey in which some 1,800 chiropractors participated, found, for example, that 1,124 employed hydrotherapy, 1,173 used light therapy, 1,257 provided electrotherapy,and a full 1,352 trusted vibration therapy.’’ In other words, they practiced naturopathy. Naturopaths were less successful in the 1940s and 1950s than osteopathy and chiropractic in accomplishing professionalization by raising professional standards, as Whorto~Pnotes, including in education. This occurred despite the formation of a National Board of Nature pathic Examiners of the American Naturopathic Association (ANA) in 1940. There was constant internal bickering, which “by the 1940s had taken on a more ominous tone.” While ”standards at naturopathic schools were steadily raised from the 1940s on, thanks to both professional idealism and the requirements of state licensing laws,” based on ”a perusal of the statutes of the dozen states in which naturopaths were licensed in the late 1940s,” the divisive trends within naturopathy ”would not begin to be reversed until the 1970s.” Whorton51observed that there was no misunderstanding where Lust himself stood on the need for professional standards: Obtaining their own licensing statutes was perceived by alternative practitioners as a critical measure for purging incompetence and quackery from their own rank. ”Where there is no official recognition and regulation,’’ the founder of naturopathy, Benedict Lust maintained, “youwill find the plotters, the thieves, the charlatans . . . (The) riff-raff opportunists bring the whole art into disrepute.” By the time Lust said this, shortly before his death in 1945, frustrating experience had demonstrated that “that is the fate of any science-any profession-which the unjust laws have placed beyond the pale.” In following the evolution of alternative medicine over the first third of the twentieth century, it is essential to keep in mind that constant battle of each system to bring itself within the pale. “Although homeopathy has undergone a small revival in recent years, very few MDs now practice it. It is currently mainly of interest to naturopaths, who earn doctor of naturopathy (ND) degrees, and to a few chiropractors. Naturopaths closely resemble chiropractors in that they use spinal manipulative therapy (henceforth SMT) and because so-called mixer chiropractors also use such naturopathic methods as heat, cold, hydrotherapy, physiotherapy, dietary supplements, and even some herbal and homeopathic remedies. That is why the traditional, or ‘straight,’ chiropractors disparagingly call them ‘medipractors.’ Until the middle of the twentieth century a few mixer schools both DC and ND degrees, either as alternatives or together after an additional semester of study.“48

NATUROPATHY’S PERIOD OF EMERGENCE-EDUCATION AND PROFESSIONAL PRESENCE Naturopathy became an element of chiropractic education and practice at least as early as 1910 with the founding of the Peerless College of Chiropractic and Naturopathy in Portland, OR.48 From this point on, naturopathic education developed in two tracks: schools of naturopathy owned and operated by naturopaths and chiropractic schools that had naturopathy curricula in addition to the core chiropractic programs. These latter schools were a central part of the mixer orientation within chiropractic.3zt48 Initial assessments of schools of naturopathy occurred in the 1920s and 1930s. These assessments came from those within, or allied with, allopathy and are therefore hardly unbiased, but much of the information in these assessments seems credible. The progression of education in naturopathy would be expected to have been similar to that of chiropractic, if somewhat smaller in scale. In this regard Walter I. Wardwell noted4? Wiese and F e r g u s ~ nidentified ~~ 392 different chiropractic schools as having existed in the United States. When those for which there is no evidence of more than a year of operation are eliminated, the number is reduced to 188. Most of them probably produced few graduates-the number of schools increased rapidly to their largest between 1910 and 1926, and then contracted, particularly during the depression of the 1930s and World War II.

The history of schools of naturopathy followed much the same pattern. Whorton51notes that this was the case. The operators of these schools seemed, at least on the surface, aware of the kind of criticisms to which proprietary trade and professional schools are subjected: limited facilities, limited resources, and an emphasis on collecting revenue versus providing a full professional education.3z*48 The leading operators of schools of naturopathy sought, at least on paper, to respond to these criticisms. By letter agreement dated October 7, 1922, four of the most identifiable leaders of naturopathyBenedict Lust, Joe Shelby Riley, F.W. Collins, and Henry Lindlahr**ommitted to the formation of the Associated Naturopathic Schools and Colleges of America and committed themselves as “the Presidents of Naturopathic Schools in the United States of America” to specific educational m i n i m u m s ”on and after January 2, 1923”: “all matriculants must have a primary school educationt and

‘Lust signed on behalf of the American School of Naturopathy, Riley on behalf of the Universal Spinal Therapy and Naturopathii College, Collins on behalf of the United States School of Naturopathy (the letter appears on this school‘s stationary), and Lindlahr on behalf of the Lindlahr College of Natumpathy. The letter‘s Mth sip natory is Dr. M.E.Yergin on behalf of the National Natumpathic and Health School. +‘Primary education”-circa 1922-was an eighth-grade education, and this educational base would have been the same as required by chiropractic.

all naturopath courses must be composed of four years of six months each." Additionally, the letter provided that "time allowance or credits may be given to practitioners in the field who desire to take up the naturopathic courses, and to licensed physicians of other methods of healing,'' the amount of such credit being left to each school's discretion. In the summer and fall of 1927, representatives of the AMA's Council on Medical Education and Hospitals conducted inspections-unannounced and incognitof schools of "chiropody, chiropractic, naturopathy, optometry, osteopathy, physical therapy, as well as a large number of institutions." From these inspections several reports were generated, including the Council's report on "Schools of Chiropractic and Naturopathy in the United States," which appeared first as part of the Council's Annual Report, 1928, and later as reprinted in The Journal of the American Medical Association.* The report identified 40 schools of chiropractic and 10 schools of naturopathy and detailed the inspections of "some schools of Chiropractic and of Naturopathy": Palmer School of Chiropractic (a straight school), National College of Chiropractic (a mixer school that was reported as having recently purchased and assimilated Lindlahr College of Natural Therapeutics), Los Angeles College of Chiropractic (another leading mixer school), the combined American School of Naturopathy, Inc. and American School of Chiropractic, Inc. (Lust's own New York City schools, though Lust was observed to have been "in Florida" at the time of the inspections), and the Naturopathic College and Hospital of Philadelphia. The reports were predictably negative with regard to facilities, resources, and the clearly proprietary nature of the establishments. The CCMC's Reed, in discussing "Naturopathic relied heavily on this report from the AMA's Council and observed that "in 1927, according to the American Medical Association, there existed twelve naturopathic colleges with not over 200 students. These figures would probably hold good for the present time." Reed also concluded that there were "a considerable number of miscellaneous drugless healers of a type similar to chiropractors practice in this country" as of 1932 and that "the naturopaths form the largest group of these practitioners. . . . Of these various cults, only the naturopaths and the sanipractors have any considerable membership. Many of the (other) cults are really part of the naturopathic As to numbers of drugless practitioners, Reed observed that ''only the roughest estimate can be made-probably there are about 2500,'' of which naturopaths "number possibly 1500," and sanipractors--"only the name distinguishes sanipractors from the naturopaths"-numbered 'VOl 9611733-1738, 1928.

some 500 in their Washington state "stronghold." Reed also observed that as of 1932:"A few states-Connecticut, Florida, Oregon, South Carolina, Utah, Washington and the District of Columbia-provide for licensing of naturopaths as limited practitioners. . . . In addition to those mentioned, certain states (Alabama, Colorado, Illinois, Indiana, Michigan, Ohio, Pennsylvania, New Jersey, and Wyoming) make (other) provision for the licensing of drugless or limited practitioner^."^^ Reed's work for the CCMC, though clearly biased against all of the healing philosophies he identifies as "medical cults" (ala Fishbein), principally osteopathy, chiropractic, and naturopathy, is the only work that attempts to survey the presence and impact of these schools of healing in the United States in the 1920s and 1930s.*A decade later, in April 1945, another work of this kind appeared in the Rhode Island Medical Journal? The article, "Naturopathic Legislation and Education," was written by the Rhode Island Medical Society's Executive Secretary, John E. Farrell, to set out some of the society's reasons for opposing legislation that would license naturopathy in Rhode Island. The article noted that according to the 1942-1943 Report of the Committee on Education of the ANA, 13 schools of naturopathy in the United States met criterion of the ANA; the article goes on to make a lengthy "Report on Schools" through visits to most of the identified schools.$The predictable criticisms of these schools as underfinanced, underresourced, and proprietary in nature appear once again, though by actual detail of description, National College (Chicago) and Western States (Portland) seem to be wellestablished, functioning mixer schools of chiropractic and naturopathy. Another source of information about the state of naturopathy, its licensure, and its schools comes from within the profession, covering the mid-1940s to the mid-1950s. The International Society of Naturopathic Physicians (ISNP)was founded in California in 1938; the ISNP's original moving spirit, and first president, was Arthur Shramm of Los A n g e l e ~ Under . ~ ~ Shramm the ISNP published a yearbook for its membership in 1945,1946, and 1948. Shramm was followed in the presidency by Mario T. Campanella, based in Graham, FL.

'The results of Reed's work are also summarized in the CCMC's Publication No. 27, The Costs of Medical Care, Falk, Rorem and Ring (1933), p. 292, as 'Naturopaths and Other Drugless Healers." Wolume 28:248-253, 262-263. With lengthy discussion of Central States College of Physiatrics (Eaton, OH), The Colorado Mineral Health School (Denver), Columbia College of Naturopathy (Kansas City), First National University of Naturopathy (Newark, NJ, earlier the United States School), The Metropolitan College (Cleveland), The Nashville College of Drugless Therapy (Tennessee), The National College of Drugless Physicians(part of the NationalCollegeof Chiropractic,Chicago),The Polytechnic College and Clinic of Natural Therapeutics (Fort Wayne, IN), The Southern Universityof Naturopathyand Physio-Medicine (Miami), The University of Natural Healing Arts (Denver), and The Western States College (Portland, OR).

The History of Naturopathic Medicine, Part II: Decline and Rejuvenation-Politics and Professionalization

Under Campanella the ISNP published a membership directory in 1952 and again in 1955. Each membership publication contained current information regarding existing schools, state associations, and licensing laws, as well as other demographic information about the state of the profession. The 1948 yearbook details the high-water mark for the emergence period, which extended past Lust's death in 1945 into the late 1940s: licensure in 13 states, the territory of Hawaii, and three Canadian provinces.* State associations were identified for 32 states, and associations were also identified for five Canadian provinces and Great Britain, Australia, New Zealand, India, Germany, the Netherlands, Luxemburg, and Spain.

THE LONG DECLINE In the face of the AMA's determination to eliminate chiropractic, and with it naturopathp7-healing philosophies that were linked through the mixer orientation within chiropractic (during the 1930s and through the 1960s the majority camp within a divided chiropractic)naturopathy went through a period of decline described by Baer.45 Wardwell is a sociology professor emeritus who became an early leader in what developed as a subspecialty in the 1950s: medical sociology. His earliest work, starting with his doctoral dissertation (1951) at Harvard, focused on chiropractic as an example of a marginalized health profession: As early as his doctoral dissertation, Wardwell discussed naturopathy as an adjunct discipline to chiropractic in the context of the continuing division of chiropracticinto mixers and straights. As he later noted43: Comparison of the survival of chiropractic with that of osteopathy and naturopathy is a quite different matter which does not involve metaphysical or epistemological differences between them. Furthermore, the overlap in theory between chiropractic, osteopathy and naturopathy is very great. Differences between osteopathic and chiropractic manipulative treatment appear to be more a matter of who applies the technique rather than differences in technique itself. The distinction between chiropractors and naturopaths is even more blurred because they often trained at the same schools and sometimesthey studied both fields simultaneously.As recently as 1948, three of the currently accredited chiropractic colleges *The laws for 12 states and Hawaii, as well as three provinces, were reprinted in the yeabook together with contact names and addresses for the respective examining boards for all but California and Pennsylvania, where licensing was done through a pluralistic medical board. The states licensed in 1948 were: Arizona, California, Connecticut, Florida, Oregon, Pennsylvania, South Carolina, Utah, Washington (which had a drugless healing law), and Virginia. Tennessee had originally been included, but note was made that the Tennessee licensure had been repealed in 1947. Licensure in these states plus Hawaii was the highwater mark for licensure before the period of decline. The three Canadian provinces were Ontario, Manitoba, and British Columbia. *Over the course of his academic career, Wardwell wrote a series of articles about the emerging concepts of medical sociology and chiropractic's evolution as a marginalized profession.

offered N.D. (Doctor of Naturopathy) and D.C. (Doctor of Chiropractic) degrees.

In this context he described naturopathy as a school of healing that became extinct as two historical factors converged: the death of Lust in 1945, leaving naturopathy without its "founder," and the mandate in the early 1950s by the major mixers' professional group, the National Chiropractic Association (NCA), that it would no longer accredit chiropractic schools that granted degrees in naturopathf3: In the case of naturopathy, chiropractic's victory is nearly complete. Although there may still be up to 2000 naturopaths in practice* with naturopaths licensed in a few states, and one small school in Portland, Oregon, still offers naturopathic degrees, none of the schools that formerly offered both chiropractic and naturopathic degrees currently does so. With practically no new recruits entering the profession, naturopathy must disappear.

By the late 1970s, Wardwell had learned of efforts in the Pacific Northwest to keep naturopathy alive. In his chapter in the handbook of Medical Sociology, Wardwell@ noted this presence in the Northwest (which had received no mention in the first two editions in 1963 and 1972): The accrediting of chiropractic colleges is encouraging uniformity, not only in curricula but in scope of practice. Those colleges that formerly offered the Doctor of Naturopathy (N.D.) as well as the D.C. degree have ceased doing so, leaving naturopathy with only one remaining small college in Portland, Oregon."

By publication of his masterwork, Chiropractic: History and Evolution of a New Profession (1992); Wardwell devoted substantial attention to the impact of naturopathy on the mixer orientation within chiropractic and traced naturopathy's final educational decline to the untimely death in 1954 of William A. Budden, DC,ND, the president of Western States Chiropractic College (WSCC, Portland, OR). Following Budden's death, WSCC continued to teach naturopathy until 1958 but dropped its Doctor of Naturopathy (ND) degree program in 1956. This was the last resistance to the position of the accrediting committee of the NCA, and no chiropractic ND programs remained. Wardwell observed, though, that the seeds of a naturopathic reemergence had been planted in the Northwest after Budden's death and that naturopathy may indeed survive. The last ND diplomas had been granted at WSCC in 1958 to students who were enrolled in the ND program at the time of Budden's death. Brinkergwrote the following: Political pressure from the chiropractic profession had begun in the late 1940s to force chiropractic schools to relinquish 'As to those calling themselves naturopaths, this number was considerably too high, as will become apparent. Whorton calls this Wardwell's "excellent survey of Chiropractic's history-'

Philosophy of Natural Medicine programs granting naturopathic degrees. After threatening loss of accreditation, the National Chiropractic Association finally forced Western States College to drop its School of Naturopathy in 1956, and it became exclusively Western States Chiropractic College? Efforts to keep naturopathy alive through education and licensure were examined by two reports prepared in 1958, a time when the Utah legislature was reexamining naturopathy’s licensure in the aftermath of a case from the Utah Supreme Court that had dealt its practicing NDs a crippling blow.* The first was A Study of the Healing Arts with a Particular Emphasis Upon Naturopathy (November 1958), prepared as “A Report to the Utah Legislative Council” by legislative council staff. As part of its work, the staff conducted inquiries of, and site visits to, seven schools accredited by the Utah Naturopathy Examining Board as of August 1957. Separately, the Bureau of Economic and Business Researcht of the University of Utah (BEBR) undertook a study focusing on schools that had granted naturopathy degrees and produced Survey of Naturopathic Schools (“Prepared for the Utah State Medical Society,” December 1958).Preparation of the study was, as noted in the title, undertaken by the university research program at the request of the state medical society, but the preparation of the study was independent, and “no attempt was made by that group to influence the results of the study.” (Foreword and Acknowledgements). The BEBR study, done with the requested cooperation of investigators from five other universities located in various sections of the United States, surveyed all of the schools listed by Utah licensees as schools of graduation or schools attended, using records maintained by the Utah Department of Business Registration.lo Since the state of naturopathic education in the 1950s is relevant, some observations from this study are worth noting: One of the most important results to emerge from this study is that there are virtually no schools now teaching naturopathy. Of the twenty-six schools investigated during this study, only nine were still in existence in the fall of 1958. Of these nine, only three are now granting naturopathic degrees and two others are teaching naturopathy.’O Of the three schools granting ND degrees, the study found that one school, Sierra States University in California, began offering a ”postgraduate” ND degree after the most highly respected chiropractic program in the country, Los Angeles College of Chiropractic, had discontinued its ND degree program in 1948. National College of Naturopathic Medicine (NCNM), the Oregon

‘The Utah Attorney General in 1955 had reversed opinions by several of his successors in office and issued an opinion that declared naturopathy in Utah to be a completely ‘drugless“ practice. The profession, represented by the examining board, challenged this opinion in court and lost. tNow the National Bureau of Economic Research.

school, had-in 1957, its first year of operation-four ND students who were starting at NCNM and 60 enrolled ”postgraduate” DCs pursuing ND degrees. The school had been recognized by the Utah examining board but had not yet granted degrees. The third school granting ND degrees as of 1957-1958 was the Central States College of Physiatrics in Eaton, OH, essentially the one-man operation of H. Riley Spitler, author of Basic Naturopathy (published by the ANA in 1948).This school granted a Doctor of Mechanotherapy (DM) degree, recognized in only Ohio and Alabama by law, or an ND degree to anyone who sought licensure in a state where an ND degree would quallfy a graduate for licensure. The course of study for both degrees was the same, and the school had graduated 10 students in the previous 2 years. Its ND degrees were recognized in Utah. This state of affairs was accurately described by Homola” in his book on the history and evolution of chiropractic: As of 1958, only five states (Arizona,Connecticut,Oregon, Virginia and Utah) separately classified and provided licensing provisions for the naturopath. A few states, however, did permit licensing of drugless healers following examination by (a) board. (A good number of states have repealed their laws licensing naturopaths in recent years.) Chiropractic schools that employ the use of physiotherapy teach a course that is very similar to the practice of naturopathy. Likewise, the three or four naturopathic schools still operating today have a curriculum similar to that of many chiropractic colleges. In fact, at least four chiropractic colleges awarded naturopathic degrees along with the chiropractic degree before they came under the jurisdiction of the national Chiropractic Association. With the approval of this organization, the schools were prohibited from issuing naturopathic degrees. This practically amounted to a death-dealingblow to the profession of naturopathy?* In 1967 the U.S. Department of Health Education and Welfare, Public Health Service, National Center for Health Statistics (NCHS) published Public Health Service Publication number 1758, State Licensing ofHeulth Occupations. With the assistance of The Council of State Governments, the NCHS collected data regarding licensure of health professionals at the state level. ”Chapter 8, Naturopaths” recorded the available data for the ‘Various sources document how dismal this status became in the 1950s and 1960s. Brinker noted that in 1955, “the Western States College School of Naturopathy was one of only two programs (together with Central States) that was recognized by the remaining professional association as the “renamed American Association of Naturopathic Physicians (AANP)” and that Western States enrollment was “49% naturopaths and 5196 chiropractors.“8 Wardwelr noted that Western States never was a large school, and that in the years following its discontinuance of its School of Naturopathy (1956-1970), it never had a total enrollment greater than 38 students. But NCNM, the successor to the WSCC naturopathy program, graduated only 29 NDs from 1956-1973.9 According to documentation provided to the federal Department of Health Education and Welfare in 1968 by the again-renamed professional associatioMy now the National Association of Naturopathic PhysiciansACNM granted only 17 degrees were granted from 1960-1968. By 1968 this association had only 168 members.

The History of Naturopathic Medicine, Part 11: Decline and Rejuvenation-Politics

naturopathic profession as of the mid-1960s. In summary, the NCHS identified five states and the District of Columbia as licensing naturopaths as of 1967 Arizona, Connecticut, Hawaii, Oregon, and Utah. California and Florida were identified as renewing existing licenses but granting no new licenses. The publication reported that by 1965, California had renewed 66 licenses and Florida, 136. Licenses in effect by state were: Arizona (loo), Connecticut (47), Hawaii (14),Oregon (la), and Utah (42). No numbers were provided for the District of Columbia. The report stated the following: In addition to Doctors of Naturopathy (N.D.) there are other limited branches of medicine; these have not been included in the study. In the State of Washington the Drugless Therapeutics Examining Committee functions (for such licensure). The Ohio law states which branches are to be specified on certificates issued by the State Medical Board to limited practitioners. No attempt has been made to collect information on these drugless healers who are few in number.12

Active state practitioners were also numbered (though the reason for the differentiationis not clear) as: Arizona (53), Connecticut (29), Hawaii (13), and Oregon (121). Given the existence of approximately 50 practitioners at the time in Washington, and some practicing in Idaho under a decision of the Idaho Supreme Court, there appear to have been perhaps as many as 600 to 700 remaining naturopaths practicing at the end of the 1960s.* According to documentation provided to the federal Department of Health Education and Welfare in 1968 by the again-remaining professional association-the National Association of Naturopathic Physicians-only 17 degrees were granted from 1960-1968. By 1968 this association had 168 members and estimated that there were perhaps 500 "active" naturopaths in the United States. Congress had adopted Medicare in 1965. The legislation covered payment for the services of physicians (essentially MDs and Dos), hospital services, and "other therapeutic services" that would commonly be provided through these conventional means. As Wardwell reported:* in 1967 Congress directed the Secretary of the Department of Health, Education, and Welfare (HEW),Wilbur Cohen, to study the inclusion services of "additional types of licensed practitioners." The surgeon general and other HEW staff prepared the resulting Independent Practitioners under Medicare using advisory committees only (Wardwellserved on the Expert Review The State Licensing of Health Occupations, U.S. Department of Health, Education and Welfare, National Center for Health Statistics, Public Health Service Publication No. 1758 (1967) reported: "Naturopaths are specifically licensed in at least five States and the District of Columbia. The absence of a State from this list does not imply that there are no licensed naturopaths. Illinois, for example, could be covered by the medical practice act. Texas and Virginia provide for naturopaths on examining boards but no information is available on licensing practices. Elsewhere licensing powers have been abolished and no new licenses have been issued for example, in 1965 naturopathic licenses renewed in California numbered 66 and in Florida, 136."

and Professionalization

Committee for Chiropractic and Naturopathy), which actually had little input.@ This report documents the ebb tide of naturopathy's "period of decline" as Baer later labeled it.4The section of the report Naturoputhy concludes that as of 1968: Naturopathic theory and practice are not based on the body of basic knowledge related to health, disease, and health care which has been widely accepted by the scientific community. Moreover, irrespective of its theory, the scope and quality of naturopathic education do not prepare the practitioner to make an adequate diagnosis and provide adequate treatment.

Considering the state of the profession in 1968, these negative assessments were hardly unexpected.

THE PERIOD OF REJUVENATION Baer is a professor of cultural anthropology at the University of Arkansas, Little Rock. Like Wardwell, Baer's scholarship in the 1980s focused on two areas: (1)the scholarship of medical anthropology and (2) the once-marginalized health philosophies-osteopathy, chiropractic, and, secondarily, naturopa thy. Baer's interest in the evolution of chiropractic as a philosophy of healing led him to Wardwell's work,+ and to Wardwell's earlier scholarship that had been tied to the mixer orientation within chiropractic.+Baer took note of his descriptions of naturopathy as a near-extinct philosophy. Predictions of extinction were consistent among the assessments of social scientists in the 1970s and continuing into the mid-1980s. R ~ t h ?Twaddle ~ and Hessler,36Rosengren,34 Whorton," and most notably Wardwel14>46sall discussed naturopathy as a onceobservable but marginalized philosophy of health and healing at odds with the conventional medical claims of a scientific medicine. These social scientists placed naturopathy's demise sometime in the 1950swhen chiropractic severed its open naturopathic link by terminating ND programs. But Baer, perhaps before Wardwell, took note of two related developments: (1) the founding in 1978 by

'In a relevant article,' he discussed the three stages undertaken toward competition by a dominant professional system in a pluralistic medical system: (1) deviance, (2) legitimization, and (3)cooptation, through an examination of organized, 'regular" medicine versus osteopathy; he referenced Wardwell as having documented these three stages of action by organized medicine toward chiropractic with no mention of naturopathy. +"The development of American chiropractic was particularly shaped by the internecine battles between "straights" and "mixers"Y-those who wished to focus on spinal adjustment as a central modality and those who wished to incorporate many other modalities from what is loosely termed naturopathy. Because of its extreme eclecficism, naturopathy provided mixers with a ready source from which to add a wide variety of techniques to their own treatment program. For many years, many mixer schools offered their students the ND (doctor of naturopathy) diploma in addition to the DC (doctor of chiropractic) diploma. Registration as naturopaths allowed chiropractors in some states to engage in a wide scope of treatment practice without danger of legal repercussions." During the 1950%however, many states repealed their laws licensing naturopaths."

naturopaths Joseph Pizzorno, William Mitchell, Lester Griffith, and Sheila Quinn of John Bastyr College of Naturopathic Medicine (JBCNM) in Seattle and (2) the professionalization represented by JBCNM’s scientific medicinebased curriculum and the publication of a JBCNMproject, The Textbook of Natural Medicine.+ In his 1992 Medical Anthropology article “The Potential Rejuvenationof American Naturopathy as a Consequence of the Holistic Health Movement,” Baer detailed his own view of Naturopathy’s ”three stages of development” noted at the outset of this chapter. Besides relying on material covered in the original chapter of “The History of Naturopathic Medicine,” which first appeared in 1985, Baer covered much of the new material regarding the emerging (1900-1930s) and declining (1940-1970s) stages of naturopathy. Baer particularly broke new ground with his recognition of a “potential rejuvenation” of naturopathy as naturopathic medicine and his recognition that the profession had knowingly or unknowingly adopted a recognized survival strategy as a matter of organizational policy: professionalization.Baer also broke new ground in advancinga theory regarding the “potential rejuvenation’’ as tied to the emergencein the 1970s of holistic medicine. Holistic medicine, as a philosophy of healing, had a cultural affinity with the eclecticism inherent in naturopathic philosophy. In his 2001 book Biomedicine and Alternative Healing Systems in America, Baer updated this view of the status of naturopathic medicine in a chapter entitled “Naturopathy and Acupuncture as Secondary Professionalized Heterodox Medical system^."^ With the passage of the additional 10 years, Baer observes: Unlike chiropractic, which no longer poses a serious threat to biomedicine because of its status as a specialty emphasizing spinal manipulation, a rejuvenated naturopathy finds itself in direct competition with biomedicine because both systems claim to provide a comprehensive approach to health care. As osteopathy and chiropractic did earlier, naturopathy . . . (is)increasingly incorporating the theory and social organization of biomedicine. (N)aturopathy . . . with (its) reductionist philosophy and (its) focus on individual responsibility for healthy living may well undergo further growth in an era of growing health

THE TWENTY-FIRST CENTURY AWAITS Baer carried his examination of the sociopoliticalaspects forward in his 2001 article, The Sociopolitical Status 0fU.S. ‘Twaddle and Hessler (professors of sociology, Universityof Missouri) were actually the first to take notice of an ‘expansion and professionalization of naturopathy“ in the second edition of A Sociology of Health.37They summarized the situation in the late 1980s in this way: Clearly, naturopaths are making a considerable effort to increase the standard of training and to define a professionalalternative to allopathic medicinethat preserves much of the natural healing traditions of the nineteenth century. They seem to be making progress, while remaining a small group with little impact on medicine as a whole at the present time. They have not yet received the attention of sociological research.

Naturopathy at the Dawn of the 21st C m t uy.6He updated the “three stages of development” explored in his earlier writings* and then examined the state of naturopathic medicine as it prepared to enter the twenty-first century. Baer saw three main twenty-first century issues confronting naturopathic medicine as critical to the future of the profession: While “professionalizednaturopathy has undergone tremendous growth and legitimization since the late 1970s, nevertheless, it finds itself in a tenuous situation at the dawn of the twenty-first century in that its strength is confined primarily to the Far West and New England; it faces increasing competition from the partially professionalized and lay naturopaths; and it faces the danger of being overshadowed by a powerful biomedical system that is increasingly incorporating aspects of holistic health into its own practice.”6 Although he offered no definitive answers to these issues concerning naturopathic medicine’s future, he also highlighted additional areas needing further attention by social scientists: continued exploration of the reasons for naturopathy’s decline and rejuvenation and continued study of the naturopathic profession in recognition of its state of professionalization. In closing, Baer observed: ”In sum, while changes in the popular ideas about health and healing unleashed the social forces that enabled professional naturopathy to get back on its feet, those same social forces may overwhelm its core claim to being a unique, natural approach to healing. Whorton expresses the view that in many respects the transition from the marginalized naturopathy to the professionalized naturopathic medicine has now been accomplished.He traces his view of this transformation as part of the larger transformation “from alternative medicine to complementary medicine” on the part of osteopathy, chiropractic, and naturopathy? Whorton describes the factors that allowed this transformation even after the death of Lust in 1945: The issue of the “field’s lack of a scientific basis” was determined internally when the ”diedin-the-wool believers in ‘nature cure’ ” were outlasted by the “liberal practitioners belonging to the so-called westem group, naturopaths concentrated in the western states who recognized the validity of mainstream medicine’s scientific foundation and sought to incorporate biomedical science into their own system and apply it under the guidelines of naturopathic philo~ophy.’’~~ As Whorton noted, “a key figure among the pseudomedicals was John Bastyr-a practitioner in Seattle since the 1930s, and particularly well-known for his advocacy of natural childbirth.” Bastyr, Whorton noted, “recognized the necessity of naturopathy staying abreast of ‘Three stages of development:(1) its emergence around the turn of the lwentieth century; (2) its period of decline beginningin the late 1930s;and (3) its recent potential rejuvenation.“‘ +Baercoauthored one publication with a professor from a West German university, Eduard Seidler.

advances in biomedical science and applying those advances ‘in ways consistent with naturopathic principles.’ ”51 Bastyr was directly involved with the formation and maintenance of the NCNM during the years of naturopathy’s decline and lived to see much of “the short history of John Bastyr College (of Naturopathic Medicine) (which) is the most compelling illustration of the triumphant rebirth of naturopathy as naturopathic medicine.”51 Bastyr has been called “The Father of Modern Naturopathic Medicine” by Pizzomo, ND,3l the moving spirit behind the professionalization of naturopathic medicine and the founding president of Bastyr University. No individual has carried the practice of NDs in the United States in the way that Lust did, but Bastyr and the others profiled by Kirchfeld and Boyle in Nature Doctors kept naturopathy alive during its decline in the 1950s and 1960s so that it could, in time, reemerge.

DEVELOPMENTS OUTSIDE THE UNITED STATES Canada Two sources of information that describe the development of naturopathy in Canada deserve mention. In 1966 the Royal Commission on Health Services published its Study of Chiropractors, Osteopaths and Naturopaths in Canada, otherwise known as the Mills Report after the chief author of the report, Donald L. Mills, professor of sociology, University of Alberta. The Mills Report observed the followinf-‘: Chiropractic,naturopathy and osteopathy have beginnings which lie outside Canada. Osteopathy and chiropractic had their start in the United States in the last 19”’ century, with osteopathy beginning about a generation earlier than chiropractic. Naturopathy,on the other hand, has antecedentsgoingback earlier in the 19* century, and its development was largely in Central Europe, but it was considerably later that it came to the North American continent. Chiropractic and osteopathy began to develop in Canada shortly after emerging in the United States-that is around the beginning of the 20* century. Naturopathy, on the other hand, appears to have developed rather later on the Canadian scene that (sic) was true in the United States. To some extent each of these health serviceswas developed as a reaction to the practice of medicine as it existed in an earlier time, and in the instances of osteopathyand naturopathy, people who had been trained in medicine of the day played important parts in this development. The Mills Report in due course covered “The Origins and Definition of Naturopathy” ”The General Development of Naturopathy in Canada,” ”The Development of Naturopathy in Ontario,” “The Development of Naturopathy in Eastern Canada,’’ and ”The Development of Naturopathy in Western Canada.”30 A later article, Naturopathy in Canada: Changing Relationships to Medicine, Chiropractic and the State, by Gort

and Cobumzoupdated the development of naturopathy in Canada. The article examined the development of naturopathy in Ontario, Canada: As well, the relationships between naturopathy, medicine, and the state will be analyzed through examination of three health commissions in Ontario (including the Mills Report). Then the changing connections between naturopathy and chiropractic will be described. We conclude by commenting on the relevance of the social history of naturopathy for issues of occupational formation, for professionalization, and for medical dominance. The authors trace an emergence of naturopathy in Canada (1930s-1950s)that mirrors that of its history in the United States, which may not be surprising considering that many naturopaths and chiropractors were trained in the United States through the mid-twentieth century. They describe a decline and rejuvenation similar to that in the United States as well: From 1964 until at least 1975 there has been little if any official contact between the chiropractorsand the naturopaths. Beginning about 1975 a number of young chiropractors took a renewed interest in naturopathy, to the point where these new recruits now form the bulwark of naturopathy. They have assumed leadership roles in both the association and on the licensing board. They upgraded their qualificationsto become full-fledged naturopaths and now identdy themselves not as chiropractorsbut as naturopaths. Thus, the history of relations between the two occupations shows chiropractic first supporting naturopathy for purposes of increased scope of practice, then narrowing its focus and trying to put as much distancebetween chiropractic and naturopathy as possible. Naturopaths were forced to cooperatewith chiropractic. More recently, however, naturopathy has begun to attract those not satisfied with spinal manipulation and related therapies even though the two occupations are now completely separate.20

Elsewhere English freelance writer Robert Bloomfield traced a short but more international history of naturopathy in Traditional Medicine and Health Care Coverage.* His historical approach confirms that the development of naturopathy in the United Kingdom-with the exception of Canada-owes more to the health philosophies of Henry Lindlahr (see previous chapter) than to the father of U.S. naturopathy, Lust. Two English-language articles published in the mid1980s by Cultural Anthropology Professor Thomas Maretzki of the University of Hawaii-based on many German-language sources-trace the modem German development of naturopathy and classic German Nature Cure (The “Kur”).

OTHER RELEVANT SCHOLARSHIP As M o r t o n noted, ”Naturopathic medical practice nevertheless is still composed of distinctive therapies

backed by faith in nature. Among the most common treatment categories are clinical nutrition, botanicals, homeopathy, acupuncture, hydrotherapy, physical medicine (massage, heat, cold, electricity), spirituality, and lifestyle ~ ~ u n ~ e l i n g . ” ~ ~ Some of these therapies originated in the German nature cure tradition, and some are more American homegrown; all of them fit within the eclecticism that was part of the naturalism and vitalism that made up Lust’s vision of naturopathy. Several of these threads, as they otherwise were woven into the American medical tradition, have been the subject of recent scholarly attention that deserves mention: 1.Nature Doctors: Pioneers in Naturopathic MedicinS7 is, as Whorton put it, “the best English-language survey of the German nature cure tradition.” 2 . A n Alternative Path: The Making and Remaking of Hahnemann Medical College and Hospital of Philadelphia,33 the modern history of America’s ’‘only institution in the world to offer an M.D. degree in Homeopathy,’’ a degree program that lasted from 1848 (its founding) until 1947 when homeopathy became an elective. It was still taught until Garth Boericke, Hahnemann’s last teacher of the therapy, retired in 1958. 3. ( A profile in) Alternative Medicine: The Eclectic Medical College of Cincinnati, 1845-1942,u the history of the flagship educational institution of America’s eclectic medical philosophy and a history of the philosophy as well. 4. Kindly Medicine: Physio-Medicalism in America, 18361 9 1 P is a history of the medical philosophy that naturopathy adopted as physiatrics. 5. Medical Protestants: Eclectics in American Medicine, 1825-193921is the definitive history of the eclectic medical philosophy in which Lust was educated and trained by the American professional botanical movement’s foremost historian, John S. Haller. 6. John Uri Lloyd: The Great American EclecticI9 is the definitive biography of the last great defender of the botanical medical tradition in the United States; a pharmacist, not a physician, Flannery is the other recognized scholar of the history of botanical medicine in the United States. 7. Vox Populi: America‘s Botanical Movements7 is “the first comprehensive study of the American botanical (medical) movement.” The authors noted that the botanic legacy survived the death of the eclectic medical philosophy because, through Lust, ”naturopathy would eventually adopt much of eclectic pharmacy as its therapeutic mainstay.” They noted that Lust received an MD degree from the Eclectic Medical College of New York in 1914, the ANA’s Naturae Medicina (1953) compiled over 5 years between 1947

and 1952 was ”a compendium of 310 botanicals covering their composition, preparation, actions and therapeutic uses, and toxicology,” and that “even postmortem, eclecticism lives on in modified forms in American naturopathy” as ”best exemplified by Bastyr University.” 8. Homeopathy in America by Martin Kaufmann appears in Other Healers: Unorthodox Medicine in America, edited by Norman Gevitz. The book also has contributions by James Whorton (on popular health reform) and Walter Wardwell (on Chiropractic). Kaufmann’s contribution is notable for these observations: In addition to the revival of classical homeopathy, a major developmentin recent times has been the teaching of homeopathy in naturopathic colleges on the West Coast. In Seattle, John Bastyr, a naturopath and homeopath who had been practicing for fifty years, led the move in 1956 to establish the National College of Naturopathic Medicine, which later moved to Portland, Oregon. The college’sfour-year curriculum includes a required third-year course in homeopathy, with homeopathic electives being available to third- and fourthyears students. In 1978, three naturopathic practitioners in Seattle founded the John Bastyr College of Naturopathic Medicine. During the sixth quarter all students at that school are required to take 44 hours of course work in homeopathy, after which they may elect to take another 66 hours and up to 238 hours of clinical homeopathic instruction. The sigruficance of the naturopathic schools to the resurgence of homeopathy is demonstrated by the fact that ”about one third of the graduating class specializesin homeopathic practice, a total of about 50 each year in all.”(citations omitted)

CONCLUSION As Baer proposed, naturopathy has developed in the United States (and in Canada as well) through stages aptly described as emergence, decline, and rejuvenation. The emergence occurred during Lust’s lifetime, between 1902 when he introduced the healing philosophy that he named naturopathy and the late 1940s. Then clearly it declined, for reasons discussed in the earlier chapter and also because of its loss of professional momentum when Lust died and because chiropractic, for its own political reasons and to reshape its political profile, separated from naturopathy. Now its rejuvenation, which began in the mid-1980s when the earlier chapter first appeared, has continued bringing naturopathic medicine to an almost identical political profile to where it was when Lust died: licensed in a similar number of states and composed of a similar number of practitioners. Naturopathic medicine is a more professionalized health system than the earlier naturopathy however, and it seems that more of an impact from the naturopathic profession lies ahead.

The History of Naturopathic Medicine, Part 11: Decline and Rejuvenation-Politics and Professionalization

1.Baer HA. Organizational rejuvenation of osteopathy Soc Sci Med 1981;15A:701-711. 2. Baer HA. A comparative view of a heterodox system: chiropractic in America and Britain. Med Anthropol1984;8:151-168. 3. Baer HA. The American dominative medical system as a reflection of social values in the larger society. Soc Sci Med 1989;28:1103-1112. 4. Baer HA. The potential rejuvenation of American naturopathy as a consequence of the holistic health movement. Med Anthropol Q 1992;13369-383. 5. Baer HA. Biomedicine and alternative healing systems in America. Madison: University of Wisconsin Press, 2001a:101-102. 6. Baer HA. The sociopolitical status of U.S. naturopathy at the dawn of the 21st century. Med Anthropol2001b;15(3):329-346. 7. Berman A, Flannery MA. America’s botanico-medical movements: vox populi. Oxford, Ms: PharmaceuticalProducts Press, 2001:157-159. 8. Bloomfield RJ. Naturopathy in traditional medicine and health care coverage. Bannerman RH, Burton J, Wen-Chieh C, eds. Geneva: World Health Organization, 1983. 9. Brinker F. The role of botanical medicine in 100 years of American naturopathy. HerbalGram 1998;42:49-59. 10. Bureau of Economic and Business Research. Survey of naturopathic schools. Salt Lake City: University of Utah, 1958:3. 11. Cody G. History of naturopathic medicine. In Pizzorno J, Murray M, eds. Textbook of natural medicine, ed 4. Orlando FL, Churchill Livingstone, 19991740. 12. Cohen W. Naturopathy. In Independent practitioners under Medicare: a report to Congress. Washington, Dc:US Department of Health, Education, and Welfare, 1968;61:126-145. 13. Engel J. Doctors and reformers. Columbia: University of South Carolina Press, 2001:63. 14. Farrell JB. Naturopathic legislation and education. Rhode Island Med J 1945;28248-263. 15. Fishbein M. The medical follies. New York Boni & Liveright, 1925. 16. Fishbein M. Quacks and quackeries of the healing cults. Girard, Ks: Haldeman-Julius Publications, 1927. 17.Fishbein M. The new medical follies. New York: Boni & Liveright, 1928. 18.Fishbein M. Fads and quackery in healing. New York Covici, FriedePublishers, 1932. 19. Flannery MA. John Uri Lloyd: the great American eclectic. Carbondale: Southern Illinois University Press, 1998. 20. Gort EH, Cobum D. Naturopathy in Canada: changing relationships to medicine, chiropractic and the state, social science and medicine. 1988;261061-1072. 21. Haller JS Jr. Medical Protestants: the eclectics in American medicine, 1825-1939.Carbondale: Southern Illinois University Press, 1994. 22. Haller JS Jr. Kindly medicine: physio-medicalism in America, 1836-1911. Kent, O H Kent State University Press, 1997. 23. Haller JS Jr.A profile in alternative medicine: the Eclectic Medical College of Cincinnati, 1845-1942. Kent, O H Kent State University Press, 1999. 24. Homola S. Bonesetting, chiropractic and cultism. Panama City, FL: Critique Books, 1963:75. 25. International Society of Naturopathic Physicians Yearbook. Los Angeles: lSNP, 1948. 26. Kaufmann M. Homeopathy in America. In Gevitz N, ed. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Press, 1988. 27. Kirchfeld F, Boyle W. Nature doctors: pioneers in naturopathic medicine. Buckeye, O H Buckeye Naturopathic Press, 1994. 28. Maretzki TW,Seidler E. Biomedicine and naturopathic healing in West Germany: a historical and ethnomedical view of a stormy relationship. Cult Med Soc 1985;9:383-421.

29. Maretzki TW. The “Kur” in West Germany, Soc Sci Med 1987;2412. 30. Mills D. Study of chiropractors, osteopaths and naturopaths in Canada. Ottawa, Canada: Royal Commission on Health Services, 1966:2,212-215. 31. P i i o m o JF’Jr., Bastyr J. The father of modem naturopathic medicine. Integr Med 2004;3:28-29. 32. Reed L. The healing cults. Committee on the Costs of Medical Care 19324148,61-62,66-69. 33. Rogers N. An alternative path: the making and remaking of Hahnemann Medical College and Hospital of Philadelphia. New Brunswick, NJ: Rutgers University Press, 1998. 34. Rosengren WR. Sociology of medicine: diversity, conflict and change. New York Harper & Row, 1980. 35. Roth J. Health purifiers and their enemies: a study of the natural health movement in the United States. New York Prodist, 1976. 36. Twaddle AC, Hessler RM. A sociology of health. New York Macmillan, 1977. 37. Twaddle AC, Hessler RM. A sociology of health, rev ed. New York: Macmillan, 1987. 38. Utah Legislative Council Staff. A study of the healing arts with particular emphasis upon naturopathy (a report to the legislature, 1958). 39. Vollmer HM, Mills DL, eds. Professionalization. Upper Saddle River, NJ: Prentice-Hall, 1966. 40. Wardwell WI. Social strain and social adjustment in the marginal role of the chiropractor (PhD dissertation). Boston: Harvard University, 1951:137. 41. Wardwell WI. A marginal professional role: the chiropractor. Social Forces. 1952;30339-348. 42. Wardwell WI. The reduction of strain in a marginal social role. Am J Sociol1955;61:16-25. 43. Wardwell WI. Comparative factors in the survival of chiropractic: a comparative view. Sociol Symp 1978;22:6-17. 44.Wardwell WI. Limited and marginal practitioners. In Freeman H, Levine S, Reeder LG. Handbook of medical sociology, ed 3. Upper Saddle River, NJ: Prentice-Hall1979:242. 45. Wardwell WI. The present and future role of the chiropractor. In Haldemann S, ed. Modern developments in chiropractic. New York Appleton, 19802541. 46. Wardwell WI. Chiropractors: challengers of medical domination. In Roth J, ed. Research in the sociology of health care. Greenwich, CT: JAI Press, 1982207-250. 47. Wardwell WI. Chiropractors. In Gevitz N, ed. Other healers: unorthodox medicine in America. Baltimore: Johns Hopkins University Pkss, 1988. 48. Wardwell WI. Chiropractic;history and evolution of a new practice. St Louis: Mosby, 19923,131-136,164-168. 49. Whorton JC. Drugless healing in the 1920s: the therapeutic cult of sanipractic. Pharm Hist 1985;28:14-25. 50. Whorton JC. Inner hygiene: constipation and the pursuit of health in modem society. Oxford, England Oxford University Press, 2000:157. 51. Whorton JC. Nature cures: the history of alternative medicine in America. Oxford, England: Oxford University Press, 2001:139,184, 203-204,234-235,288-292. 52. Wiese G, Ferguson A. How many chiropractic schools? An analysis of institutions that offered the D.C. degree. Chiropract Hist 1988;8(1):27-36. 53. Wardwell WI. Orthodox and unorthodox practitioners: changing relationships and the future status of chiropractors. In Wallis R, Morley P, eds. Marginal medicine. London: Peter Cohen, 1976. 54.Baer HA. Divergence and convergence in two systems of manual medicine: osteopathy and chiropractic in the United States. Med Anthropol Q 1989;1:176-193.

Philosophy of Naturopathic Medicine Randall S. Bradley, ND CHAPTER CONTENTS Introduction 79 Medical Philosophy 79 Vitalism versus Mechanism 80 Meaning of Disease 82 Changing Society 83 Scientific Medicine 84

Natural Medicines and Therapies 85 Family and Specialty Practice 86 The Philosophical Continuum Conclusion

86

87

Naturopathic Philosophy 84 Vis Medicatrix Naturae 85

INTRODUCTION This chapter examines the philosophical foundation of naturopathic medicine and its modem applications. Unlike most other health care systems, naturopathy is not identified by any particular therapy or modalities. In fact, a wide variety of therapeutic styles and modalities is found within the naturopathic community (Box 6-1). For example, there are still practitioners who adhere to the strict “nature cure” tradition and focus only on diet, ”detoxification,” lifestyle modification, and hydrotherapy. There are also those who specialize in homeopathy, acupuncture, or natural childbirth. At the other end of the spectrum are naturopathic physicians who use natural medicinal substances extensively to manipulate the body’s biochemistry and physiology. Finally, there is the majority, who practice an eclectic naturopathic practice that includes a little of everything. From its inception more than 100 years ago, naturopathic medicine has been an eclectic system of health care. This characteristic has allowed it to adopt many of this century’s more effective elements of natural and alternative medicine as well as to adopt conventional medicine’s basic and clinical sciences and diagnostics (see Chapter 4 for further discussion).Through all of this eclecticism, naturopathic medicine has always identified the Latin expression vis medicatrix naturae (the healing power of nature) as its philosophical linchpin. However, the expression vis medicatrix naturae, by itself, does not provide a clear picture of naturopathic medical philosophy or an understanding of the practice

of naturopathic medicine in all of its varied forms. With the profession’s history of eclecticism, no two practitioners treat any individual patient exactly alike. This situation has its advantages (e.g., individualization of each patient’s care, more therapeutic options) but also makes it difficult to perceive the profession’s philosophic cohesiveness. Another major disadvantage of this eclecticism is the difficulty in developing consistent practice staiidards. To attempt to solve this problem, the modem profession has articulated a general statement of naturopathic principles that expand on vis rnedicatrix naturae (Box 6-2). However, this statement of principles is probably still not adequate to address the issues that concern modern students of naturopathic medicine or other professionals. Therefore, in order to gain a more in-depth understanding of naturopathic medicine, one must discuss medical philosophy in general.

MEDICAL PHILOSOPHY The issues fundamental to medical philosophy have changed little since naturopathy first appeared as a distinct profession at the end of the 19th century. What has changed is the level of understanding of the biologic process and the language of science. Most people who study the early writers on naturopathic medical philosophy quickly get lost in the archaic language and arguments used to justify the theories. This chapter translates these concepts and issues into modem terms. 79

Naturopathic physicians are trained to use a number of diagnostic and treatment techniques. These modalities include the following: Diagnosis. All of the conventional clinical laboratory, physical diagnosis, and imaging (e.g., radiography) techniques, as well as holistic evaluation techniques Counseling. Lifestyle, nutritional and psychological Naroral medicines. Nutritional supplements (i.e., all food constituents, constituents of biochemical pathways, etc.), botanical medicine, and homeopathy Physical medicine. Hydrotherapy, naturopathic manipulative therapy, physiotherapy modalities, exercise therapy, and acupuncture Family practice. Natural childbirth, minor surgery, natural hormones, biologicals, and natural antibiotics

The Healing Power of Nature: V/s Medlcatrix Naturae

Nature acts powerfully through healing mechanisms in the body and mind to maintain and restore health. Naturopathic physicians work to restore and support these inherent healing systems when they have broken down by using methods, medicines, and techniques that are in harmony with natural processes. First Do No Harm: Primum Non Nocem

Naturopathic physicians prefer noninvasive treatments that minimize the risks of harmful side effects. They are trained to know which patients they can treat safely and which ones they must refer to other health care practitioners. Find the Cause: Toile Causam

Vitalism versus Mechanism Historically, there have been two main medical philosophies, those of vitalism and mechanism. Their origins can be traced to the Hippocratic writings of ancient Greece. Throughout history, the line separating these two schools of thought has not always been clear, but their philosophical perspectives have generally been in opposition. The conflicting goals and philosophical foundations of these two concepts remain relevant as the modem practices of conventional and altema tive physicians come into conflict. As will be seen, the foundations of naturopathic medical philosophy are found in vitalism. However, naturopathy also recognizes the practical value of the mechanistic approach to health care.

Mechanism Up to the early part of the twentieth century, there was considerable debate over the issue of vitalism v&us mechanism in the field of biology. The mechanists, or materialists, maintained that the phenomenon of life could be explained exclusively as the product of a complex series of chemical and physical reactions. They denied the possibility that the animate had any special quality that distinguished it from the inanimate. It was their contention that the only difference between life and non-life is the degree of complexity of the system. Mechanism has several other distinctive characteristics. Its most obvious is that it is reductionistic. In fact, reductionism is often used as a synonym for mechanism. Mechanistic science is also characterized by an emphasis on linear causality. Without this emphasis on reductionism and linear causality, Western science and medicine would probably have not been so successful. As the twentieth century advanced, each new discovery in biologic and medical science reinforced the arguments for mechanism, until by the middle of the century, the biology community had almost exclusively embraced the philosophy of mechanism.

Every illness has an underlying cause, often in aspects of the lifestyle, diet, or habits of the individual.A naturopathic physician is trained to find and remove the underlying cause of a disease.

Doctor as Teacher: Docere A principal objective of naturopathic medicine is to educate the patient and emphasize self-responsibilityfor health. Naturopathic physicians also recognize and employ the therapeutic potential of the doctor-patient relationship. Treat the Whole Person

Health or disease comes from a complex interaction of physical, emotional, dietary, genetic, environmental, lifestyle, and other factors. Naturopathic physicians treat the whole person, taking all of these factors into account. Preventive Medicine

The naturopathic approach to health care can prevent minor illnesses from developing into more serious or chronic degenerative diseases. Patients are taught the principles with which to live a healthy life; by following these principles they can prevent major illnesses.

Mechanism is the philosophical foundation of biomedical science and conventional medicine. Mechanistic medicine identifies disease and its accompanying signs and symptoms as simply the result of a disruption of normal chemical reactions and physical activities. Such disruptions are caused by the direct interference in these reactions and activities of a “pathogenic agent.” (For the purposes of this discussion, the general expression pathogenic agent refers to any known or unknown etiologic agent or condition; examples are microbial agents, autotoxins, genetic defects, environmental toxins, non-endproduct metabolites, and physical and emotional stress and trauma.) A living organism, then, is simply a very complex machine that, owing to external agents and ”wear and tear,” breaks down. Because the signs and symptoms of disease are thought to be due only to these mechanical disruptions and interference with reactions,

Philosophy of Naturopathic Medicine

they are considered to be completely destructive phenomena and are therefore to be eliminated. Disappearance of the signs and symptoms indicates that the pathogenic agent and its resulting disease have been eradicated, or at least controlled. The goals of mechanistic medicine tend to be the quick removal of the signs, symptoms, and pathogenic agent. Mechanistic medicine is being practiced in cases in which the intention of the therapy is to intervene in the perceived mechanism of the disease and/or to relieve the symptoms. Examples would be the use of antihistamines to relieve rhinitis, vitamin B6 to help premenstrual syndrome, surgery and emergency care for traumatic injuries, coronary bypass surgery, antiinflammatory agents in systemic lupus erythematosus (SLE), and insulin in juvenileonset diabetes. Mechanism is also being used when an identified pathogenic agent is directly attacked or eliminated, for example, the use of antibiotics or the isolation of a patient from a particular allergen. Clearly, mechanistic medicine can be very effective in achieving its goals. In the presence of modem medical technology, it is easy to see how this philosophy came to dominate biology, medicine, and the attention of the public. However, the unsolved problems of mechanistic medicine-particularly those of chronic degenerative disease; authoritarianism, which alienates patients from responsibility for their own health, and the rising cost of health care-suggest that there are limits to the mechanistic perspective and explain why vitalism has not disappeared and is, in fact, in resurgence.

Vitalism The philosophy of vitalism is based on the concept that life is too well organized to be explained simply as a complex assemblage of chemical and physical reactions (i.e., a living system is more than just the sum of its parts). This is in contrast to the mechanist’s contention that ”the only difference between life and non-life is the degree of complexity.’’ Throughout the nineteenth century, the debate between vitalism and mechanism was carried on mostly by biologists, whose interests were mainly in the study of the organism’s specific cellular activities, such as morphologic development. These activities were argued to be “vital” and, therefore, not explainable by mechanistic science. The tendency was to infer a metaphysical quality to this concept. As can be imagined, these earlier debates lurched from one specific argument to the next as modem biology unraveled the secrets of cellular metabolism. Fortunately, the debate has now shifted back to the relevant and holistic general concepts. Although modem vitalism is inherently holistic in its view and has an emphasis on circularity as its causality (i.e., feedback loops), there is no conflict with the findings of biomedical science. Eventually, all of the individual

chemical and physical reactions that are found in the processes of life will probably be identified. What is significant is not the individual reaction, but the fact that they are all coordinated to such a degree as to produce the special activities of a living organism. An organism’s unique complexity-as demonstrated by its ability to grow and develop, respond to stimuli, reproduce, and repair itself-requires a level of organization and coordination that suggests a distinct quality that is not readily explained by mechanism. This organization and coordination have been identified as ”homeostasis” by physiology. All organisms, up to the point of death, are attempting to return to this ideal state whenever injured or ill. Because there is no inanimate counterpart to this level of complexity and organization, ”homeostasis” is the most dramatic general argument in favor of vitalism. A less dramatic argument used to support the vitalistic perspective is the ”problem of entropy.” Entropy is the tendency of any closed system to find equilibrium, that is, the state of least organization. In other words, systems tend to run down and become less complex over time. In defiance of this universal rule, life, up until the point of death, consistently creates more complex systems out of simple ones. To do this, life actively pursues external matter and energy to incorporate into itself while also selectively eliminating by-products from its utilization of this matter and energy. When the problem of entropy is examined on the molecular level, the same individual chemical processes and elements may be found in both animate and inanimate systems. In the inanimate system, however, there is a constant move toward a state of chemical equilibrium. This type of system cannot maintain an unstable chemical state and always seeks stabilization. Even after the addition of external exciting energy, the system returns to the simplest, least reactive state possible. The animate system is virtually the opposite. It is continuously in a state of dynamic chemical instability, actively seeking energy to maintain this instability and consistently moving to more complex and more organized states (and back again). It is only at the onset of death that an animate system begins to move toward equilibrium. The third general argument in favor of a vitalistic view of life is evolution. For evolution to exist as a force in nature, generations of living organisms have to survive long enough to grow, reproduce and then evolve. In order for this survival to take place, the organisms’ homeostatic and repair processes must be consistently directed toward maintaining a state of balance with the external environment (i.e., health). Any organisms that did not behave biochemically and physiologically in this manner would have died and would not have evolved. Thus the phenomenon of evolution, as the action of countless living organisms over eons, multiplies life’s

Philosophy of Natural Medicine antientropic quality and is incompatible with a mechanistic view of living systems. These easily observable examples of life’s ”special quality” suggest an “organizing force” that goes beyond what is possible from mere chemistry. This quality that makes life unique should not be mistaken as a metaphysical concept, although an argument for or against such concepts is not intended here. The point is only that vitalism is a medical philosophy based on observable scientific phenomena. Unfortunately, a definitive definition of this quality (in the old literature called the “vital force,” defense mechanism, or simply “Nature”) will have to wait for more research. At this point in the discussion, not many mechanistic practitioners would have reason to be uncomfortable, because the ideas proposed are relatively noncontroversial and just follow generally accepted physiologic principles. Interestingly, many of these practitioners probably have personal belief systems that are quite compatible with this stage of the vitalistic argument. However, the conflict becomes evident with examination of the premises upon which the practice of vitalistic medicine is based. What truly separates vitalism from mechanism, and makes it useful as a medical philosophy, is its perspective on disease and the associated symptoms.

Meaning of Disease Vitalism maintains that the pathogenic agent does not directly cause the symptoms accompanying disease; rather, they are the result of the organism’s intrinsic response or reaction to the agent and the organism’s attempt to defend and heal itself. Symptoms, then, are part of a constructive phenomenon that is the best “choice” the organism can make, given the circumstances at any particular time. These symptoms can be further described as arising from two situations. The first and most common situation is when they are from a ”healing reaction,” which is the organism’s concerted and organized attempt to defend and heal itself. These healing reactions produce what can be called “benign symptoms.” Examples are fever and inflammation in infections, almost any reaction of the immune system, and many of the symptoms of chronic disease. This interpretation of symptoms is generally ignored by mechanism. Instead, it views a symptom as the result of a destructive process and focuses on intervening by relieving the symptom or manipulating the pathologic mechanism. Mechanistic medicine is therefore most often working contrary to homeostasis and the organism’s attempt at healing (in fact, this is usually its intent). When this therapeutic approach is effective, vitalists call the result a ”suppression” (Box 6-3). This approach to health care is so pervasive that most people, lay and

When symptoms improve following treatment (regardless of the therapeutic system), it is for one of three reasons: Cure. The symptoms go away and the patient’s overall health improves. In this case the treatment can be discontinued and the patient continues to do well. Suppression. The symptoms go away but overall the patient becomes less healthy. The treatment can be discontinued and the symptoms will stay away, but either the patient feels worse generally (i.e., deceased sense of well-being, less energy, or experiencing moods) or new, often more limiting, symptoms eventually develop (e.g., suppressed eczema leading to asthma). Palliation.The symptoms are improved but only as long as the treatment is continued. At best, palliation is something that is given while a curative treatment is given time to work. In and of itself, palliation will never lead to a cure, but unfortunately, continued palliation may eventually lead to suppression.

The four types of healing reactions Reaction

Description

Acute, asymptomatic

Organism easily defends itself Relative strengths of pathogenic agent and organism similar; symptoms of body defending itself apparent

“Healing crisis”

Vigorous but unsuccessful Chronic, mildly symptomatic

Pathogenic agent stronger than organism; death if no intervention Healing reaction feeble but adequate to maintain life; progressive degeneration

professional alike, today routinely suppress mild fevers with antipyretics. In contrast, vitalism considers these symptoms to be the product of a constructive phenomenon and therapeutically stimulates and encourages this directed healing process. Rather than simply trying to eliminate a pathogenic agent, as mechanistic therapy might, vitalism focuses more on augmenting the organism’s resistance to that agent. That is not to say that vitalists object to removing the agent, only that it should be done in the context of simultaneouslyincreasing resistance (in other words, decreasing susceptibility).The importance of this approach becomes evident when one recognizes that disease is only possible when both a pathogenic agent and a susceptibility to that agent are present. Healing reactions can take several forms, as shown in Table 6-1. In the first type, an organism’s response to a pathogenic agent does not produce symptoms. When the organism is capable of easily defending itself from the agent, no symptoms are perceivable. This is a common homeostatic process and is demonstrated when a potential pathogen, such as beta-hemolytic streptococcus, is

Philosophy of Naturopathic Medicine

cultured from a healthy person’s throat. However, when the organism is more susceptible or the relative strength of the pathogenic agent is greater, a threshold is reached and symptoms become perceivable. Successful healing reactions of this type include vigorous acute diseases that quickly resolve. The early naturopaths would have called these acute reactions “healing crises.” As the susceptibility of the organism increases relative to the strength of the pathogenic agent, there is a greater likelihood that the healing attempt will not be successful. When such a reaction is unsuccessful but vigorous, death may result, unless there is timely application of vitalistic or mechanistic therapy. Examples of this situation are acute bacterial meningitis and cholera. When the healing attempt is feeble and therefore ineffective, the reaction usually goes into the “chronic disease” stage. Vitalists observe that suppression seems to increase the likelihood that the reaction will be forced to go into such a chronic stage. In this situation the reaction is “smoldering,” and most often the organism cannot overcome the pathogenic agent unassisted. It just “holds its own,” and if the organism’s general health decreases over the years, the reaction gradually degenerates, producing symptoms that become less benign as it moves to an end-stage pathology. If the organism can be therapeutically stimulated to produce a more vigorous healing reaction, it can often successfully complete the original healing attempt. This augmented reaction is another example of a naturopathic healing crisis and would also be called an “aggravation” by the vitalists who practice homeopathic medicine. Intervening in the mechanism of disease by relieving symptoms does little to stimulate or encourage the healing response; in fact it usually actually inhibits the healing response. In contrast, vitalistic therapies can be very effective in helping these healing reactions, because the goals of such therapies are precisely the same as those of the organism. Thus, it is thought that vitalistic medicine works because, by honoring this process and thereby strengthening the whole organism, it encourages a more effective healing effort. Ideally, the organism is then able to accelerate and complete its reaction against the pathogenic agent, leading to the permanent disappearance of the symptoms as it returns to a state of health. It would be naive to say that every stage of the healing reaction is positive and in the best interest of the organism or that no symptoms should be palliated. The modern vitalist acknowledges that intervention is sometimes necessary. On the other hand, it is important to note that routine intervention can encourage its own worstcase scenarios. When mechanistic therapies successfully suppress an organism’s chosen healing reaction, a less effectiveand less desirable response is often produced. Therefore, when suppression occurs, it can lead to a more complicated medical situation. Consequently, the

very practice of mechanistic medicine tends to reinforce its practitioner’s conviction that intervention is usually necessary. It should be noted, however, that not all intervention leads to suppression. It happens less often when the pathogenic agent can be readily eliminated, such as in nonrecurring acute bacterial infections, or when relatively noninvasive therapies are used, such as natural medicines. The second type of symptom-producing situation occurs when the organism produces symptoms in response to an organic lesion that arises from the direct pathologic influence of a pathogenic agent. These can be called ”morbid symptoms,” examples of which are symptoms from the mass of an invasive tumor, shortness of breath from emphysema, and pain of an injury or myocardial infarction. It should be mentioned that even these symptoms are the result of the organism’s overall effort to maintain homeostasis; benign symptoms are also often present. In addition, a morbid symptom is not necessarily produced for a negative reason. For instance, pain is valuable as an indication of tissue damage. As can be seen, many, if not most, of these situations involve ”end-stage” disease. Here mechanistic therapies can be very positive when the goals of the therapy do not conflict with those of the organism. There are instances when invasive intervention will probably be required to save “life and limb.” These include such conditions as birth and genetic defects, serious traumatic injuries, crisis situations, overwhelming infections, and many malignancies. Unfortunately, conventional intervention does not guarantee a successful outcome either. Even in these situations, however, the effectiveness of vitalistic and natural therapy should not be underestimated, and their concurrent use will certainly augment any mechanistic intervention. The concept of benign and morbid symptoms can be a useful tool to help the understanding of the healing and disease process, but in many situations, it may not be possible to categorize the type of symptoms produced. A rough rule of thumb, however, would be that virtually all symptoms accompanying “reversible” or functional diseases are benign. On the other hand, many of the symptoms associated with traumatic injury and end-stage pathology would be morbid symptoms.

Changing Society After this discussion of vitalism’s perspective on disease, the question that comes to mind is “If most health problems are likely to respond to vitalistic medicine, then why is mechanism dominant?” The best answer is probably found in examination of the general attitudes held by society during the Industrial Age just ending. Mechanism came into dominance during this period because it fit neatly into the Industrial Age‘s worldview. This is the ”man conquers nature” view that regards

Philosophy of Natural Medicine

humanity as above and separate from the world in which it lives. It follows that nature is simply a resource that technology will eventually subdue or subjugate and put into order. Although this perspective is still very strong in Western society, there has been a dramatic change within the last 40 years. Attitudes are now shifting in favor of the ecologic integration of humanity into the environment. This "new" worldview holds that humanity is part of an orderly nature and that to ignore this fact creates situations that eventually become problems. Most ecologic disasters are excellent examples of the results of the old view. In addition, the new view contends that if an effort is made to understand how nature functions and an attempt is made to work within that understanding, humanity's needs can be more efficiently met. Mechanistic medicine, as part of the "old" worldview, generally sees disease as something to conquer and put into order. Vitalistic medicine, on the other hand, looks at the order that is already present and attempts to integrate its therapy into that orderly process. As a result, vitalism is becoming increasingly popular as society shifts from the old to the new worldview. The belief systems of many mechanistic practitioners recognize this order. However, because of education and peer pressure, these personal beliefs are rarely translated into clinical practice. The mechanistic view is still relatively pervasive in society, and because mechanism is convenient (e.g., taking aspirin for a headache), vitalistic practitioners can generally shift their perspective and successfully use mechanistic therapy (although their therapeutic goals may be different). On the other hand, because mechanists dispute the premises upon which vitalistic medicine is based, they generally have great difficulty when attempting to practice or research a vitalistic therapy and frequently cannot demonstrate its efficacy.

Scientific Medicine Although mechanism and vitalism represent opposing perspectives, the systems of medicine that represent these philosophies can be successfully tested and examined with the scientific method.+ That is not to say that the philosophy of vitalism has been unquestionably proven-only that the validity of vitalistic interventions can be scientifically demonstrated. If a therapy can be proven effective, the effectiveness implies the accuracy 'A thorough review of all health care modalities in use today reveals a category that could be called 'esotericia." Although the category is not historically relevant to this discussion of medical philosophy, and its brief mention is not intended as an argument for or against "legitimacy," esotericia would include such things as prayer, faith healing, psychic healing, Healing Touch, Touch for Health, and medical dowsing. Generally speaking, the actual operator of the therapy must call on God or have some special endogenous skill or 'power" that goes beyond intellectual knowledge. These modalities are all 'operatordependent" and cannot be examined separate from the practitioner-thus greatly increasing the dmuity of their scientific verification.

of the philosophy upon which it is based. Unfortunately, very few of the vast resources of the twentieth century biomedical community have been directed toward investigating vitalistic medicine. Conventional medicine, as the dominant health care system and a representative of mechanism, has claimed for itself the title "scientific medicine." However, it is inherently no more or less scientific than vitalistic medicine. A system is scientific only when it has met the criteria of the scientific method. This method requires the collection of data through observation and experimentation, and the formulation and testing of hypotheses. Nonprejudicial science can effectively study any system, but the researcher must understand the system's particular paradigm. Experiments on a vitalistic therapy based on a reductionistic and mechanistic model would be less than satisfactory. The criteria of the scientific method can be met by vitalistic medicine, but only when the researchers recognize that it cannot be studied as though it is reductionistic or based on a simplistic model of linear causality. When the experimental model acknowledges the complexity of a living system in a social context (i.e., holism and circularity), vitalistic medicine proves to be both verifiable and reproducible and, thus, scientific. Unfortunately, because of its current political and economic dominance, conventional medicine is in the position to dictate (through economic and publication control) that research, and therefore the scientific method, will be applied primarily to itself. The result is that most conventional practitioners dismiss vitalistic medicine, along with all alternatives, as unscientific. This is unfortunate because most vitalistic physicians also have extensive training in mechanistic and/or conventional medicine. Generally, they are capable of practicing mechanistically, and do so to greater or lesser degrees. The conflict between the practitioners of these different systems is very often due to a lack of constructive dialogue. This can be attributed to two general causes: The first is simply that each system defines the world of "correct" medicine in terms of its own principles; the second is the issue of who controls the economic and political power.

NATUROPATHIC PHILOSOPHY Historically, naturopathy is a vitalistic system of medicine. However, over the last 100 years it has also incorporated a number of therapies that can function mechanistically. What makes them acceptable, given naturopathic medicine's vitalistic foundation, is that they are natural therapies. Natural medicines and therapies, when properly used, generally have low invasiveness, and there is little evidence that they cause suppression or side effects. When used mechanistically, they entail

some intervention while still allowing the organism’s healing abilities the opportunity to continue unopposed, especially when they are used to support the body’s own healing processes.

Vis Medicatrix Naturae Naturopathic physicians assert that all true healing is a result of vis medicatrix nafurae (the healing power of nature). Unfortunately, some people in the field of alternative medicine (including some naturopathic physicians and students)have mistakenly translocated this concept to the therapy. These practitioners tend to operate as though this ”healing power” is an intrinsic property of the natural therapy or medicinal substance itself. In contrast, proponents of vitalism and naturopathic medicine have always understood that the “healing power of nature” is an inherent property of the living organism. Vis medicafrix nafurae is the living organism’s ”desire” and ability to heal itself. The application of this principle in practice depends, of course, on the patient’s needs. Ideally, it involves only the use of therapies that support the organism and encourage its intrinsic healing process to work more effectively.It also avoids the use of medicines and procedures that interferewith natural functions or have harmful side effects. Natural medicines and therapies are therefore preferred, because when they are used properly and in appropriate circumstances, they are the least harmful, least invasive, and best able to work in harmony with the natural healing process. The total organism is involved in the healing attempt, so the most effective approach to diagnosis and treatment is to consider the whole person. In addition to physical and laboratory findings, important consideration is given to the patient’s attitude, psychological and spiritual state, social circumstances,lifestyle, diet, heredity, and environment. Careful attention to each person’s unique individuality and susceptibility to disease is critical to the proper evaluation and treatment of any health problem. Naturopathic physicians contend that most disease is the direct result of the ignorance and violation of what would be traditionally called “natural living laws.” These general lifestyle rules (includingdiet) are based on the concept that there is an environment (both internal and external) that optimizes the health of an organism. Analysis of the lifestyles of Paleolithic and healthy primitive and modern cultures gave naturopathic physicians and their progenitors many clues as to what a healthy lifestyle should involve. Throughout most of modern history, biomedical science has focused primarily on researching the sick. Recently it has finally begun to evaluate what makes for a healthy lifestyle. To no one’s surprise, this lifestyle looks like the same one advocated by naturopaths for

the last 100 years. A healthy lifestyle could be generalized to include the following: Consuming natural unrefined foods Getting adequate amounts of exercise and rest Living a moderately paced lifestyle Having constructive and creative attitudes Connecting to other people socially Being present to the spiritual aspects of life Avoiding toxins and polluted environments Maintaining proper elimination It is also important to control these areas during illness, in order to remove as many unnecessary stresses as possible and to optimize the chances that the organism’s healing attempt will be successful. Therefore patient education and responsibility, lifestyle modification, and preventive medicine are fundamentalto naturopathic practice. Although the practice of naturopathic medicine is grounded in vis medicatrix naturae, it also recognizes that intervention in the disease process is sometimes efficacious and, at times, absolutely necessary. Naturopathic physicians treat patients with a wide variety of therapeutic modalities. Some of these are vitalistic and some mechanistic. It is the goal of the therapy that ultimately determines which approach is utilized. Naturopathic physicians have a long-standing tradition of integrating the best aspects of traditional, alternative, and conventional medicine in the interest of the patient. As appropriate, patients are referred to other health care practitioners. Whenever possible, every effort is made to use all treatment techniques in a manner that is harmonious with the naturopathic philosophy.

Natural Medicines and Therapies The medicines administered and prescribed by naturopathic physicians are primarily natural and relatively unprocessed. Although it is recognized that some situations may require the use of synthesized medicines, their use is considered less desirable. Some of the argumentsin favor of natural medicinal substances have already been discussed. In addition to the reasons noted previously, natural agents are preferred because their constituents have been encountered in nature for millions of years. This long period of exposure has enabled the body to develop metabolic pathways capable of effectivelyutilizing, processing, and detoxifying these medicines. Four categories of natural medicines can be defined. The first consists of substancesfound in nature that have been only minimally processed. Examples include, but are not limited to, foods, clean air and water, and whole herbs. The early ”nature cure” practitioners used this category primarily. The second category involves agents extracted or made from naturally occurring products. Although these medicines have undergone pharmacologic processing, their constituents are still in the form

Philosophy of Natural Medicine

found in the original natural substance. These first two types of natural medicinal substances have synergistic constituents that allow their use at lower doses with a resultant broader and safer therapeutic index. Examples of this category are tinctures and other botanical extracts, homeopathic medicines, glandular extracts, and other substances of animal origin. The third category of natural medicines comprises those highly processed medicinal substances that are derived from a natural source. Often everything has been removed from such substances but the identified active in@ent, and they no longer have any synergistic constituents. Examples are many new phytotherapeutic agents, constituents of biochemical pathways, enzymes, amino acids, minerals, vitamins, and other food extracts. The fourth category that may be considered "natural" are those manufactured medicines that are presumed to be identical to naturally occurring substances.They have the advantage of being less expensive and are typically available in higher concentrations. However, their use is less desirable for the following reasons: The difficulty of determining whether they are indeed the equivalent of the natural product. Their lack of natural synergistic components. The inclusion of contaminates from the manufacturing process; these contaminates are often chemically and structurally similar to the desired medicine but generally interfere with the normal pathways rather than enhance them. Examples of these manufactured "natural" medicines include hormones, synthetic vitamins, and analogues of plant and animal constituents. Increasingly, medicines of the types identified in the third and fourth categories are being grown "synthetically" by microorganisms specially engineered to produce the desired medicinal substance.It is difficult to say which of these categories best describes this situation. There are also potential problems with this kind of manufacturing process, as evidenced by the tryptophan disaster of 1989. Naturopathic physicians also use many natural therapies. What makes a therapy "natural" is that it is derived from a phenomenon of nature and is used to stimulate the body to heal itself. Examples of these phenomena are air, light, heat, electricity, sound, and mechanical force. Some of these natural therapies are mechanical and manual manipulation of the bony and soft tissues (naturopathic manipulative therapy), physiotherapy modalities (e.g., electrotherapy and ultrasound), hydrotherapy, and exercise therapy. Naturopathic physicians also use lifestyle modification, counseling, and suggestive therapeutics. These therapies are all discussed in more detail in other chapters.

Family and Specialty Practice Naturopathic physicians, like other types of primary care providers, develop practices that meet their personal interests and skills. Although most are engaged in general and family practice, many have also specialized in particular therapeutic modalities and/or types of health problems. In all situations, however, the emphasis is still on treating the whole person. The practice of family medicine requires the use of some techniques and devices that are not, in the strict sense of the word, natural therapies but belong among the comprehensive family practice services offered by the naturopathic profession. Included in family practice are such services as the prescription and fitting of birth control devices, first aid, and minor surgery. Minor surgery includes the repair of minor wounds and lesions and the removal of growths and foreign bodies from superficialtissues. When necessary, it involves the use of local anesthetics and appropriate first aid procedures. First aid comprises the treatment of ambulatory acute injuries and conditions that are routinely seen and handled in general practice. Many naturopaths have also developed advanced expertise in different natural therapeutic modalities. These practitioners have usually invested in postgraduate training, such as that available through residencies. Three therapeutic specialties that merit mention are natural childbirth, acupuncture, and homeopathy.

THE PHILOSOPHICAL CONTINUUM When the various healing systems are examined and placed on a philosophical continuum, mechanism and vitalism are on different ends of the same health care spectrum. Both ends of this health care continuum have their strengths and weaknesses. Mechanistic medicine is effective for trauma, crisis care, end-stage disease, and many acute disorders. It is essentially a failure for chronic disease. In fact, conventional medicine considers most chronic diseases incurable. Vitalistic medicine, on the other hand, has its most dramatic successes with chronic disease and is effective with many kinds of acute disease. It is not very effective with trauma and crisis care or with end-stage disease, although it can be a very useful complement to conventional medicine. As can be seen, both ends of the health care spectrum are necessary if every patient's health care needs are to be met: Although aspects of naturopathic medicine (e.g., constitutional hydrotherapy) and conventional medicine (e.g., chemotherapy)represent the archetypes of vitalism and mechanism, the space between the ends of this spectrum is a gray area within which both naturopathic and conventional physicians operate on a continual basis. Naturopathic physicians integrate vitalistic therapies

Philosophy of Naturopathic Medicine

With a thorough grounding in vis medicatrix naturae, modern naturopathic medicine will flourish and achieve a leadership position as the dominant health care paradigm shifts to the integrated medicine of the future.

with some mechanistic therapies, but it is not possible for everyone to be experts in everything. The vast majority of naturopathic or conventional physicians cannot learn and competently practice all types of health care. Consequently, to effectively meet society’s health care needs, it is necessary to create an integrated health care system. Such an integrated system would have both vitalistic and mechanistic practitioners working together in the same clinical settings. The trends of popular culture and a biomedical science that is finally beginning to study alternative medicine suggest that the creation of an integrated health care system is now under way. However, it takes no great skill for a mechanistic medical doctor to switch from giving a synthetic drug for a disease to giving a natural medicinal substance. If naturopathic medicine becomes just another mechanistic system using natural medical substances to treat disease (instead of a system identified with treating the whole person vitalistically), it will lose its unique niche in an integrated health care system. To survive and thrive in this new environment, naturopathic medicine must keep its vitalistic roots.

The practice of naturopathic medicine can be summarized most simply as helping the body/mind heal itself in the least invasive, most fundamentally curative manner possible. This approach is not tied to any particular therapy or modality, but rather is oriented to a rational blend of vitalistic and mechanistic principles working with the whole person and educating the patient in the ways of health. As naturopathic knowledge of health and disease grows, new therapies and approaches to health care will be added as they satisfy the principle of vis rnedicatrix naturae. With integration of the larger health care system, naturopathic medicine’s place is assured as the profession that truly understands each unique human being’s power to heal.

Baer HA. The potential rejuvenation of American naturopathy as a consequence of the holistic health movement. Med Anthropol 1992;13:369-383. Coulter HL. Divided legacy. Richmond, CA. North Atlantic Books, 1975 (vol. I), 1977 (vol. 2), 1982 (vol. 3), 1994 (vol. 4). Coulter HL. Homeopathic science and modern medicine. Richmond, CA North Atlantic Books, 1980. Dubos R. Mirage of health utopias, progress, and biological change. New York Harper, 1959, p. 131. Kirchfeld F, Boyle W. Nature doctors: pioneers in naturopathic medicine. Portland, OR: Medicina Biologica, 1994. Lindlahr H. Philosophy of natural therapeutics. Maidstone, Kent, U K Maidstone Osteopathic Clinic, 1975. McKee J. Holistic health and the critique of western medicine. Soc Sci Med 1988;26775-784.

McKeown T. The role of medicine: dream, mirage or nemesis? Oxford: Basil Blackwell, 1979. Payer L. Medicine and culture: varieties of treatment in the United States, England, West Germany, and France. New York: Henry Holt and Company, 1988. Schubert-Soldern R. Mechanism and vitalism: philosophical aspects of biology. Notre Dame, IN: University of Notre Dame Press, 1962. Selys H. The stress of life. New York McGraw-Hill, 1956. Sinnott E. The bridge of life: from matter to spirit. New York Simon and Schuster, 1966. Spitler HR. Basic naturopathy: a textbook. New York American Naturopathic Association, 1948. Zeff JL.The process of healing: a unifying theory of naturopathic medicine. J Nat Med 1997;7122-125.

CONCLUSION

Placebo and the Power to Heal Peter Bennett, ND CHAPTER CONTENTS Introduction 89

The Vis Medicatrix Naturae 95 Conscious Control over Homeostasis 95

Placebo Response 90 Why Study the Placebo Effect? 90 History of Placebo 91

Physiologic Mechanisms 95 Brain Region Activity 96 Placebo and Stress Physiology 96 Physiologic and Psychologic Stress 97 Endorphins, Hormones, and Neuropeptides 97

Origin of theTerm Placebo 91 Clinical Observations of “Known” Placebo Therapy 92 Other Clinical Observations 92 Placebo Myths 93 Myth1 93 Myth2 93 Myth3 94 Myth4 94 Pharmacodynamics 94 Packaging and Delivery 94 Placebo Interactions 94

Clinical Application 98 Prima Non Nocerum: Prioritize a Treatment Program and Establish a Hierarchy of Care Tollem Causum: Remove the Cause of Disease 99 Support the Therapeutic Relationship 99 Enhance Positive Emotional States 100 Implement Therapeutic Conditioning or Learning 102 Use Altered States of Consciousness 104

98

Ethics 105 Conclusion 106

Placebo Healing Mechanisms 94 The Role of Emotions 95

INTRODUCTION As living organisms, we have evolved with an innate capacity for self-healing. This most remarkable fact is one of the most interesting discoveries in medicine. In November 2000’17 health centers and agencies gathered together for 3 days to explore the science of self-healing hidden in the power of placebo. This conference focused on the powerful mind-brain physiology of placebo and its potential for affecting the course of human disease.’ One of the conclusions of the conference was that the “placebo response’’ has potential use for medical application and needs further exploration. Research has shown that the impressions and thoughts in a patient’s mind and the attending physician’s intention have such a profound effect on the

health of the patient. The ability of the patient’s mind to affect the process of virtually every disease has been well documented,23 and the internal mechanisms and pathways by which the mind can positively or negatively affect the immune and healing processes has been investigated in the scientific literature of psychoneuroimmunology.45 As the body of knowledge documenting the critical role of the patient’s psyche in the therapeutic environment has grown, it has become increasingly important for all schools of medicine to teach the healing potential of the human mind. Conventional medical thinking has tumed its opinion of placebo from that of a nineteenth century pejorative to a concept that sums up the complex mind-body interactions affecting the power of people to heal.’ 89

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Unfortunately, the most modern abuse of the concept of placebo comes from biased critics of alternative medicine who have chosen to label the beneficial effects of these therapies as merely from placebo. These critics dismiss the science of natural healing as an imaginary phenomenon and the last resort for quack doctors who had no real medical treatments to offer their patients? The most interesting aspect of placebo literature is exploration of extent of the potential of the mind to influence human health. The “power of placebo” draws upon the innate ability of the body to spontaneously heal itself, a fundamental principle of naturopathic medicine. This point separates the care delivered by naturopathic physicians from the pharmaceutical and surgical approaches of current medical “standard of care” procedures. If common medical texts on internal medicine or ambulatory care are examined, the word ”healing”is not found in the index. Except for the diagnostic evaluation of “self-limitingdiseases’’and “spontaneousregression,” the ability of the human organism to self-right and repair from a state of acute or chronic disease is explored in modem medicine except under the designation “placebo response.” The placebo response therefore, represents all the “unknown” variables that conspire to heal a patient in spite of pharmaceutical and surgical intervention.

PLACEBO RESPONSE Placebo response represents the power of the mind, through intention, to effect (1)a change in oneself, (2) a change in those around one, and (3) a change in the environment one lives in. Intention has been observed to affect machines7and remote biologic systems? Distantly influenced systems include another person’s electrodermal activity, blood pressure, and muscular activity; the spatial orientation of fish; the locomotor activity of small mammals and the rate of hemolysis of human red blood cells. Prayer, an example of intention, has been extensively studied as a therapeutic healing modality? One study showed a dramatic result in cardiac intensive unit recovery when patients were prayed for by someone at a distant location.’O Patients in this study were 5 times less likely to require antibiotics, 3 times less likely to experience pulmonary edema, 12 times less likely to require endotracheal intubation, and significantly less likely to suffer cardiac mortality. Our biologic systems must conform to the laws of physics. Modem physics has investigated the effect of an observer on the system observed. It has been shown that an electron will acquire a definite axis of measurement in the process of measurement. Bell’s theorem supports the idea that our universe consists of particles unified instantly as an indivisible whole; our biologic homeostatic systems cannot be analyzed in terms of independent parts. The interconnected nature of our biologic systems

has been known for thousands of years; the ancient Buddhist concept of “interdependent phenomena” accurately describes this paradigm. Our current medical system has not shifted with the developments in modem physics. These modem ideas of biologic systems are diametrically opposed to Cartesian paradigms that our internal and external environment consists of separate parts joined by local connections. Medicine must take a ”quantum leap” to catch up with the knowledge we possess about our environment through quantum physics. We can see clearly that it is impossible for a doctor to observe a patient without the observation’s affecting the health of the patient. Pierre Teilhard de Chardin postulated, and Rupert Sheldrake proved, the possibility of a ”morphogenetic field” for the subliminal communication to all members of our species.” The effect of human thought on other members of society has been described in human society since the beginning of our earliest cultures. Naturopathic physicians believe that the body has a powerful ability to maintain health and repair to a healthy state after disease by virtue of its inherent power of vitality. This homeostatic healing mechanism has been selected by Nature in the same way that the organs that we consider to be vital to our survival have been selected. Healing happens unaided by simply maintaining an environment that does not obstruct the path of cure. Because placebo literature documents the philosophical foundations of naturopathic health care model, it is important to review the full scope of this subject. Integrating known placebo initiators in clinical practice is essential for good patient care.

WHY STUDY THE PLACEBO EFFECT? For hundreds of years, physicians have watched their patients respond to therapies with a wide range of results. Some patients recover fully, whereas others, with apparently identical diseases and therapies, wither and die. Today, a skilled physician can correctly diagnose the condition of a patient by applying the sophisticated techniques of modern medicine. Then an appropriate therapy, the efficacy of which has been thoroughly proven in research and clinical trials, can be prescribed. Through this process the patient will have received the best care available through current medical technology. But if the diagnosis, therapy, and therapeutic interaction do not stimulate the hope, faith, and belief of the patient, the chances of success are measurably diminished. It has been repeatedly demonstrated in the literature on the placebo effect,’2 psychoneuroimmunology~and psychosomatic,I3beha~iora1,’~J~ and psychiatric16medicine that the beliefs of the both the patient and the doctor, and their trust in each other and the process, generate a sigruficant portion of the therapeutic re~u1ts.l~

Placebo and the Power to Heal

The placebo and its effect are not separate from any aspect of the therapeutic interaction, nor are they ”nuisance variables” muddying a clear clinical picture. Rather, they send the physician a strong message: It is a patient’s own belief system that mobilizes the inherent healing powers of the mind. By studying the placebo effect, a physician is better able to fully harness this power to trigger internal healing mechanisms. Yet, despite the quantity of documentation, the placebo effect remains one of the most misunderstood areas in modern medicine. The physician should always strive to stimulate selfhealing, or the placebo effect, as fully as possible to maximize its potential for healing. Someday physicians will be able to explore the deepest recesses of the unconscious to directly access therapies that assist the body in restoration of internal homeostasis. The optimal model for health care is the marriage of appropriate medical technology with the factors that have been shown to generate the placebo effect. This exciting scenario shines on the horizon as the health care of the future. Because the doctor-patient relationship is such fertile ground for stimulating the healing response,1E2o it serves a physician well to comprehend the nature of the placebo phenomena in order to fully realize this potential for healing.

HISTORY OF PLACEBO Both the modern physician and primitive medicine men and shamans of the past have used ineffective therapies to stimulate healing in their patients. As Shapiro observes, ”the true importance of placebo emerges with a review of the history of medical treatment.”21It has been noted that the historic therapies of the medical profession and traditional healers, ”purging, puking, poisoning, puncturing, cutting, cupping, blistering, bleeding, leeching, heating, freezing, sweating, and shocking,”22 worked because of the placebo effect. Although in retrospect, these practices might seem ludicrous, all of these therapies were once considered effective. As an embarrassing epilogue, placebo literature has shown that ineffective procedures are just as pervasive in modern medicine as in the jungle hut of the shaman. We must therefore ask ourselves how unfounded medical therapies can survive peer review literature and centuries of cultural acceptance. The power of the patient’s belief in the potential for cure has been consistently observed throughout history. Both Galen and Hippocrates recognized the strong effect of the mind on disease and recommended that faith, treatment ritual, and a sound doctor-patient relationship could provide important therapeutic results.= Recognition of the power of positive expectation was recorded frequently in the medical literature of the seventeenth and

eighteenth centuries. It was in the eighteenth century that placebo was first defined as a ”commonplacemethod of medicine.”24As the importance of drug therapy grew in the nineteenth century, the term placebo became identified with medicines involving substances that resembled drugs. But in the 1940s, because of the increase in double-blind research, it became associated with inert substances that were used to replace active medication.

ORIGIN OF THE TERM PLACEBO The original Latin meaning of placebo is ”I shall please.”25 Although the term had a purely medical application in the first half of the twentieth century, its meaning has been subject to various interpretations throughout the last several hundred years. Before the 1940s, placebos were pharmacologically inactive substances, such as saline and lactose pills, used to satisfy patients that something was being done for them-in other words, the doctor was ”pleasing” the patient. The 1940s and 1950s saw an explosion of the use of double-blind experimental procedures to evaluate the growing number of new drugs and medical procedures. Suspicion arose that all medical therapies contained an element of placebo phenomena.26This new understanding pressed the scientific community to offer new, far broader definitions. ShapiroZ offered the classic definition of a placebo: Any therapeutic procedure (or that component of any therapeutic procedure) which is given deliberately to have an effect, or unknowingly has an effect on a patient, symptom, syndrome, or disease, but which is objectively without specific activity for the condition being treated. The therapeutic procedure may be given with or without the conscious knowledge that the procedure is a placebo, may be an active (non-inert) or inactive (inert) procedure, and includes, therefore, all medical procedures no matter how specific-oral and parenteral medications, topical preparations, inhalants, and mechanical, surgical, and psychotherapeutic procedures. The placebo must be differentiated from the placebo effect which may or may not occw and which may be favorable or unfavorable. The placebo effect is defined as the changes produced by placebos. The placebo is also used to describe an adequate control in research.

A more accurate definition would be as follows: “Placebo effect is the process of a physician working with the self-healing processes of a patient. Placebo response means healing that results from the patient’s own natural survival and homeostatic defense mechanisms.” Modern placebo definitionsextend to its nature, properties, and effects. Placebo can be known or unknown, active or inactive, positive or negative in results (placebo effect vs. nocebo effect), and can extend to all forms of diagnostic or therapeutic m~dalities?~ further defined in BOX7-1.

Philosophy of Natural Medicine now gone, his last hope vanished, and he succumbed in less than two days.B Known placebo: Placebo used in a single-blindexperiment. The doctor knows it is placebo but the patient does not. Unknown placebo: Double-blind use of placebo. Neither the doctor nor the patient knows that the medication is a placebo. Active placebo: Any substance that has an intrinsic physiologic effect that is irrelevant to the ensuing placebo effect. The vasodilating effect of niacin would make it a good active placebo. Inactive placebo: Any substance that is used with medicinal intent but that has no inherent physiologic effect. Aside from the glucose effect in a sugar pill (or, to complicate things, an allergic reaction to some component of the supposedly inert substance), it has no physiologic effect. Placebo edfect Any changes that occur in a patient as the result of placebo therapy. Nocebo effect: Any changes that occur as a result of placebo therapy that are perceived as negative or counterproductive to the path of cure.

CLINICAL OBSERVATIONS OF “KNOWN” PLACEBOTHERAPY One of the more dramatic examples of the placebo effect reported in the medical literature involved a patient with advanced lymphosarcoma, which KlopferZ8 reported was highly susceptible to the patient’s faith in a n experimental drug called Krebozion. When the patient was started on the drug injections, his enthusiasm was so intense that ”The tumor masses had melted like snowballs on a hot stove, and in only a few days, they were half their original size!”28The injections were continued until the patient was discharged from the hospital and had regained a full and normal life, a complete reversal of his disease and its grim prognosis. Within 2 months of this recovery, reports that the drug Krebozion was ineffectual were leaked to the press. Learning of this report, the patient quickly began to revert to his former condition. Suspicious of the patient’s relapse, his doctors decided to take advantage of the opportunity to test the dramatic regenerative capabilities of the mind; a single-blind study was performed on the patient using pure placebo. He was told that a new version of Krebozion had been developed that overcame the difficulties described in the press, and some of the drug was promised to him as soon as it could be procured. With much pomp and ceremony saline water placebo was injected, increasing the patient’s expectations to a fevered pitch. Recovery from his second near terminal state was even more dramatic than the first. Tumor masses melted, chest fluid vanished, he became ambulatory, and even went back to flying again. At this time he was certainly the picture of health. The water injections were continued, since they worked such wonders. He then remained symptom-free for over two months. At this time the final AMA announcement appeared in the press“nationwide tests show Krebiozen to be a worthless drug in the treatment of cancer.” Within a few days of this report, h4r.Wright was readmitted to the hospital in extremis. His faith

Other famous placebo case studies are one reported by on “voodoo death” caused by belief, and one reported by Kirkpatrick,30who documented the spontaneous regression of lupus erythematosus resulting, in part, from the patient’s belief in the removal of a curse.

Other Clinical Observations Belief sickens, belief kills, belief heals.31 Evans3* and B e e ~ h e rreviewed, ~~ between them, 26 double-blind studies on the efficacy of active analgesic drugs in the treatment of pain. Independently, they concluded that 35% of patients suffering from pain experienced a 50% reduction in their symptoms after placebo medication. These are particularly remarkable results when viewed in the context of Evans’s observation that with a standard dose of morphine, only 75% of the patients experience a 50% reduction in pain. In calculating the efficiency index of placebo analgesia, a method often used to determine the relative efficiency of drugs, placebo was 0.56 as effective as a standard dose of morphine. This prompted Evans to remark, ”Thus, on average, placebo is not a third as effective as a standard injection of morphine in reducing severe clinical pain of various kinds but is in fact 56%as effecti~e.”~~ As discussed previously, placebo has been evaluated in a wide variety of clinical settings in addition to pain management (Box 7-2). When a phenomenon such as placebo has been observed to be active in diverse clinical situations, such as surgery, drug therapy, psychotherapy, and biofeedback, and over a range of physical and mental symptoms, the conclusion that it must be a factor in all aspects of medicine is inescapable. In addition to the variety of positive effects that placebo produces are the nocebo effects, perceived as counterproductive to the therapeutic goals. These side effects are frequently consistent with those of the medication that patients believe they are getting. For example, the studies that measure the effects of a supposed aspirin usually show nocebo effects of ulcerlike p a h a

AngeP Anorexia% Behavioral changess Depression37 Dermatitis medicamentosa35 Diarrhea= Drowsiness37 Epigastric pain%

Hallucinations3 He a d a ~ h e ~ ~ Lightheadedness% Pal~itation~~ Pupillary dilations Rash% Weakness35

Placebo and the Power to Heal

In homeopathy, aggravations and ameliorations are commonly seen when a placebo is given to fend off a patient’s need to take a medication while the homeopathic physician is waiting to see whether a high-potency remedy will effect a cure. Homeopathic doctors report that placebos can cause anxiety and loneliness as well as calmness and immediate relief from insomnia.4l

PLACEBO MYTHS ~

~~

Investigation of the understanding of placebo found in the current medical literature reveals the misconceptions that prevail about the nature of placebo therapy and its eff&tiveness.q A study undertaken to examine doctors’ and nurses’ attitudes about the efficacy and use of placebos showed that both groups underestimated the number of patients who could be helped by placebo.q Physicians showed a consistent pattern of placebo use, as follows: Placebos were used to prove the patient wrong through diagnosis of psychogenic symptoms in patients who were thought to be exaggerating, imagining, or faking their symptoms. Placebos were used in the treatment of alcoholic, psychotic, and demanding patients who were disliked by the staff of the hospital. In situations in which standard treatments had failed or the patient was getting worse, placebos were used as treatment. These misconceptions regarding the nature of the placebo have accounted for its widespread misuse for patients who are perceived as uncooperative or who are suspected of malingering. Myths about placebos continue to hinder full understanding about the power inherent in thisaspect of health care. The most common myths are discussed here.O

Heart

Improved exercise toleranceu*& Decreased serum lipoprotein^^^ ImprovedT waves47 Decreased pulse rate and arterial pressure“

Sympathetic stimulation

Decreased tremulousness, sweating, and tachycardia%

Claudication

Increased walking distance49 Addictive drug withdrawal=

Postsurgical trauma

Decreased facial swelling51

Diabetic blood sugar dyscrasias (NIDDM)

Lowered fasting blood sugaFB

Gastrointestinal secretion and motility

Decreased gastric acid secretion% Changes in gastric motility55.56 Healing of duodenal

Hypertension

Lowered blood p r e s ~ u r e ~ ~ - ~ Reduced urinary catecholaminessl

Motor dysfunction

Improved tremor magnitudeB2

Anginau.eama Anxiety35.66.67 Arthritis40-68*69 Asthma7073 Behavioral problems74 Claudication, intermittenPg Common Cough7g DepressionrnfB1 Diabetes (non-insulin-dependent diabetes mellitus)s.53 Drug dependence= DysmenorrheaB2 Dyspepsias3

Gastric ulcersw Hayfe~eP~,~ Temporal and vascular headachesB74s H y pert ens i ~ n~ - ~ l Labor and postpartum painw Premenstrual syndromeg3 MBniere’s diseaseM Nausea of pregnancy35 Paing5.= Psychoneur~ses~~~~~ Rhinitis= Sleep disturbanceslW TremoP

Myth 1 ”Since placebos tend to be physiologically inert, it is not possible for them to have an effect on physiologic homeostasis.”

Fact. Research shows that placebos have a wide range of effects (Table 7-1) that are found throughout all aspects of human physiology.

Myth 2 “Placebos are useful only with symptoms that are associated with psychologic or psychosomatic complaints. Patients who need a placebo are hypochondriacs with vivid imaginations and need to be palliated with something ’to please them.’”

Fact. Placebos have been shown to be effective in the care of all types of patients, with a consistent level of positive results for a wide variety of accuratelydiagnosed diseases.

Beecher17was one of the first to compile a listing of the therapeutic effectiveness of placebo, thereby uncovering the wide range of therapeutic applications, which were previously thought to be limited to only pain control. He concluded, ”there is too little scientific as well as clinical appreciation of how important unawareness of these placebo effects can be and how devastating to experimental studies as well as to sound clinical judgement lack of attention to them can be.”*’ The large and ever-growing number of studies on placebo and double-blind research (Box 7-3)supports the following assertion made by Beecher1730 years ago: Many “effective” drugs have power only a little greater than that of placebo. To separate out even fairly great true effects above those of placebo is manifestly difficult to impossible o n the basis of clinical impression. Many a drug has been extolled o n the basis of clinical impression when the only power it had was that of a placebo.

Philosophy of Natural Medicine

Myth 3 "The placebo effect is found only in substances that are inert."

Fact. Placebo phenomena have been observed across a wide spectrum of medical disciplines, including surgery;O1 drug therapy,lmand biofeedback.'03

Myth 4 "The patient who responds to placebo can be characterized as someonewho is of a typical neurotic disposition.""

Fact. Although many studies have tried to impute a personality type, d i s p o ~ i t i o n , ' ~or~ Jcertain ~ epidemiologic class105 to the patient who responds to placebo, this has yet to be well-demonstrated, because given the right circumstances, any person can become a placebo rea~tor.'~J~' After reviewing the bulk of the research on this subject, Bush'O* and Wolf and Pinsky35 concluded that the attempts to pigeonhole personalities into a clinical profile ignored the complexity of the human mind. Gliedman et alv similarly reported that age, sex, marital status, social class, and intelligence are unimportant factors in determining a patient's response to placebo. Wolf summarized that attempts to idenhfy placebo reactors need to "idenhfy the nature of the symptom being treated, the motivation of the patient and physician, the nature of the test agent, its mode of administration and the life situation of the subject at the time he is tested. The sigrulicant point here is not the apparently conflicting findings of investigators with respect to placebo reactors, but rather that in any given situation,responses to a placebo may vary as compared to any other situation and the significanceof situations to human subjects cannot be precisely d~plicated."~~

PHARMACODYNAMICS The physiologic response of the "inert and inactive'' placebo extends into the realm of drug pharmacodynamics. Dose-response time curves, cumulative effects (increasing therapeutic efficacy with repeated doses),lW variable strengths of analgesia based on a patient's drug e~pectation,6~ drug i n t e r a c t i ~ n s , ~ ~ and J l ~ carryover have all been demonstrated. The effects of placebo are so pronounced that some observers have suggested that they can exceed the effects attributable to potent pharmacologic agents.35

Packaging and Delivery Several studies have found that the effectiveness of a placebo therapy depends on the mode of deli~ery.4~ For example, one study found that green tablets improved anxiety and yellow tablets improved depression,"'

whereas another study found that blue capsules were more sedative and pink capsules were more stimulatinga Placebo injections appear to be more effective than oral administration after oral placebo has failed to relieve the symptoms.40

Placebo Interactions Benson112writes that the patient's belief is also a powerful force in determining the level of relief afforded by the placebo. An increase in patient expectation enhances the physician's ability to elicit a placebo response. Even if patients know that they are receiving placebos, the expectation and relief brought about by the therapeutic interaction provides positive re~ults."~ The importance of expectation is further demonstrated by the observation that the greater the stress level of the patient and the greater his or her need for assistance, the greater the effectiveness of placebo.37This is seen even in patient responses to psychotropic drugs: LSD-25 (Dlysergicacid diethylamide tartrate 25) can have no effect if the patient is told that the drug is a p l a ~ e b o . ' ~ ~ J ~ Patients, such as war heroes, who have severe injuries but do not have great mental suffering attached to their pain need less pain medication than persons with similar injuries who have pain that engenders anxiety and connotes di~aster."~

PLACEBO HEALING MECHANISMS When animals or humans can react to their own deviations from homeostasis and when these deviations set off restorative processes, therapeutic intervention, including placebo, has an already existing substrate of recovery for exp10itation.l~ A human being has an intrinsic ability to "selfright"-vis medicufrix naturue (the healing power of nature). This is the keystone of a philosophy that has been held for thousands of years by naturally oriented physicians (see Chapter 6). The concept of a homeostatic, self-regulatingmechanism is central to the understanding of basic concepts of physiology: Negative feedback loops control virtually all systems of the body. According to Guyton,116"the body is actually a social order of about 75 trillion cells organized into different functional structures. . . . [Elach cell benefits from homeostasis and in turn each cell contributes its share towards the maintenance of homeostasis." The body can maintain health and reestablish a healthy state after disease by virtue of its inherent vitality. This is part of the definition of a homeostatic mechanism; it has been selected by nature in the same way that organs vital to our survival have been selected. The surviving species are those most fitted and best able to cope with dysfunction. Those organisms that can tolerate the greatest stresses and still maintain a normal physiology

Placebo and the Power to Heal

are the hardiest survivors and ensure the species' ability to increase the limits of its adaptation. Therefore, given that an organism is self-maintaining when in an environment that it has been selected for, healing happens unaided through simply maintaining an environment that does not obstruct the path of cure. As Norman Cousins117observed, "without any help, the human body is able to prescribe for itself. It does so because of a healing system that is no less real than the circulatory system, the digestive system, the nervous system, or any of the other systems that define human beings and enable them to function."

The Role of Emotions Reviews of studies that explore how specific emotions can increase cancer sus~eptibility,l'~J~~ examine the effect of emotions and recovery from cancer,'z0 investigate the increased incidence of sudden and rapid death during psychological stress,lZ1 and monitor the changes in immune function during emotional all confirm that emotions play a powerful role in the prognosis of a patient. Cannonz9and Tregearl" document dramatic case histories of pioneering anthropologists who witnessed the power of taboos and curses to kill strong healthy men and women in third world cultures throughout Africa, South America, and the South Pacific. TregearlZ4wrote, "I have seen a strong young man die the same day he was tauped [tabooed]; the victims die under it as though their strength ran out as water."

The Vis Medicatrix Naturae The healing process described as vis medicatrix naturae demonstrates the sigruficant power and potential of the self-generated healing capacity. For a physician, there is no more powerful stimulator of this healing mechanism, the placebo effect, than a strong the doctor-patient interaction. Just walking through the door of the physician's office nudges a patient's internal homeostatic mechanisms into seeking higher levels of health, healing, and adaptation. The placebo effect is a result or effect of the patient's seeking the assistance of the doctor's ability to heal and cure. As Benson1lZnoted: When we dissected the placebo effect a number of years ago, we found three basic components: One, the belief and expectation of the patient; two, the belief and expectation of the physician; and three, the interaction between the physicianand the patient. When these are in concert, the placebo effect is operative. . . . Perhaps nothing is being transmitted from the healer to the patient, but rather it's the belief the patient has in the healer that's helpful.

Conscious Control over Homeostasis The body has two internal forces to maintain homeostasis: a lower drive and a higher drive. The lower drive is the inherent internal healing mechanism, the vital force,

or the primitive life support and repair mechanism that can operate even in a person who is asleep, unconscious, or comatose. The higher drive is the power of the mind and emotions to intervene and affect the course of health and disease by depressing or stimulating the internal healing capacities. The effect of this drive can be seen in the clinical observation of patients who move toward spontaneous remission of a life-threatening disease through positive emotional supportlzJzOand in patients who fail to express emotions compatible with the body's attempts to survive.120 In any disease process, the consciousnessof the patient decides the effectiveness of any therapy. Experiments in remote intention-generated healing and prayer show that the intention of others is a factor in the homeostatic capabilities of the mind and body. The fact that the homeostatic mechanism can sense and respond to these remote intentions is a reflection of the power of the human mind. Some authors believe that there is a physiologic basis for the unlimited possibility of human voluntary control.125 The ultimate control of psyche over soma demonstrates the priority of the conscious mind over physiologic processes such as immunity and pain control.126This Puts an enormous responsibility on the physician. He or she must take fullaccount of a patient's mental and emotional states when treating chronic or lifethreatening disease.

PHYSIOLOGIC MECHANISMS Identification of a biochemical mechanism for placebo analgesia has done more to change the image of placebo than any amount of arguing about the importance of beliefs and the mind.lZ7 The mechanisms of placebo response have been suggested to be a mixture of psychological interactions mediating physiologic responses.16 Psychological components of the patient's placebo effect have been shown to include the decreased anxiety and the increased relaxati0n,6~~onditioning,'~expectation,2O and well-being generated by the establishment of a sound doctorpatient r e l a t i ~ n s h i p . ~ ~ ~ J ~ ~ The physiologic mechanisms of the placebo effect have been suggested to include chemicals, catalysts, and enzymes. It is believed that steroids, catecholamines,lz the autonomic nervous ~ y s t e m , ~neuropeptides, ~J~~ and endorphins131are also involved. These physiologic mechanisms interrelate synergistically and are rapidly being researched within the rapidly developing field of psychoneuroimmunology? through which the links between depression, affective disorders, emotions, and the immune system and central nervous system (CNS) are being explored. Susceptibility to depression and sensitivity to pain have now been found to be mediated through neurotransmitters such as catecholamines, serotonin, and dopamine.

technology. This functional MRI (fMRI) can measure The current model for explaining the mechanism by blood flow into specific areas of the brain. One study has which emotions, mood, and psychologicalstress suppress shown that expectation or hope is able to stimulate a cerimmune function involves cerebral-hypothalamic and tain part of the brain that is activated by pain medicapituitary interaction, which translates stress and anxiety tions and is associated with pain relief. Placebo analgesia into an autonomic-endocrine response. This response has been found to be related to decreased brain activity adversely affects the immune function, particularly after in pain-sensitive brain regions, including the thalamus, chronic stimulation. Stressful stimulation is received in h u l a , and anterior cingulate cortex. It was also associthe sensory cortex of the brain and is then referred to the ated with increased activity during anticipation of pain limbic system and the hypothalamus. This interface of the in the prefrontal cortex, providing evidence that placehigher brain functions and homeostatic regulating centers bos alter the experience of pain.134 provides the communication linkbetween the psyche and In another study, researchers found that empathy soma. According to Rossi,’6 “The hypothalamus is thus could activate a portion of the brain. They showed that the major output pathway of the limbic system. It intesome of the brain regions involved in feeling physical grates the sensory-perceptual, emotional, and cognitive pain become activated when someone empathizes with function of the mind with the biology of the body.” another’s pain. Using fMRI, study subjects were In the hypothalamus are the nerve centers that control observed when they experienced a painful stimulus, and both branches of the autonomic nervous system, both the results were compared to those elicited when the parasympathetic and sympathetic, nerve cells that subjects observed their spouses receiving a similar pain secreteendocrine-releasingfactors, and neural pathways stimulus. The bilateral anterior insula, rostra1 anterior that release hormones directly into the posterior cingulate cortex, brainstem, and cerebellum were actipituitary. The corticosteroids and catecholamines from vated when subjects received pain and also by a signal sympathetic stimulation are key factors in the alterthat a loved one experienced pain.135 A group of ation of disease susceptibility in response to stress. researchers at University of California at Los Angeles Corticosteroidsinhibit the function of both macrophages and lymphocytes, as well as lymphocyte ~roliferation.’~~(UCLA), using a new technology called quantitative electroencephalography (QEEG)showed that “effective” Corticosteroids also cause the thymic and lymphoid placebo treatment induces changes in brain function that atrophy noted by Hans Selye in his experiments on are different from those associated with antidepressant stress-induced immune dysfunction. The autonomic release of catecholamines stimulates medication. Placebo responders (those who showed a response to placebo) showed a sigruficant increase in receptors on the surface of lymphocytes, thereby increasprefrontal activity starting early in treatment that was ing their maturation rate. When in a mature state, the not seen in medication responders or in subjects who lymphocytes’ ability to kill bacteria and cancer cells and showed no response to medication or placebo. Because a produce interferon seems to become paralyzed.I3 Thus high percentage of antidepressant medication represents a population of mature lymphocytes develops, ready the placebo effect, it is important to be able to predict to defend the body from infection and inflammation who will be placebo responders.136 yet remaining paralyzed until the ”red alert” signal of sympathetic fight or flight is turned off, signaling the Placebo and Stress Physiology appropriate time to rest and repair. Stress “letdown” of a patient in the therapeutic environA number of other peptides, E-type prostaglandins, ment is one of the mechanisms producing the placebo somatotropin, histamine, insulin, endorphins, antidieffect. It results from the patient’s perception that a tranuretic hormone (ADH),and parathyroid hormone (F’TH) all have receptor sites on lymphocytes and can stimulate sition from a stressful situation to a nonstressful situation has occurred. M ~ w r e r observed ’~~ that with a decrease the same cyclic --mediated response resulting in in anxiety there is a concomitant increase in hope, sigrufylymphocyte maturation and inhibition.132A study of the ing that the period of suffering is over. Certain familiar effect of catecholamines on the human immune system images and signals, such as white coats, syringes,behavshowed that when a physiologic dose of epinephrine is ioral procedures, and clinical protocol, create a condiinjected into a healthy volunteer, there is an increase in tioned response-relief now that help has arrived. Evans the number of circulating suppressor T lymphocytes and and Hoylea similarly observed that ”the reduction of a decrease in the number of circulating helper T lymphofear through the shared expectations that the doctor’s cytes (changes similar to those found in acquired medicine will work-even if unknown to the patient immunodeficiency syndrome [AIDS]).132 it is placebemediates powerful therapeutic effects.” Brain Region Activity The placebo effect in the clinical environment transforms the emotional and mental stress of the Some of the most interesting research on placebo has patient. These effects, also observed and described by evolved out of the new magnetic resonance imaging

Placebo and the Power to Heal Franz Ale~ander,'~ Hans George Solomon,138 and Walter allow the patient to escape the "fight or flight" response that can cause, and maintain, the state of illness.

Physiologic and Psychologic Stress S e l ~ edemonstrated '~~ that physiologic stress can have a dramatic effect on the immune and endocrine systems of the body. Laudenslager" went on to show that it is not just stress that creates these physiologic changes, but also the perception that stress is "inescapable" that is critical to the response. More recently, studies on the effects of psychological stress have demonstrated significant changes in immune capability. Maladjustment to "life-change stress" correlates with reduced activity of natural killer cells,138decreased T- and B-cell responsivity,'" and diminished lymphocyte cytotoxicity.142For example, Riley143observed increased tumor activity in a controlled stress environment and concluded: Emotional, psychosocial, or anxiety-stimulated stress produces increased plasma concentrations of adrenaline, corticosteroids and other hormones through well-known neuroendocrine pathways. A direct consequence of these increased corticoid concentrations is the injury to elements of the immunologic apparatus, which may leave the subject vulnerable to the action of the latent oncogenic viruses, newly transformed cancer cells, or other incipient pathologic processes that are normally held in check by an intact immune system.

The damage to the immune system by stress, mediated though the hypothalamic-pituitary axis, has been shown to be due to the increase in serum levels of cortisol. In one study, elderly caregivers were shown to have higher cortisol levels and poor antibody response to influenza vaccine.lMThe impact of cortisol on immune and other regulatory functions like blood sugar, dehydroepiandrosterone (DHEA), insulin,testosterone, bone resorption flag it as having highly destructive potential. Anxiety, depression, heart disease, AIDS and osteoporosis have all been linked with elevated cortisol levels. DHEA, another adrenal hormone is also modulated by stress physiology though it seems to have the opposite effect to cortisol. High levels of DHEA seem to protect the body from the damaging effects of elevated cortisol. In fact, ratios of DHEA to cortisol are highly predictive of the individual's ability to tolerate stress.145 Current reviews of the literature relating psychological stress and immune dysfunction support the hypothesis that the homeostatic immune mechanisms, both humoral and cellular, are sigruficantly impaired by both natural and experimental s t r e ~ s . h " ~ J ~ ~ , ~ ~ common colds,148coronary artery and myocardial ischemia" have been linked to adverse stress physiology. Stress even has the ability to increase

permeability of the blood-brain barrier.151The implications of stress-relatedalterations in the blood-brain barrier exposes important insights into enigmatic diseases like chronic fatigue syndrome and stress-induced neurologic disorders.

Endorphins, Hormones, and Neuropeptides . . . one rapidly activated psychoneuroendocrine mechanism through which a placebo stimulus may reduce both depression and pain is produced by stimulating the endorphin system.15 Research on endorphins is a relatively new area of study in the field of psychoneuroimmunology. Original research by Levine et a195suggested that the pain relief noted in placebo studies could be explained by the simple mechanism of endorphin-mediated actions. The original emphasis on endorphins and enkephalins was plausible, considering their known modulation of pain and mood functions. This position was further supported by later observations that depression increases chronic clinical pain152and that decreased activity in endogenous opioids may be part of the pathophysiology of depression.13 With the information that placebo can stimulate endorphins, Levine et aP5 believed that an explanation for the action of placebos had finally been found. However, this hypothesis failed to account for the broad spectrum of placebo effects as well as for the fact that the analgesia associated with hypnosis is not affected by an opioid a n t a g ~ n i s t . ' ~ItJ is ~ ~important to note that later literature suggests that Levine et a195were not entirely wrong in implicating the role of endorphins in the placebo mechanism; rather, these researchers were right for the wrong reason. Endorphins are mainly derived from three precursor proteins (by separate biochemical processes).lMThese opioid peptides are released from central and peripheral areas in response to pain, stress, and emotions and perform many physiologic functions, of which analgesia is but However, it is becoming evident that the boundaries between the CNS and the immune system are not as clear as once thought. The several known effects of endorphins on immune system function are listed in Table 7-2.lS When the functions of neurotransmitters such as endorphins are found to have such an intimate relationship with immune integrity, the paradigm of a body with functions performed independently by its parts-a newtonian type of thinking-begins to lose credibility. To further blur the already hazy distinction between the CNS and the immune system, research has demonstrated that endorphins and peptide hormones, such as adrenocorticotropic hormone (ACTH), thyroid-stimulating

Immune system function

Endorphin effect@)

Lymphocyte production

Increased and decreased

Chemotaxis

Increased

T-cell sensitivity to prostaglandin E2

Increased

Antibody production

Increased and decreased

Complement

Binding of fractions C5B-C9

T-cell proliferation Natural killer cell function

Modulation of Modulation of

B a l l differentiation

Modulationof

hormone (TSH), human chorionic gonadotropin (hCG), and luteinizing hormone (LH), are produced by lymphocytes.lB It is clear that the demarcation between the CNS and the immune system is impossible to distinguish. The brain and the immune system are the only tissues in the body that have a memory, and the level of communication between the two argues a taxonomy that identifies them as one. Evidence of the innervation of the thymus gland, bone marrow, spleen, and lymph nodes supports the finding that the immune system is subject to efferent CNS information.’B In addition, studies demonstrating the atrophy of the thymus and lymphatic tissues in the absence of growth hormone,’59corticotropin (ACTH), and increased steroid production by adrenal cells after interferon stimulation, indicate that “in the future it will be difficult to distinguish the receptors and signals that are used within and between the neuroendocrine and immune system.’’158

CLINICAL APPLICATION A physician with an interest in the psychopharmacologic treatment, which can be expensive, elaborate, detailed, time consuming, esoteric, and dangerous, usually has considerableknowledge about such treatment. He or she is interested in the symptoms of the patient and the differential response to various drugs and is careful to observe side effects, which may be dangerous. The physician may encourage the patient to call at any time if side effects develop.= The application of placebo phenomena in clinical practice should not be a vague attempt to replace the skill of the medically trained physician with obscure ”hand waving,“ incantations, and inert lactose pills. In primary care and specialty clinical practice, the physician’s intent should be to optimize patient care by engaging restorative defense mechanisms. To effectively apply current placebo research, the physician must

Prima non nocerum: Prioritize a hierarchy of therapeutic intervention. Tolem causum: Remove the obstacles. Support the therapeutic relationship. Enhance positive emotional states. Implement therapeutic conditioning or learning. Use altered states of consciousness.

understand several principles (listed in Box 7-4 and discussed here).

Prima Non Nocerum: Prioritize a Treatment Program and Establish a Hierarchy of Care Prima non noceium is the Hippocratic injunction dictating that a physician care for the patient so that self-healing mechanisms can engage. This ancient phrase means “Do not disturb the organism’s ability to heal itself.” The body must be given the full range of possibilities in allowing the power of homeostasis, vis medicatrix naturue, to have its optimum capability. ”Doing no harm” means that a patient is supplied with the level of medical intervention that is appropriate to his or her ability to maintain life support. The job of the physician is to determine when homeostasis or defense mechanism has lost the ability to respond to disease. Acute traumatic swelling and inflammation and shock are examples of the human defense mechanism responding in a way that threatens the health of the organism. It is most interesting that the organism would make choices, as in shock and inflammation, that could kill it. To practice the principle of prima non nocuum, a physician must learn when to act and when to let the body heal itself. This is the highest art of medicine; each case and situation is different and it is up to the physician to interpret the needs of the moment. By implication, the physician who seeks to apply this principle understands the principles of physiology upon which human life depends for homeostasis. Prima non nocerum does not necessarily mean that a physician withholds invasive therapy: it is the physician’s responsibility to determine when the body is unable to reestablish homeostasis and therapy is indicated. If an arm must be severed to save the patient’s life, there is no violation of prima nun nocerum. However, to enhance the principle of prima non nocerum, a physician sometimes must withhold therapies and must be content to leave the patient to self-heal. Hippocrates understood the wisdom of letting the body heal on its own that is implicit in the “do no harm”

Placebo and the Power to Heal

injunction. The following account of the treatment of Charles I1 of England is a case in point: A pint of blood was extracted from his right arm and a half pint from his left shoulder, followed by an emetic, two physics, and an enema comprisedof fifteen substances;themyal head was shaved and a blister raised; then sneezing powder, more emetics, and bleeding, soothing potions, a plaster of pitch and pigeon dung on his feet, poisons containing ten different substances, chiefly herbs, finally forty drops of extract of human skull and an application of bezoar stone; after which his majesty died.’60 When this treatment is compared with modem procedures such as mammary artery ligation for the relief of angina-a procedure that has no more benefit than sham artery ligation-it appears that physicians have continued throughout the centuries to rely on the placebo effect for the care and cure of their patients. Because this effect plays such an important role in health care, simple, noninvasive, and effective treatments should be the goal of all therapeutic approaches. Robert Burton161wrote in 1628, “an empiric oftentimes, and a silly chirurgeon, doth more strange cures than a rational physician . . . because the patient puts confidence in him.” The rational physician will also recognize that healing and curing are not necessarily the same. If a patient is helped in any way by the doctor, with or without the use of placebo, the path of cure has been assisted, although the specific disease may not have responded. Not all patients can be cured, but most patients can be helped.

Tollem Causum: Remove the Cause of Disease Tollern cuusum is the principle that seeks to remove the obstacles to cure. The forces “inhibiting the floodgates of health from opening” must be removed for the full force of the patient’s beliefs to effect the path of cure. This concept is fundamental to the philosophy of naturopathic medicine with its strong emphasis on diet, detoxification, and a pattern of living that is consistent and compatible with the context in which humans evolved. Obstacles to cure block the self-healing capacity of the organism. Contamination with heavy metals and xenobiotics (see Chapter 36), focal infections, electromagnetic pollution, scar tissue, genetic metabolic abnormalities, and parenchymal organ damage defeat the best therapeutic intentions and must be addressed. The patient’s habitat is an important aspect of the therapeutic protocol, not only in the diagnosis and care of internal mental and physiologic dysfunction but also in determining which environmental factors may be contributing to dysfunction and disease. These factors might include diet, lifestyle, and living environment. It is of the utmost importance to remove a patient from surroundings that are associated with illness or to assist the patient in creating an environment more conducive to health.

Factors that provide conditioning that reinforces the disease process can be associated directly or indirectly with one’s environment. For example, if animals are returned to situationswhere their experimental neuroses were induced, their pathologic behavior reactivates.162 When a patient leaves the offending environment to receive treatment from a physician, the prognosis is correspondingly more fav0rab1e.I~ The physician has the added advantage of a patient’s heightened expectation during an office visit-a patient’s positive associations with the ”healing” environment increases his or her receptivity to treatment.la If the home or work environment is a source of “dis-ease” and an obstacle to cure, providing an alternative environment may be a most helpful way to remove the obstacles to cure.

Support the Therapeutic Relationship Confidence should surround all aspects of the therapeutic interaction. The patient must have confidence in the doctor’s ability to assist a cure, the doctor must have confidence in the efficacy of his or her therapy,’” and there must be an understanding or relationship between the doctor and patient that is mutually conducive to respect, trust, and compassion. The quality of the doctor-patient relationship is paramount. The therapeutic approach to a patient that optimizes the confidence of the patient in the skill of the doctor stimulates the inherent self-regulating healing mechanisms by relaxing the anxiety the patient has about the illness. Anxiety is a well-known immunosuppressant and aggravates the body’s defense mechanism. An optimum therapeutic relationship, when combined with the clinical skill to remove the cause of homeostatic dysfunction, is the height of therapeutic acumen. As Lewith’G so accurately states, “The general practitioner may therefore wish to employ all his knowledge, enthusiasm, consultation technique and sympathy, to create the best possible atmosphere in which to elicit a placebo response from the patient.” Current research on factors contributing to the genesis of the placebo effect consistently documents the importance of the doctor-patient relationship.16168 The healing power of the therapeutic interactionhas been demonstrated by the commencement of the placebo effect even before the actual administration of the pill.169 The physician facilitates the cultivation of a sound relationship by developing good communication skills. The art of the bedside manner has been recognized throughout history as the primary skill a successful physician needs.l’O Indeed, the history of medicine is as much a history of the relationship between doctor and patient as the evolution of medical technology and techniques. Through centuries in which doctors were doing more harm than good, little more than the esteem of their

Philosophy of Natural Medicine aspects of the situation producing this effect include not only clientele sustained the medical profession. But however presentation of a symbol of the physician’s healing powers little real help the doctor had to offer, it was to him that (a pill), but any attention and interest shown by professional people turned when illness struck.171 personnel. Bedside manner has been found in clinical studies to This phenomenon was also observed in industry and entirely alter the course of double-blind studies, and the termed the ”Hawthorne effect.” As a direct result of the quality of a therapeutic encounter has been found to facilgreater attention factory workers received during invesitate or disrupt the efficacy of a treatment.lR Listening to tigation, the quality of their work improved.lmIn concluthe patient,’n verbal and nonverbal communication of the physician, amount of time spent with the patient,’73 sion, the importance of a doctor-patient relationship and the confidence that it engenders shows that all human patient education,”* demeanor of the ph~sician,’~~ and beings need to share their feelings and experience the interview skills173have been suggested as factors and therapeutic benefits of touch: The doctor-patient relacomponents of effective physician communication skills. tionship provides an ideal way to meet these fundamenTouch is an important form of communication and is sometimes forgotten as a key aspect of the doctor-patient tal needs. relationship. Highly skilled clinicians with many years Enhance Positive Emotional States of experience, such as now deceased Dr.John Bastyr (whose remarkable healing abilities inspired the foundLove in all its subtleties is nothing more, and nothing less, ing of Bastyr University by those privileged to have been than . . . the psychical convergence of the universe upon itself. his students), frequently impressed upon clinicians the -Pierre Teilhard de Chardin, The Phenomenon of Man importance of always using diagnostic and therapeutic touch during a patient visit. The doctor’s touch can be diagnostic, therapeutic, and, perhaps most important, a For optimum enhancement of the psychoneuroimmune system, the physician must assist the patient in developmeans of communicating that he or she is deeply attuned to the problems, needs, and fears of the patient.176Touch ing practices that amplify positive emotional states and can heal by increasing tissue mobility and fluid exchange, reduce negative emotional state. A negative mental as in massage, or by relieving pain, as demonstrated by state (anxiety, stress, panic, anger, depression, neurotic research on healers who use their hands.174Touch has behavior, self-deprecation, self-destructive feelings and also been documented in well-designed double-blind tendencies, and a weak will to live) hinders the ideal research to extend an unusual healing power that can be functioning of the psycho-neuro-immune-endocrine transmitted through the hands to plants and animals.178 axis, disrupting homeostasis. Englelsl has termed this Among other methods of enhancing confidence the giving-uplgiven-up complex: between the doctor and patient, the setting in which a Study of the life settings in which patients fall ill reveals that doctor provides therapy to a patient also determines its iUness is commonly preceded by a period of psychological effectiveness. The doctor’s office setting is very impordisturbance, during which the individual feels unable to cope. tant for optimum and effective treatment: Tools and This has been designated the giving-up/given-up complex support systems are more accessible, and a heightened and has the following five characteristics: a feeling of giving patient response results from seeking out the “healing” up, experienced as helplessness or hopelessness; a depreciated environment. In a clinical trial with hypertensive image of the self; a sense of loss of gratification from relationpatients, placebo alone was not as effective as when it ships or roles in life; a feeling of disruption of the sense of was administered in conjunction with hospitalization. continuity between past, present, and future; and a reactivation The visit to the physician represents a search for changes of earlier periods of giving-up. It is proposed that this state that cannot be found through “self-care” or overreflects the temporary failure of the mental coping mechanisms the-counter medicines. According to Frank’? with a consequent activation of neurally regulated biologic

In short, it appeared that the placebo situation relieved chiefly anxiety and depression, that the degree of relief was unrelated to personality and autonomic measures, and that the patients who responded strongly to a placebo at one time might not at another. In conjunction, these results suggest that the extent of responsiveness to a placebo depends on the interaction of the patient’s state at a particular time with certain properties of the situation. The finding that administration of tests and questionnaires seemed to have at least as beneficial an effect as had the pill implies that any interaction between patient and situation that heightens expectations of help may lead to symptom reduction and improvement in mood. The

emergency patterns. Changes in body economy so evoked may alter the organism‘s capability to deal with concurrent pathogenic processesl permitting disease to develop.

The importance of reducing negative mental states in acute and chronic conditions has been discussed extensively.lZ1Acute psychologic stress is documented to cause various forms of cardiopulmonary dysfunction, even death.l13 Chronic mental and emotional strain causes breakdown of the immune system and disease. The homeostatic processes become overwhelmed by autoimmune,

Placebo and the Power to Heal

microbial, or neoplastic invasion. Major writers on the subject of acute and chronic stress emphasize the high priority of managing the physiologically and immunologically destructive effects of the human body's response to stress. Pelletier182lists hypertension, arteriosclerosis, migraine headache, cancer, chronic bronchitis, emphysema, asthma, and arthritis as disease processes that are caused or exacerbated by stress physiology. A study researching the relationship between resistance to streptococcal infections in families and stress load in the family found a positive correlation.ls3 Another study on the psychosomatic susceptibility to infectious mononucleosis found that two psychosocial factors, high motivation and poor academic performance, significantly increased the risk of "dis-ease" infection.184 In still another, anticipation of mood and menstrual discomfort were positively correlated and manipulated, thereby supporting the suspicion that expectations act as a determinant of mood.185 The conclusion that there is no acute, chronic, or degenerative disease that is not affected by a patient's mental and emotional state must be drawn from the pervasive immunoendocrine effects generated by the mind and emotions. WolFS6and Cousins18' write of the power of panic as a factor in myocardial infarction, Marbach et describe depression as a component in myofascial pain dysfunction, and Shekelle et allmnote, in a 17-year follow-up study, a twofold increase in the incidence of cancer in depressed patients. The clinical scenarios these observers describe imply that the placebo effect can control the onset and advance of a disease by shutting down the destructive thoughts, images, and feelings that mediate stress. Enhancing positive emotions is the corollary to controlling the damaging effects of negative mental and emotional states. Laughter?O hope,lS9acceptance,'15 and the reduction of suffering'% have been shown to speed the course of healing and reduce the level of pain and distress reported by patients. Although pain is sometimes the only language nature can use to adequately communicate to the patient that something is in need of healing, "the relief of suffering and the cure of disease must be seen as twin obligations of a medical profession that is truly dedicated to the sick."'% Acceptance has been observed to be a key factor that assists patients in better understanding their pain.l15 Acceptance does not mean complacency in the face of disease, but a rational understanding of the situation and the limitations that can sometimes accompany a disease process. The importance of cultivating hope in a patient also cannot be ~nderestirnated.'~~ The fact that a patient seeks the help of a physician or "caregiver" already implies a substrate of hope and is a signal that the patient can visualize the potential for recovery. The treatment needs

to merely stimulate this willingness to envision a future of health. Hope is an embodiment of the patient's and the doctor's ability to visualize an image of healing and recovery. This process is a recurrent theme in imagery therapy,192visualization therapy,'93 therapeutic and psychic healing.lg5Hope is both an active and a passive placebo. Passive hope placebo is that brought with the patient as the act of seeking help generates a level of unspoken faith in an image or potential for cure. Active hope placebo is generated by the physician, who consciously instills a vision or image of cure in the patient as an adjunct to therapy. Frank'79 performed a double-blind study in which patients were divided into control and induction groups. The induction group was led through a process whereby their hope was strengthened to conform with the expectations of the therapist: It introduces some perceptual clarity into the process of treatment; and to the extent that all our therapists adhered roughly to the insight model of therapy, it helped to bring the patient's expectations in line with what actually occurred in treatment, and also helped him behave in accordance with the therapist's expectations of a good patient.ln

The induction group were actually being consciously strengthened to a level of optimal response but not being led into false expectation^.'^^ This type of patient education or active placebo is a necessary and useful tool for framing and directing a positive outlook and prognosis. If a patient can conceive of a state of wellness, then that state of wellness can be achieved. It is the job and domain of the physician to discover those images, emotions, and perceptions that reside in the conscious and subconscious mind of the patient that block the image of a positive state of health. He or she must actively work to control these with the same level of intent as with any presenting gross complaint or physiologic dysfunction. Finding these dysfunctional mental substrates and working with the patient to try to change them is fundamental to treating the true cause of disease (see earlier discussion of tollum causum). Research has demonstrated the importance of positive and negative thinking in heart disease and cancer, the two areas of disease that cause the highest death rate: Doctors' health care management protocols should reflect this research in the same way that attention to proper diet is a part of a management approach to high serum cholesterol. It is now clearly established, for instance, that even low levels of stress trigger the onset of myocardial ischemia.lg7We also know from the work of Steven and David SpiegeP that the attitude and emotional exploration are critical to breast cancer survival. Knowing these scientific facts, all doctors must have strategies for helping their patients explore the

Philosophy of Natural Medicine areas of stress management, group therapy, and support groups and skills in building positive attitudes.

Implement Therapeutic Conditioning or Learning Those who remain at least dimly aware that everything they say or do to a patient conveys a major or minor, positive or negative, helpful or harmful psychologic impact are likefy to be more flective physicians.200 Conditioning of the mind has been suggested as a mechanism by which the placebo effect becomes a learned r e s p ~ n s e . ’ ~ , The ’ ~ J ~future of therapeutic application of placebo will probably hinge primarily on the use of conditioning. A doctor who can understand this will pay close attention to the stimuli of his or her patients and mod@ these stimuli in a scientific way to help treat immune-related and neurologically related diseases. Modem psychology acknowledges two models of conditioning or reinforcement of learning behavior, operant and classical. Operant conditioning is a behavior response that theoretically occurs in the presence of some stimulus that is a positive reinforcement; for example, a rat will leam to press a conditioning bar if a food pellet is dispensed as a result. Classical conditioning is a behavior response created by the simultaneous pairing of unconditioned and conditioned stimuli prior to an evoked response. This is best illustrated by the experiments of Pavlov and his “salivating dog.” In Pavlov’s experiment with the conditioning of a dog’s salivary response to the ringing of a bell, the bell ring is the conditioned stimuli, the food the unconditioned stimuli. The salivation is the unconditioned response to the food that becomes the conditioned response. When the dog finally associates the bell ring with the food, the ringing alone causes salivation, the conditioned response. The principle of classical conditioning has far-reaching implications for the diagnosis and treatment of disease because of the pervasive and permeating implications that conditioning has in all the sensory stimuli of daily existence, in sickness and in health: “Pavlov’s teachings, concepts and basic notions afford the real and ultimately scientific basis for the recognition of the potentialities of medical science attacking diseases from both the psychic and somatic sides.”201 For the purposes of this discussion, one must recognize that classical conditioning happens randomly in our environment and is closely linked to health and healing phenomena. Subconsciously, we note random events and associate them with previous events and observations, independent of an intended learning behavior. Operant conditioning happens in the context of reward, and classical conditioning happens in the context of

associated stimuli. There is a much greater predominance and range of associated stimuli (classical conditioning) than operant conditioning for the genesis of the placebo effect. This is because the operant depends on reward, although operant conditioning can happen in the medical mode: “Pain-killing drugs that I have taken in the past kills pain; therefore this capsule, which is a painkiller, will kill my pain.” Gliedman et all4 note that drugs that affect the CNS are readily conditioned, whereas drugs that affect the peripheral nervous system and are secretory stimulators (e.g., atropine and pilocarpine) do not result in the establishment of a conditioned response. The primary importance of psychological states to CNS excitation demonstrates that the pivotal loci of command for conditioning reside within the hypothalamus and the limbic system. Therefore, a doctor who can induce a state of central excitation in the patient can encourage and condition the patient to make those changes that are deemed necessary for the recovery of health. The conditioning of a patient to a placebo response is modified by learning stimuli associated with the illness, the stimuli of the doctor and the therapeutic setting, the stimuli of the therapy, previous health, medical therapy, and authority-related experiences.202The way that all of these factors interact in the psyche of the patient determines the nature of the placebo response that is achieved. Satiation obscures the conditioned response, whereas situations of increased stress seem to potentiate the responsiveness of the placebo effect.lI5 Placebo, conditioning, and learning may therefore be subject to the nature of central excitatory states as well as levels of stress and distress. The physiologic breadth of the placebo response in humans can now be understood in terms of the variety of interactions and effects that drugs, therapeutic procedures, and sensory phenomena of the medical environment have on the psychosomatic matrix of a patient’s consciousness. Rossi16notes that this complicated web of sensory processing reveals how any facet of therapy “that alters any aspect of the body’s sensory, perceptual or physiologic responsiveness on any level can disrupt the more or less fragile state-dependant encoding of symptoms and thereby evoke a ’nonspecific’ but real healing effect that we call the placebo response.” In fact, the scientific basis of therapeutic applications of psychoneuroimmunology is based on classical conditioning. Ader and CohenZo3 performed research to show that the immune system could be conditioned for therapeutic purposes. They conditioned immunosuppression in rats by injecting them with a conditioned stimulus of cyclophosphamide (a potent immunosuppressing agent) while feeding them a saccharine solution as an unconditioned stimulus.203The idea of conditioning for

Placebo and the Power to Heal

immunomodulation in human patients is therefore a realize that the patients are taking in all the information promising therapeutic modality. Applying conditioning about the surroundings, interactions, and therapy and techniques for the treatment of systemic lupus erytheare making associations that can potentially affect the matosus involving a dosage that normally had minimal course of their responsiveness to therapy. results resulted in a delay in the development of the M ~ w r e r ’observed ~~ that the “safety signals” of disease.204 syringes, lab coats, and behavioral procedures are all To fully account for the extent of previous and future retained in the patient’s psyche for future association. A conditioning in a patient, the physician must take a physician can skillfully take advantage of these signals by complete and exhaustive history in order to explore the encouraging and cultivating response generalization or influences of family, work, accidents, emotional predisby associating previous therapeutic situations with subsepositions, past medical history, and neutral stimuli as quent treatments by means of unconditioned stimuli such contributing factors during the onset of an illness. as office music, odors, and images. Giving patients some Lifestyle and emotional, behavioral, or physiologic factors sort of unconditioned stimulus that can be taken home might contribute to maintaining the state-dependent allows them to associate with the conditioned response, learning pattern of disease and dysfunction or give clues eliciting the memory of the therapeutic interaction while to a successful therapeutic intervention. A good example patients are away from the doctor‘s office. These uncondiof this is the demonstration by Batterman and L0wel.2~~ tioned stimuli or placebos can be given in multiples at one and delivof increased analgesics effectiveness based on similar time,’29 changed for more powerful ~timuli,~ previous therapy. A physician who knows which theraered at the end of an induction, suggestion, or imagery pies succeeded and which failed can take advantage of procedure. They should not be limited to pills or other the patient’s conditioning and encourage biochemical apparent medicaments, but should extend to sounds, smells, visualizations, and feelings. pathways that the body has learned. Drug or therapeutic interventions are not procedures that can be predicted It should be remembered that therapeutic conditionin the same way that in vivo experimental results can. ing depends on a perceived physiologic shift or change in the patient as described in the theory and research of The variables involved in human responses to therapy are clearly underestimated in the current rush of researchbiofeedback.*@This shift can be experienced as a sense oriented therapeutic e v a l ~ a t i o nTherefore, .~~ a patient of relaxation, increased warmth or circulation, altered who has been treated by a number of physicians or pracautonomic tone, or change in some sensory perception. Patients know immediately when there is no change in titioners for a complaint and has received no results or relief has been conditioned to believe that consultation their disease or dysfunction after they have been given and treatment by a physician will provide no positive placebo.209Therefore some patients need a more active form of therapeutic management that allows for some changes. When the patient visits the next practitioner, even if this practitioner can offer a diagnosis and treatlevel of perceived change. Ideally this perception would ment that are correct answers to the long-sought cure, be a sense of being free from pain or alteration from a state of abnormal physiologic function to a state of improved there are very real patient conditioning factors that must physiologic function. Acupuncture, spinal manipulation, still be considered. Consider the case of a young woman who was underdrug therapy, physiotherapy, hydrotherapy, and surgery going treatment for breast cancer and the clinical course are all therapies that can create an immediate biochemiof the ensuing metastases. Each time she had a positive cal impact perceived by the patient. response to therapy, she experienced a subsequent The optimum model to apply to the concept of condiremanifestation of the cancer. The result of this conditioning therapy and the selection of an appropriate thertioning was that she came to equate each new course of apy or modality was proposed by Greene and Laskin210 chemotherapy as a herald of some new manifestation: in their evaluation of myofascial pain dysfunction (MPD). She ”was torn between a desire to live and the fear that During an 11-year follow-up study of patients with MPD, allowing hope to emerge again would merely expose her these researchers concluded that, when comparing the effectiveness of a wide variety of reversible and nonreto misery if the treatment failed.”206 The parameters of conditioning in a clinical setting versible (surgical)therapies, conservative and reversible extend to all aspects of the patient’s sensory perceptions. therapies were the most important and appropriate Consciously, or unconsciously, the physician is providtreatment factors for the patient’s health and well-being. ing an environment for patient learning. LipkinZo7 points Focusing on patient communication, educating patients out that every drug, every apparatus, every injection, about reversibility of the condition and the nature of and every piece of information or advice carries a sugmuscle dysfunction as it relates to stress-pain-spasm, gestion of help and hope, regardless of the physiologic developing a therapeutic strategy based on increasing effects that may accompany it. The physician must patient awareness and self-management skills, and

Philosophy of Natural Medicine

selecting a flexible treatment strategy were all found to be essential for achieving a good initial response that could lead to long-term wellness. Greene and Laskin210 believed that the specifics as to which therapy was most indicated were not as important as the need to focus on the nature of presenting musculoskeletal problems and the factors and complexity of the treatment environment. Routine use of active pharmacologic substances reinforces the relationship between conditioned and unconditioned stimuli. However, routine use of unconditioned stimuli in the absence of a conditioned response weakens the therapeutic efficacy of the practitioner and has been described as ”placebo sag.”15Therefore the learning of a conditioned response from unconditioned stimuli could diminish if the conditioned stimuli fail to produce an adequate or reliable conditioned response. Without the intermittent demonstration of active strength, the placebo effect will get weaker and weaker. The implications of placebo sag for practitioners of alternative medicine, who try to work with the body’s own defense mechanisms without overwhelming medical intervention, are that periodic use of perceptually active therapy is needed to support a patient who is not able to respond to, or responds too slowly to, a gentler therapeutic nudge. In this case, the physician must recondition the vital force to open a path to homeostasis. In a sense, this may be a paradigm of the therapeutic situation, in which changes towards health are induced in the patient by a doctor who is able to cultivate a basic state of arousal, presumably central in nature. This state of arousal causes the patient to become accessible to the doctor’s expectations of the patient.I4 The typical placebo burst, in which a therapy is initially effective after a short period but then wanes, is now understood in terms of the placebo sag from lack of effective unconditioned stimuli to maintain the conditioned framework.68Physicians who lack the ability to extract themselves from a series of unsuccessful therapies risk eventual placebo sag: [Tlherapists who primarily use their active strengths (or unconditionedstimuli) paradoxically will get stronger placebo effects than quacks, will enjoy escalating credibility, and will seem as miracle men-when in fact perhaps only half their miracles can be traced to their active ingredients while the other half is a function of the anticipatory (or conditioned) response elicited by their conditioned features.15

Because the visit to a physician is often initiated by the physical pain of the patient, it stands to reason that skillfulpain management is a high priority in establishing a therapeutic conditioned response. Pain management by hypnosis, transcutaneous electrical nerve stimulation (TENS),therapeutic touch, direct or indirect manipulation, imagery, acupuncture, rneditation,2l1and an understanding that aims to elicit the nature of suffering206can

all be valuable therapeutic adjuncts to establishing a therapeutic environment that conditions the patient for full potentiation of his or her healing capabilities. (See Chapter 42 for a full discussion of these techniques.) With the recent development of standardization of, research into, and concentrationof the active components of plant medicines, vitamins, and biochemical precursors, naturopathic medicine as well as other forms of alternative medicine stands on a stronger therapeutic base because of an ever-growing verification of its pharmaceutical and therapeutic armamentarium. These therapeutic modalities are characterized by safe, yet physiologically active, substances and procedures; therefore they provide some defense against placebo sag.

Use Altered States of Consciousness Since ancient times, aboriginal humans have recognized the tremendous therapeutic power that lies dormant in the subconscious mind. For thousands of years, shamans and medicine men have used trance states to engage the most subtle aspects of the patient’s subconscious to affect factors in disease pathogenesis and In modern medicine, it has been documented that shamanistic healing involving altered states can offer dramatic “spontaneous remissions”30; the mechanisms of this process have been explored in the theory and application of hypnosis.2J26 Most currently accepted techniques employed to trigger the subconscious to effect positive changes in somatic or psychic health involve hypnosis. Placebo effect has been linked with hypnosis, or “low arousal states,” which are therefore believed to be critical factors in the evaluation of the mechanisms and perimeters of placebo.201A review of the literature documenting the potency of hypnosis and the observed results of placebo clearly demonstrates that these two areas yield remarkably similar clinical results. The inquiry into hypnosis grew out of the simple intent to validate the effectiveness of the mind in healing processes, whereas most placebo literature grew out of the intent to demonstrate a certain percentage of chance, fluke, spontaneous remission, or psychosomatic illness as a factor to be ruled out in the delivery of intelligent, scientific health care. Using these antiquated definitions of placebo and hypnosis, one is led to believe that hypnosis describes a process of healing based on the skillful guidance of a qualified practitioner, and that placebo describes a process based on chance, regardless of the professional circumstances. On closer inspection, the distinction between the two blurs: They appear to be much the same process. Illness, healing, and health states shift constantly in the homeostatic system, a system that is affected by stimuli received through the different levels of awareness and can be accessed, investigated, and modified by a variety of techniques. These include placebo, hypnosis,

Placebo and the Power to Heal

and induced altered states of consciousness. Ros@ notes that because memory depends on and is limited to the level of awareness in which the memory was acquired, it is “state bound information”: State dependent memory, learning, and behavior phenomena are the missing link in all previous theories of mind body relationships. . . . The major thrust of these hypotheses is that mind-body information and state-dependent memory, learning and behavior mediated by the limbic-hypothalamic system, are the two fundamental processes of mind-body communication and healing. . . . The new approach to mind-body healing and therapeutic hypnosis may be conceptualized as processes of accessing and utilizing state-dependent memory, learning and behavior systems that encode symptoms and problems and then reframing them for more integrated levels of adaptation and development.

Some psychosomatic phenomena are coded into the behavior of an individual through state-induced patterning. Until the patient can access the state in which somatic complaints are induced, possibly through hypnosis or other methods that break the sympathetic dominance of “encoded” shock,21° the psyche cannot clear them from the soma: A person in a traumatic car accident experiences an intense rush of the alarm reaction hormones. His detailed memories of the accident are intertwined with the complex psychophysiological state associated with these hormones. When he returns to his usual or “normal” psychophysiological states of awareness a few hours or days later, the memories of the accident become fuzzy or, in really severe cases . . . the victim may be completely amnesic. The memories of the accident have become ”state-bound”-that is, they are bound to the precise psychophysiological state evoked by the alarm reaction, together with its associated sensory-perceptual impressions.I6

In accessing these psychosomatic state-dependent areas of homeostatic dysfunction, the physician must use techniques that relax the conscious mind and allow access to subconscious content for reframing. The nature of the visit to a physician encourages a patient into more accessible unconscious states as demonstrated by higher placebo effects when patients present in a hospital setting.’@These labile states of consciousness are quite natural; humans constantly cycle in and out of different consciousness states.l@ These cycles, or ultradian rhythms, are described as alternating cycles of hemispherical dominance that change every one-and-a-half hours. When these cycles are interrupted by behavioral stress, psychosomatic behavioral responses such as ulcers, gastritis, asthma attacks, and rashes develop.214 A change in these rhythms manifests as a period of psychic repose. If an individual is in the midst of performing a task, daydreaming or the perceived need for a rest or coffee break may be the external manifestation of an

internally sensed signal of a change in rhythm. This is also a period when one is highly susceptible to hypnotic suggestion. Because these rhythms are very flexible and labile, they can be invoked through hypnosis, or if the physician senses a natural lull indicating a hemispherical switch, a “natural” trance can be induced. Centuries ago in India, practitioners of hatha yoga observed the effect of mental states on the breathing patterns of an individual. With anger, frustration, and mental instability, the breath reflects a short, arrhythmic pattern that mirrors the disturbed psyche of the person. Conversely, when a person is in a peaceful, relaxed, deep meditative state, the breath is long, rhythmic, and barely perceptible. Their discovery formed the basis for the development of breathing exercises called prunayurnu (literally, regulation or restraint of the vital energy),which aimed to calm the breath so that deep states of meditation and focused concentration could be attained. Current research has affirmed the powerful effect these exercises have on asthma, diabetes, chronic gastrointestinal disorders, and psychosomatic and psychiatric dysfunction.215 Therapeutic exercises that use somatic stimuli to effect changes in the psyche create fertile environments for stimulating the placebo response. A breathing technique used to decrease sympathetic tone or alter nostril predominance for causing shifts in hemispherical activity,216 an exercise to release fascia1 muscle tension and thereby effect mood enhancing blood flow in the brain,217,218 and a biofeedback treatment that aids in slowing the heart rate and decreasing negative emotional states208are all examples of how the psyche can be accessed by the soma. The whole process of eliciting the placebo response involves an attempt to marshal all the reserves and potential for healing through a doctor-patient interaction, engaging both the patient’s mind and body to reestablish homeostatic equilibrium. Health care professionals can use the wisdom of psychosomatic therapies as a central part of their therapeutic protocol. In addition to the specific therapeutic regimen, treatment of the whole patient can be achieved through these harmonious techniques. If physicians could persuade patients to care daily for their emotions, minds, and spirits the way they care for their hair or teeth, the effectiveness of any prescribed treatment would be greatly enhanced. As a primary therapeutic adjunct and important basis for preventive medicine, this line of treatment is all too often ignored.

ETHICS It is important to remember that there are two forms of “conscious” placebo use by the physician. The use of placebo as a gentle therapeutic agent by a practitioner is very different from the use of placebo in a controlled trial in which the possibility of a known therapy is withheld

in a treatment group. Some researchers believe that use of placebo in clinical trial breeches the Declaration of Helsinki, which states that every patient should be assured of the best proven diagnostic and therapeutic method.219The ethical problems of delivering health care in a research design, in which there is a possibility of favorableoutcome and half of the group is denied access to this possible favorable outcome, make it a troubling issue. The ethical use of placebo has also been questioned in an attempt to determine whether a physician should be deceiving patients during the process of healingz0 Although some writers advocate a restricted use of pure and impure placebo because of its ”deceptive”natureFm it becomes clear in a brief review of the current literature* that any argument for or against the use of placebo assumes the existence of medical procedures that are free of potential placebo effect. BrodyZ6concludes that placebo can be called the ”lie that heals.” However, closer examination shows that it is not the lie that does the healing, but rather the relationship between the patient and doctor that stimulates a natural self-healing mechanism via psychologic, symbolic, and biologic intervention: For some time, medical science has looked almost exclusively at technical means of diagnosis and treatment; the doctor/ patient relationship that forms the setting for their application has been naively viewed as a noncontributory background factor, relegated to the amorphous realm of the “art of medicine,’’ or simply ignored. In this setting, the placebo effect has inevitably been viewed as a nuisance variable, interfering with ow ability to elicit ”clean data” from clinical trials; and deception in medicine has been seen either as an unimportant side issue or as a tolerated means toward an end. But as the doctor/patient is rediscovered as a worthy focus for medical research and medical education, the placebo effect assumes center stage as one approach to a more sophisticated understanding of this relationshipF6

indications even more carefully than when prescribing specific therapy and (2) to avoid missing a disease process that can be easily treated with an empirically proven protocol (e.g., vitamin BI2-deficientperipheral neuropathy), the physician should not relax a diagnostic protocol because a patient seems to be responding to placebo.u0 The final ethical hurdle of placebo use, or for that matter any medical treatment, is the abuse of hope in the patient’s path of healing. It is one thing to make a harmless recommendation that provides no therapeutic value, but another to subject a patient to known consequences of a dangerous procedure in the pursuit of a dubious outcome. Hope can be abused, leading the patient to experience unreasonable suff ering.221

CONCLUSION Health practitioners must be equipped with a better understanding of placebo therapeutics.6m For many years now, the study of placebo has been recommended to doctors and other health care professionals. The ideal environment for the dissemination of the therapeutic implications of the doctor-patientrelationship is in medical schools as a required part of the curriculum. After finding a pattern of misuse and misunderstanding about the nature and efficacy of placebo, Goodwin et al“ recommended that better education might result in more effective placebo use. In 1938, Hou~ton’’~ wrote of the need to reaffirm the art of medicine because he perceived a trend in medicine that invested in a concept of the therapeutic dodorpatient interaction as “undisciplined thought.” Houston’s remedy for the intellectual bias that viewed medicine as a ”tight, fast-set science” was to emphasize the importance of psychobiology in medical schools:

A physician’s correct understanding of the nature of placebo therapy has been observed as able to coexist with its inaccurate use and abuse.“ It has been recommended, however, that: (1)pure placebo should not be prescribed unless the physician has examined the exact

One of the most hopeful moves in medical education is teaching to first-year students the elements of psychobiology. A system of belief is implanted best in the young. It would be my suggestion that psychobiology be taught in the premedical years, that the doctor/patient relationship be the beginning of medical studies.A deep insight into this fundamental philosophy is a chief concern of the

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200. Cornell Conference on Therapy. The use of placebos in therapy. NY State Med J 1946;46:1718-1726. 201. Volgyesi FA. “School for patients,” hypnosis therapy and psychoprophylaxis. Br J Med Hypn 1954;5:8-17. 202. Epstein JEi. Understanding placebos in dentistry. J Am Dent Assoc 1984;109:71-74. 203. Ader R, Cohen N. Behaviorallyconditioned immunosuppression. Psychosom Med 1975;37333-340. 204. Ader R. Behaviorally conditioned modulation of immunity. In Guillemin R, Cohn M, Melnechuk T, eds. Neural modulation of immunity: proceedings of an internationalsymposium held under the auspices of the Princess Liliane Cardiology Foundation in Brussels, Belgium, October 27 and 28, 1983. New York Raven Press, 1985. 205. Batterman RC, Lower WR. Placebo responsiveness-influence of previous therapy. Curr Ther Res Clin Exp 1968;10136-143. 206. Cassel EJ. The nature of suffering and the goals of medicine. N Engl J Med 1982;306:639-645. 207. Lipkin M. Suggestion and healing. Perspect Biol Med 1984;28: 121-126. 208. Schwartz GE. Biofeedback, self-regulation, and patterning of physiological processes. Am Sci 1975;63314-324. 209. Modell W, Houde RW. Factors influencing clinical evaluation of drugs. J Am Med Assoc 1958;1672190-2199. 210.Greene CS, Laskin DM. Long-term evaluation of treatment of myofascial pain-dysfunction syndrome: a comparative analysis. J Am Dent Assoc 1983;107235-238. 211. Kabat-Zinn J. An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results. Gen Hosp Psychiatry 1982;433-47. 212.Halifax J. Shamanic voices: a survey of visionary narratives. New York: Dutton, 1979. 213.Klinghardt DK. Neural therapy. J Neurol Orthop Med Surg 1993;14:109-114. 214. Orr WC, Hoffman HJ, Hegge FW.Ultradian rhythms in extended performance. Aerosp Med 1974;45:995-1OOO. 215. Goyeche J. Yoga as therapy in psychosomatic medicine. Psychother Psychosom 1979;31:373-381. 216. Wemtz D. Cerebral hemispheric activity and autonomic nervous function, doctoral dissertation, San Diego, University of California, 1981. 217.Zajonc RB. Emotion and facial efference: a theory reclaimed. Science 1985;22815-21. 218.Critchley EM. The human face. Br Med J (Clin Res Ed) 1985; 291:1222-1223. 219.Rothman KJ, Michaels KB. The continuing unethical use of placebo controls. N Engl J Med 1994;331:394-398. 220. Bok S. The ethics of giving placebos. Sci Am 1974;231:17-23. 221. Mukejee S. The anatomy of hope: care of the vital organ. New York T i e s February 22,2004. 222. Leslie A. Ethics and practice of placebo therapy. Am J Med 1954;16854-862.

Positive Mental Attitude Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 111

Attitude and Self-Actualization 112

Attitude, Personality, Emotions, and Immune Function 111

Clinical Aspects of Learned Optimism 114

Attitude and Cardiovascular Health 112

INTRODUCTION A positive mental attitude is one of the important foundational elements of good health. This axiom has been contemplated by philosophers and physicians since the time of Plato and Hippocrates. In addition to simple conventional wisdom, modern research also has verified the importance that attitude-the collection of habitual thoughts and emotions--plays in determining the length and quality of life. Specifically,studies using various scales to assess attitude, including the Optimism-Pessimism (PSM) scale of the Minnesota Multiphasic Personality Inventory (MMPI), have shown that individuals with a pessimistic explanatory style have poorer health, are prone to depression, are more frequent users of medical and mental health care delivery systems, exhibit more cognitive decline and impaired immune function with aging, and have a shorter survival rate compared with optimists.14This research highlights the fact that although life is full of events that are beyond one’s control, people can control their responses to such events. Attitude goes a long way toward determining how people view and respond to the stresses and challenges of life. Attitude is reflected by explanatory style, a term developed by noted psychologist Martin Seligman to describe a cognitive personality variable that reflects how people habitually explain the causes of life events.8 Explanatory style was used to explain individual differences in response to negative events during the attributional reformulation of the learned helplessness model of depression developed by Seligman (described in Chapter 144). To determine a patient’s level of optimism, have him or her take the Attributional Style Questionnaire developed by Seligman (see Appendix 11) or use the PSM

scale of the MMPI. Techniques to help patients learn to be optimistic are given in the following discussion.

AlTITUDE, PERSONALITY, EMOTIONS, AND IMMUNE FUNCTION The importance of attitude to human health has been examined in the link among the brain, emotions, and the immune system. Research in the field of psychoneuroimmunology indicates that every part of the immune system is connected to the brain in some way, either via a direct nervous tissue connection or through the complex language of chemical messengers and hormones. What scientists are discovering is that every thought, emotion, and experience sends a message to the immune system that either enhances or impairs its ability to function. A simplistic view is that positive emotions, such as joy, happiness, and optimism, tend to boost immune system function whereas negative emotions, such as depression, sadness, and pessimism, tend to suppress it. Studies examining immune function in optimists versus pessimists have demonstrated sigruficantlybetter immune function in the optimists. Specifically, studies have shown that optimists have increased secretory immunoglobulin A (IgA) function, natural killer cell activity, and cell-mediated immunity, which is demonstrated by better ratios of helper to suppressor T-cells, than p e s s i r n i ~ t s . ~ , ~ - ~ ~ The immune system is so critical to preventing cancer that, if emotions and attitude were risk factors for cancer, one would expect to see an increased risk of cancer in people who have long-standing depression or a pessimistic attitude. Research supports this association; for example, smokers who are depressed have a much greater risk of lung cancer than smokers who are not depressed.13 111

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Depression and the harboring of other negative emotions contribute to an increased risk of cancer in several ways. Most of the research has focused on the impact of depression and other negative emotions on natural killer cells. Considerable scientific evidence has now documented the linkbetween a higher risk of cancer and negative emotions, stress, and a low level or activity l cells.14 Negative emotions and stress of ~ t u r akiller paralyze many aspects of immune function and literally can cause natural killer cells to b ~ r s t . ’ ~Furthermore, *’~ the prototypical cancer personality-an individual who suppresses anger, avoids conflicts, and has a tendency to have feelings of helplessness-has lower natural killer cell activity than other personality types.I1J2These studies also indicate that individuals with a personality type that is prone to cancer have an exaggerated response to stress, which compounds the detrimental effects stress has on natural killer cells and the entire immune system. Depression and stress not only affect the immune system but also appear to hinder the cell’s ability to repair damage to DNA. Most carcinogens cause cancer by directly damaging DNA in cells, thereby producing abnormal cells. One of the most important protective mechanisms against cancer in the cell’s nucleus is the enzymes responsible for the repair or destruction of damaged DNA. Several studies have shown that depression and stress alter these DNA repair mechanisms; for example, in one study, lymphocytes (a type of white blood cell) from depressed patients demonstrated impairment in the ability to repair cellular DNA damaged by exposure to x-rays.16J7 Just as research has identified personality, emotional, and attitude traits that are associated with impaired immune function, likewise the field of psychoneuroimmunology has identified a collection of ”immune power” traits that include a positive mental attitude, an effective strategy for dealing with stress, and a capacity to confide traumas, challenges, and feelings to oneself and others.14J8

AlTlTUDE AND CARDIOVASCULAR HEALTH In addition to the brain and immune system, the cardiovascular system is another body structure intricately tied to emotions and attitude. The relationship of an optimistic or pessimistic explanatory style with incidence of coronary heart disease was examined as part of the Veterans Affairs Normative Aging Study, an ongoing cohort study of older men.7 These men were assessed by the MMPI PSM scale. During an average 10-year follow-up, 162 cases of incident coronary heart disease occurred: 71 cases of incident nonfatal myocardial infarction, 31 cases of fatal coronary heart disease, and 60 cases of angina pectoris. Men reporting high levels of optimism

had a 45% lower risk for angina pectoris, nonfatal myocardial infarction, and coronary heart disease death than men reporting high levels of pessimism. Interestingly, a clear dose-response relationship was found between levels of optimism and each outcome. To illustrate how closely the cardiovascular system is linked to attitude, one study showed that measures of optimism and pessimism affected something as simple as ambulatory blood pressure.19 Pessimistic adults had higher blood pressure levels and felt more negative and less positive than optimistic adults. These results suggest that pessimism has broad physiologic consequences. Excessive anger, worrying, and other negative emotions have also been shown to be associated with an increased risk for cardiovascular disease; however, these emotions may simply reflect a pessimistic explanatory style.

AlTITUDE AND SELF-ACTUALIZATION A physician’s role should include not only facilitating the health of the patient but also helping the patient achieve self-actualization, which is a concept developed by Abraham Maslow, the founding father of humanistic psychology. His work and theories were the result of intense research on psychologically healthy people over more than 30 years. Essentially Maslow was the first psychologist to study healthy people. He strongly believed that the study of healthy people would create a firm foundation for the theories and values of a new psychotherapy. Maslow discovered that healthy individuals are motivated toward self-actualization, a process of “ongoing actualization of potentials, capacities, talents, as fulfillment of a mission (or call, fate, destiny, or vocation), as a fuller knowledge of, and acceptance of, the person’s own intrinsic nature, as an increasing trend toward unity, integration, or synergy within the person.”2o Maslow developed a five-step pyramid of human needs in which personality development progresses from one step to the next. The needs of the lower levels must be satisfied before the next level can be achieved.When needs are met, the individual moves toward well-being and health. Figure 8-1 displays Maslow’s hierarchy of needs. The primary needs that form the base of the pyramid are basic survival or physiologic requirements: the satisfaction of hunger, thirst, sexuality, and shelter. The second step consists of the needs for safety, which are essential for dealing with the world: security, order, and stability. The individual then progresses to the third step, which involves the ability to love and be loved: belonging. The fourth step involves self-esteem and selfrespect: approval, recognition, and acceptance. The final step is self-actualization: the use of one’s creative potential for self-fulfillment. In modern life, a person’s occupation often correlates with the ability to achieve these needs. Table 8-1 provides

Positive Mental Attitude

Deficit Needs Figure 8-1

Maslow’s Hierarchy of Needs.

an application of Maslow’s Hierarchy of Needs in an occupational environment. Maslow studied and noted that self-actualized people had strikingly similar characteristics. Here are some of Maslow’s key findings in an abbreviated form: Self-actualized people perceive reality more effectively than others and are more comfortable with it. They have an unusual ability to detect the spurious, the fake, and the dishonest in personality. They judge experiences, people, and things correctly and efficiently. They possess an ability to be objective about their own strengths, possibilities, and limitations. This self-awareness enables them to clearly define values, goals, desires, and feelings. They are not frightened by uncertainty.

I

Practical application of Maslow’s Hierarchy of Needs

Level of need

General rewards

Occupationalfactors

Self-actualization

Growth Achievement Advancement Creativity

Challengingjob Opportunities for creativity Achievement in work Promotion

Self-esteem

Self-respect Status Prestige

Social recognition Job title High status of job Feedback from the job itself

Belonging

Love Friendship Belongingness

Work groups or teams Supervision Professionalassociations

Safety

Security Stability Protection

Health and safety Job security Contract of employment

Physiologic

Food Water Sleep Sex

Pay Working conditions

Self-actualized people have an acceptance of self, others, and nature. They can accept their own human shortcomings without condemnation. They do not have an absolute lack of @t, shame, sadness, anxiety, and defensiveness, but they do not experience these feelings to unnecessary or unrealistic degrees. When they do feel guilty or regretful, they do something about it. Generally they do not feel bad about discrepancies between what is and what ought to be. Self-actualized people are relatively spontaneous in their behavior and even more spontaneous in their inner life, thoughts, and impulses. They are unconventional in their impulses, thoughts, and consciousness. They are rarely nonconformists, but they seldom allow convention to keep them from doing anything they consider important or basic. Self-actualizedpeople have a problem-solving orientation toward life instead of a self orientation. They commonly have a mission in life, some problem outside themselves that enlists much of their energies. In general, this mission is unselfish and is involved with the philosophical and ethical. Self-actualized people have a quality of detachment and a need for privacy. Often it is possible for them to remain above the battle, to be undisturbed by what upsets others. They are self-governing people who find meaning in being active, responsible, self-disciplined, and decisive rather than being pawns or helplessly ruled by others. Self-actualized people have a wonderful capacity to appreciate the basic pleasures of life, such as nature, children, music, and sex, again and again. They approach these basic experiences with awe, pleasure, wonder, and even ecstasy. Self-actualized people commonly have mystical or “peak” experiences, times of intense emotions in which they transcend the self. During a peak experience, they have feelings of limitless horizons and unlimited power while simultaneously feeling more helpless than ever before. There is a loss of place and time, and feelings of great ecstasy, wonder, and awe. The peak experience ends with the conviction that something extremely important and valuable has happened, so that the person is transformed and strengthened by the experience to some extent. Self-actualized people have deep feelings of identification with, sympathy for, and affection for other people in spite of occasional anger, impatience, or disgust. Self-actualized people have deeper and more profound interpersonal relationships than most other adults, but not necessarily deeper than children’s. They are capable of more closeness, greater love, more perfect identification, and more erasing of ego boundaries than other people would consider possible. One consequence is that self-actualized people have

Philosophy of Natural Medicine

especially deep ties with relatively few individuals, and their circle of friends is small. They tend to be kind or at least patient with almost everyone, yet they speak realisticallyand harshly of those who they feel deserve it, especially hypocritical, pretentious, pompous, or self-inflated individuals. Self-actualized people are democratic in the deepest possible sense. They are friendly toward everyone, regardless of class, education, political beliefs, race, and color. They believe it is possible to learn something from everyone. They are humble, in the sense of being aware of how little they know in comparison with what could be known and what is known by others. Self-actualized people are strongly ethical and moral. However, their notions of right and wrong and good and evil are often unconventional. For example, a selfactualized person would never consider segregation, apartheid, or racism to be morally right even though it may be legal. Self-actualized people have a keen, unhostile sense of humor. They do not laugh at jokes that hurt other people or are aimed at others’ inferiority. They can make fun of others in general, or of themselves, when they are foolish or try to be big when they are small. They are inclined toward thoughtful humor that elicits a smile, is intrinsic to the situation, and is spontaneous. Self-actualizedpeople are highly imaginative and creative. The creativeness of a self-actualized individual is not of the special-talent type, such as Mozart’s, but rather is similar to the naive and universal creativeness of unspoiled children.

CLINICAL ASPECTS OF LEARNED OPTIMISM Fortunately, humans are optimists by nature, according to Martin Seligman, the world’s leading authority on attitude and explanatory style.21Optimism not only is a necessary step toward achieving optimal health, as emphasized in the preceding, but also is critical to happiness and a higher quality of life. In many instances, it is not what happens in one’s life that determines one’s direction; to a large degree, it is the response to those challenges that shapes the quality of life and determines one’s level of health. Surprisingly, it is often true that hardship, heartbreak, disappointment,and failure serve as the sparks for joy, ecstasy, compassion, and success. The determining factor is whether these challenges are viewed as stepping stones or stumblingblocks. A person’s attitude is like his or her physical body: It must be conditioned to be strong and positive. Conditioning an attitude to be positive and optimistic

requires adopting specific healthy habits. Here are three key areas of focus for helping patients develop a positive mental attitude: Help them become aware of self-talk.Tell them that all people conduct a constant runningdialog in their heads. In time the things people say to themselves and others percolate down into their subconscious minds. Those inner thoughts, in turn, affect the way people think and feel. Naturally a steady stream of negative thoughts will have a negative effect on a person’s mood, immune system, and quality of life. The cure is to become aware of self-talk and then to consciously work to feed positive self-talk messages to the subconsciousmind. Help them ask better questions. The quality of a person’s life is equal to the quality of the questions habitually asked. For example, if a person experiences a setback, does he or she think “Why am I so stupid? Why do bad things always happen to me?” or “Okay, what can be learned from this situation so that it never happens again? What can I do to make the situation better?” Clearly, the latter response is healthier. Regardless of the situation, asking better questions is bound to improve one’s attitude. Some examples of questions that can improve attitude and self-esteem when asked regularly follow: “What am I most happy about in my life right now?” “What am I most excited about in my life right now?” ”What a m I most grateful about in my life right now?” “What am I enjoying most in my life right now?” “What am I committed to in my life right now?” “Who do I love? Who loves me?” ”What must I do today to achieve my long-term goal?” Help them set positive goals. Learning to set achievable goals is a powerful method for building a positive attitude and raising self-esteem. Achieving goals creates a success cycle: A person feels better about himself or herself, and the better he or she feels, the more likely he or she is to succeed. Some guidelines for helping patients set health goals follow: State the goal in positive terms and in the present tense; avoid negative words. It’s better to say, ”I enjoy eating healthy, low-calorie, nutritious foods” than to say “I will not eat sugar, candy, ice cream, and other fattening foods.” Make the goal attainable and realistic. Start out with goals that are easily attainable, like drinking six glasses of water a day or switching from white to whole-grain bread. Initially choosing easily attainable goals creates a success cycle that helps build a positive self-image. Little things add up to make a major difference in the way a person feels about himself or herself.

Positive Mental Attitude

Be specific. The more clearly the goal is defined, the more likely it will be achieved. For example, if a person wants to lose weight, he or she should define the desired weight and the body fat percentage or measurements to be achieved. Counseling is necessary for the severely pessimistic individual. Forms of cognitive therapy appear to be the most useful therapy at this time. Cognitions comprise the whole system of thoughts, beliefs, mental images, and feelings. Cognitive therapy can be as effective as the use of antidepressant drugs in the treatment of moderate depression, and there tends to be a lower risk of relapsethe return of depression-with cognitive therapy? One reason for this is that cognitive therapy teaches people practical skills they can use to combat depression any time, anywhere, every day for the rest of their lives. Cognitive therapy avoids the long-drawnout (and expensive) process of psychoanalysis. It is a practical, solution-oriented psychotherapy that teaches skills a person can apply to improve the quality of life.

1.Maruta T, Colligan RC, Malinchoc M, Offord Kl? Optimismpessimism assessed in the 1960s and self-reported health status 30 years later. Mayo Clin Proc 2002;77:748-753. 2. Taylor SE, Kemeny ME, Reed GM, et al. Psychological resources, positive illusions, and health. Am Psychol 2000;55:99-109. R. Cognitive bias of 3. Schweizer K, Beck-Seyffer A, %eider optimism and its influence on psychological well-being. Psychol Rep 1999;&1.627-636. 4.Chang EC, Sanna LJ. Optimism, pessimism, and positive and negative affectivity in middle-aged adults: a test of a cognitiveaffective model of psychological adjustment. Psychol Aging 2001;16:524531. 5. Segerstrom SC. Optimism, goal conflict, and stressor-related immune change. J Behav Med 2001;24441-467. 6. Maruta T, Colligan RC, Malinchoc M, Offord Kp. Optimists vs pessimists: survival rate among medical patients over a 30-year period. Mayo Clin Proc 2000;75:140-143. 7. Kubzansky LD, Sparrow D, Vokonas P, Kawachi I. Is the glass half empty or half full? A prospective study of optimism and coronary heart disease in the normative aging study. Psychosom Med 2001;63910-916. 8. Peterson C, Seligman M, Valliant G. Pessimistic explanatory style as a risk factor for physical illness: a *-five year longitudinal study. J Pers Soc Psychol 1988;55:23-27. 9. Brennan FX,CharnetskiCJ. Explanatory style and immunoglobulin A (IgA). Integr Physiol Behav Sci 200035251-255. 10. Kamen-Siege1L, Rodin J, SeligmanME, Dwyer J. Explanatory style and cell-mediated immunity in elderly men and women. Health Psych01 1991;10229-235. 11. Imai K, Nakachi K. Personality types, lifestyle, and sensitivity to mental stress in association with NK activity. Int J Hyg Environ Health 2001;204:67-73.

Mental health specialists trained in cognitive therapy seek to change the way the depressed person consciously thinks about failure, defeat, loss, and helplessness. To do so, they employ five basic tactics that help patients to do the following: Recognize the negative automatic thoughts that flit through consciousness at the times when they feel the worst. Dispute the negative thoughts by focusing on contrary evidence. Learn a different explanation to dispute the negative automatic thoughts. Avoid rumination (the constant churning of a thought in one’s mind) by helping the patient better control his or her thoughts. Question depression-causing negative thoughts and beliefs, and replace them with empowering positive thoughts and beliefs.

12.Segerstrom SC. Personality and the immune system: models, methods, and mechanisms.Ann Behav Med 2000;22:180-190. 13. Jung W, Irwin M. Reduction of natural killer cytotoxic activity in major depression: interaction between depression and cigarette smoking. Psychosom Med 1999;61:263-270. 14. Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R. Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology. Annu Rev Psychol 2002;5383-107. 15. Maddock C, Pariante CM. How does stress affect you? An overview of stress, immunity, depression and disease. Epidemiol Psichiatr Soc 2001;10153-162. 16. Kiecolt-Glaser JK, Stephens R, Lipitz P, et al. Distress and DNA repair in human lymphocytes. J Behav Med 1985;8:311-320. 17. Glaser R, Thorn BE, Tam KL, et al. Effects of stress on methyltransferase synthesis: an important DNA repair enzyme. Health Psychol 1985;4403-412. 18. Kiecolt-Glaser JK, Glaser R. Psychoneuroimmunology and cancer: fact or fiction? Eur J Cancer 199935:1603-1607. et al. Effects of optimism, 19. Raikkonen K, Matthews KA, Flory JD, pessimism, and trait anxiety on ambulatory blood pressure and mood during everyday life. J Pers Soc Psychol 1999;76:104-113. 20. Maslow A. The farther reaches of human nature. New York Viking, 1971. 21. Seligman M. Learned optimism. New York Knopf, 1991. 22. Casacalenda N, Perry JC, Looper K. Remission in major depressive disorder: a comparison of pharmacotherapy, psychotherapy, and control conditions. Am J Psychiatry 2002;1591354-1360.

Research in Natural Medicine CadaCalabrese, ND, MPH CHAPTER CONTENTS What Is Natural Medicine? 117 Purpose of Research

Observational Studies 123 Basic Science Studies 124

117 Criteria for a Prioritized Research Program 125

Methodologic Problems and Strategies 118 Clinical Trials 118

The improvement of understanding is for two ends:first, our own increase of knowledge; secondly, to enable us to deliver that knowledge to others. -John Locke

WHAT IS NATURAL MEDICINE? For the purposes of this chapter, natura2 medicine is defined as a paradigm of healing found throughout the world and guided by several distinguishing principles. Care is patient-centered rather than practitioner-centered. Emphasizing self-responsibility and self-care, it supports the body's own healing processes and treats causes rather than simply alleviating symptoms. Especially in the modem era, natural medicine distinguishes itself in a preference for medicines and health aids from the natural environment (e.g., those with which human beings have coevolved). Despite the preference for remedies from nature, natural medicine is a practice; it is not defined only by the substances it uses. Under the proper social cultivation, such practices have evolved to be internally coherent and efficient, although the theories governing them may not be well articulated. The skills are distributed over numerous professional groups (e.g., naturopathic doctors, traditional east and south Asian medical systems, mixer chiropractors, practitioners of many indigenous medicines), and also are practiced widely among conventional medical doctors and other eclectic healers. In some cases they represent the vestigial core, the first principles, of what modem medicine has become. It may be perilous to ignore the precepts of natural medicine, but they can be obscured in the fascination with modem civilization's abilities to manipulate the molecular fine points. As such, natural medicine may be a wellspring of aids to ameliorate the diseases of civilization. In other cases,

however, the practices may be harmful sociocultural delusions. How does one tell the difference? Multifarious separate practices, procedures, and substances can be included under the term natural medicine. Many of the practices considered to be complementary or alternative medicine (CAM), holistic medicine, or integrated medicine may be subsumed in the natural medicine rubric. There have been a great many published reviews of its practices and especially of its substances and approach to diseases, including the present volume.'" Nevertheless most of the practices have not borne the level of scrutiny of modem conventional medicine, in part because their practitioners are healers who may not have the facility or interest in modem scientific methods and in part because the practices may be difficult to study scientifically. Some within CAM ranks have resisted the usual scientific evaluation as necessarily reductionistic and an inappropriate means to the understanding of healing. This chapter addresses needs in the development of relevant original data in natural medicine.

PURPOSEOFRESEARCH What is the role of research in natural medicine? The improvement of healing practices is the purpose of health research. The purpose is not defense of a theory, guild, or faith nor the amusement of wandering through the arcana of methodology. An improvement could be clinical (with which individual patients may be helped) or economic (in which society's abilities to reduce total suffering and maximize health enhancement are enhanced). Various parts of the community (e.g., consumers, practitioners, government, industry) hope for research to respond to the questions "Does it work?" "Does it work better?" and "What works best?" To 117

Philosophy of Natural Medicine respond, one should know what “it” is (learned through observation and qualitative research) and what “works” means (the measures of the reduction of suffering and improvement of performance). Research tools such as descriptive statistics and hypothesis testing are epidemiologic techniques: They lead to generalizations about populations. They have limitations in clinical practice, in which the focus is on one patient at a time. Current biomedical research inmasingly focuses on strategy developed from molecular (lately genetics and proteomics) and physical (surgical and prosthetic) models. In research practice, hypothesis testing is usually more sensitive to a selected outcome and more internally valid (able to answer the precise question it set for itself) when it is redudionistic. The more discrete variables of chemistry and mechanics lend themselves to more reductionistic hypothesis testing. In turn,the validity of the reductionistic approach depends on the precision (narrowness) of the question. Natural medicine is ecologic and holistic in its orientation, with numerous broad inputs and outputs with more analog data and what might appear to be intuitive discriminations. The common models in research that emphasize transferability, internal validity, replicability, and generalizability in molecular and physical systems may conflict with model validity when one is studying natural medicine system^.^ Model validity ensures that the study design reflects the structure and logic of the practices of interest. Thus one might ask whether alternative medicine calls for alternative science. It may be so; in fact some philosophers of science and mathematicians are working toward methods that may be better suited to the evaluation of natural medicine While the development of accepted research methods that incorporate more complex and subtle biomedical quanta are awaited, much can be done with the biomedical research tools currently available.

METHODOLOGIC PROBLEMS AND STRATEGIES Medical research rightly results in a generalizable approach to human degeneration and injury. Thus one can expect to do research only with medical practices that are defined and transferable to other practitioners and patients. Successful research determines whether it is true that interventions produce benefit and how reliable they are in their effects. Research needs to be replicable if it is to evaluate a therapy for potential promulgation and thus qualifies for social support. The obvious is stated here because studies of natural medicine may have difficulty achieving these well-accepted research ideals. What does replicability mean for a medicine that may offer individualized treatment to every patient?

How does individualized treatment map onto an evaluative system in which outcomes typically refer to populations? Some have argued that a new research paradigm needs to be shaped for what has been described as an alternative paradigm of practice. Is alternative science needed for alternative medicine? There is no doubt that better tools are needed to understand and evaluate these practices, particularly informational tools that go beyond current physiologic, psychological, pharmaceutical, and epidemiologic method^.^,^ In the meantime, many accommodations within clinical study methodology can be made that will reduce the apparent contradictions of the different medical value systems. For example, the fact that conditions and treatments should be replicable does not mean that every patient needs to be denominated with a disease and that the treatment of every patient with that denomination needs to be the same. It is a corollary of individualized holistic medicine that such categorization should be done cautiously if the optimal outcome is to be reached. When performing research studies in natural medicine that might lead to improved practice and relief of suffering, one must address issues that are different from or need more emphasis than those in conventional biomedicine. All of the conventional biomedical research domains (e.g., clinical, physiologic, epidemiologic,in vitro, animal) may have an appropriate part in better defining and measuring the effects of natural medicine practices. This chapter touches on some of the methodologic issues for clinical trials, observational studies, and basic science studies.

Clinical Trials Properly performed clinical research in conventional medicine is a demanding discipline that encompasses study design, determination of sample size and population characteristics, ethics, clinical care, definition and sensitive measurement of diseases and outcomes, project management, recruitment, participant adherence and retention, data management and statistics, analysis, and interpretation. For any type of natural medicine clinical trial, the following issues bear additional attention beyond those required for pharmaceutical trials: 1.Standardization 2. Individualizationof treatment: nosology and indication 3. Combination therapies: effect size and safety 4. Nonspecific healing effects 5. Outcomes and measures 6. Controls and blinding 7. Whole practice models

It is necessary to consider these issues in the variety of types of clinical trials that may be useful in the

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investigation of natural medicine. Different approaches to clinical trials include: (a) efficacy trials, which are randomized and placebo-controlled; @) comparative trials, which test treatments against each other; and (c) pragmatic trials, in which model everyday practice conditions to the extent possible.

Standardization Replicability is a hallmark of the scientific method. Specifically what is tested (e.g., a substance, treatment procedure, or system of practice) must be defined, described, and stabilized so that it can be delivered reliably from patient to patient and study to study. Although standardization is a great strength of modern medicine’s pharmacotherapeutics, natural medicine does not have as a definitive a codex. Rather, its practices evolve year by year, with some areas highly dependent on current scientific discovery, and in others they rely empirically, rather than rationally, on procedures that are hundreds or thousands of years old. The concepts of natural medicine are often implicit in the practices rather than academically and replicably explicit. The organized natural medical professions are just beginning to evolve more definitive articulations of philosophy and clinical strategies. What constitutes a competent practitioner often remains uncertain, and many natural medicine approaches, like those of indigenous practices, are unlikely ever to be codified.’ Even with the better-regulated practices (e.g., naturopathic medicine, acupuncture, and chiropractic),health insurance coverage for those licensed practices that have practitioner-review panels (are impaneled by third-party payers) is only recent. It is only in the last few years that coding systems for alternative practices have begun to describe the array of interventionsavailable in the United States? The current emphasis on research in CAM practices calls for speeding up the process of standardization toward replicability. Communication about natural medicine research issues can be problematic when using standard clinical practice and biomedical research metaphors. One way to understand the problem is to say that natural medicine’s critical practices lack articulation and operationalization of accepted and, within the respective practitioner groups, widely understood memes. Memes are collective concepts: ideas, behaviors, or skills that are transferred from one person to another by imitation and replicable on a population basis. The term was coined by Richard Dawkins in his best-selling 1976 book, The Selfish Gene. When a meme is expressed in a phrase, it invokes meaning beyond those of the words themselves, such as in the principle vis medicutrix nuturue (the healing power of nature). Dictionaries of memes may be needed: one for the collective concepts of natural medicine practice, and another for the departures from standard research methodologies that may be necessary as the practices are

investigated. The development of memes through which to express the syncretic concepts of natural medicine is one of the benefits of researching the practices. The dearth of thisarticulation of its conepts accounts in part for natural medicine’s remarkable variation among practitioners. Its transfer from mentor to student may be imprecise or misinterpreted even before practitioner preferences and personalities are brought into play. This is not to say that the concepts of natural medicine practice are not reliably transmitted from mentor to student; only that they are not yet always articulated in ways that can be operationalized into clinical trials. The simpler problems in standardization of natural remedies are increasingly well understood; for example, those of botanical medicine. It is possible to perform a single-agent controlled trial of herbs in a specific disease; however, numerous choices should be made about the intervention. Studies should begin with verification of plant species used, growth and harvesting conditions, and the stability of purported active compounds. Selections should be made of plant parts, various crude extracts, or specific chemical constituents that may be concentrated in various ways and to varying degrees of purity. Crude fresh extracts, to which many clinical herbalists are partial, are susceptible to deterioration. In more sophisticated systems of botanical medicine preparation, a product is standardized to guarantee the minimum or maximum concentration of a number of ingredients. For example, this is true of Egb 761 (Schwabe GmbH, Karlsruhe, Germany), the Ginkgo bilobu that has been the most researched. Standardizing on particular constituents has its challenges. Active ingredients in plants often are classes of molecules (e.g., polysaccharides, saponins, terpenes) that are difficult to distinguish in biological activity among its members. Different compounds in a single species may have similar, possibly complementary effects, such as the polysaccharides and isobutyramides in Echinuceu spp. During in vitro assays, which guide fractionation of the crude extract toward a single active molecule, it is not uncommon for activity to increase but then diminish as greater purity of an identified molecular species is reached, as was the case of the terpenes of Androguphis puniculufa (AndroVir,Paracelsian, Inc., Ithaca, NY), which have an influence in cell signaling. Some manufacturers add cellular activity assays in the effort to standardize for a biologic effect rather than the quantity of a chemical constituent. When such problems are addressed successfully, these levels of standardization lead to testing the industrialization of plant medicine rather than its origins and do not answer the questions of whether the more commonly used crude plants produce the hoped-for clinical benefits. Nevertheless, most manufacturers are moving rapidly toward chemical standardizationand certified Good Manufacturing Practices (GMP). The Policy Announcement on

Philosophy of Natural Medicine

the Quality of Natural Products of the National Institutes of Health (NIH) National Center for Complementary and Alternative Medicine (NCCAM) has brought some light to the botanical standards for NlH-sponsored trials (http:/ /www.nccam.nih.gov/research /policies/naturalproducts.htm). Nutrition can be divided into dietary practices and nutritional supplements. Studies in dietary interventions are demanding. The gold standard for dietary intervention is a residential facility to maintain adherence to the therapeutic regimen, but this solution is expensive and difficult to recruit for. Frequently a long observation time is needed in dietary studies because diets are often intended as preventives or restoratives for which clinical outcomes would take a long time to observe. There are special foods and nutritional supplements, such as probiotics (live bacteria and taken to normalize commensal bacterial populations) and algae. Studies in these types of interventions have some of the same complications as botanical medicine studies. In addition, the interactions of live probiotics with commensal bacteria and the gut are incompletely understood. Homeopathy is a special case in standardization, in that chemical standards are largely irrelevant for remedies that rely on ultradilutional ”potentization” and that may contain no molecules of the material originally potentized. Biologic testing of homeopathics is in its infancy, and reliability is not ensured. Thus only the manufacturing process can be standardized at this time. ”Body, mind, spirit” is a leitmotif of natural medicine. The interplay of psychodynamic phenomena and physical health are only partially encompassed by the behaviorist approach of most recent health psychology research. Otherwise there has been relatively little progress in specific methods since the publication of George Engel’s seminal 1977 Science article that popularized the term biopsychosocial medicine, though the interplay of mindbody techniques and C A M has been explored?JOOne exception to the lack of methodologic advance has been in growing attention to the placebo effect, at times in an inclusive way as well as mechanistically.”J2Conversely the realm of meaning has been relegated most often by modem medicine to spiritual caretakers. Yet intentional spiritual interventions (e.g., personal prayer, meditation, religious practice or belief) are frequently arenas of critical importance to many natural medicine practitioners. Patients may turn to them because they afford greater attention to a spiritual dimension and their world view is consonant with the patient’s own. Although they are a small proportion of all health studies, questions about spirituality remain of persistent investigative interest. However, there are few authoritative and widely used research methods in the study of spiritual medical practices. Operationalizationof spiritual experience is likely to be idiosyncratic or culture specific.

It was only in the fourth edition of the Diagnostic and Statistical Manual (DSM-IV), published in 1995, that the possibility of a religious or spiritual problem was even recognized. Definitions of spirituality in the medical literature may refer to hope and meaning, a personal relationship with God, serenity, or connectedness, all perhaps related to states of the patient’s consciousness.13~14 A number of thinkers bemoan the lack of definition in the area.15 Although efforts to present a cogent, broadly acceptable definition have been made, they have not been widely successful.16J7Thus a better approach to speclfying spiritual interventions may be needed before they will be accessible to replicable research. In a March 2005 PubMed search, in which the denominator “spiritual” was crossed with “clinical trial,” only 12 of the 48 citations were controlled trials of spiritual interventions. There have been no replications despite the fact that most of the studies reported positive results.

Individualization of Treatment Natural medicine’s disease taxonomies (classificationsof human illness) are not always congruent with those of Western molecular biomedicine. Primary variance (differences in outcome) of efficacy is more likely to vary with the conditions of a practice’s native taxonomy than with a foreign one. For example, “strengthening the immune system,” “decreasing toxicity,” and “fortdying the will to health” are common goals in natural health therapeutics but rare in conventional practice. Treatment response would be expected to have a different profile because different diseases are being treated. Thus the speed to healing as well as the disease being treated may be confounded in the evaluation of one system by the other’s definitions and rules. These concepts are themes to be described more explicitly in natural medicine diagnosis. Some natural medicine concepts may no longer have or may never have had a biomedical equivalent, and although they are not diseases, they are diagnoses that help guide treatment. An example is the concept of ”constitution” used in naturopathy, homeopathy, and Asian medical systems. This is a patient’s given biologic potential, tendencies, and patterns of long-standing psychophysical strengths and weakness that are genetically and embryologically determined. Others are the ”biologic terrain” (the background physical health and individual context for the immediate medical problem) and the “vital force” (the motive plan or spirit animating mind and body expressed as physiologic and psychological functionality and adaptability). Biomedical equivalents exist in some parameters for system control concepts; however, they are therapeutically exploited more thoroughly by holistic practitioners. Such concepts are “balance” (as in the immune system, among microbial symbionts, hormones, and neurotransmitters), deficiency

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(not just nutritional but organ deficiencies, such as hypochlorhydria and hypothyroidism), functional reserves, endogenous and exogenous toxicities, and dysmetabolisms (e.g., syndrome X). An important concept is that a disease syndrome may be an attempt by the body to adapt to ecologic stress and so should not be unnecessarily suppressed. This is of interest not only because it is an independent variable (baseline factor) but also because it influences the measurement of the dependent variable (outcome). A skilled natural medicine practitioner necessarily expects success through individualization of treatment regimens. Individualization means that remedies are prescribed not solely on the basis of disease entities but also according to other characteristics of the specific patient. Such characteristics may be transient, constitutional, or representative of the entire constellation of the patient’s health problems and strengths and his or her capacity for self-care. The lack of fit of a person’s health syndrome with a conventional disease model, expressed perhaps in the inability or reluctance of a conventional practitioner to diagnose a particular health problem, may be the very reason a patient turns to natural medicine. A medical system that does not recognize an entity is unlikely to have an effective therapy for it. The complaint will be managed as something else, resulting in ineffective treatment while exposing the patient to the side effects of the ”remedy.” Conversely a medical system that provides an adequate explanatory model for a patient’s symptoms-their origin, aggravators, and ameliorators-has a better chance of effective treatment or management of the condition. Thus individualization of treatment is a strength of natural medicine rather than merely a research problem. Compromises may be made in practice to make a trial of specified therapy possible, but they may diminish therapeutic effect. If the need for individualization is neglected in natural medicine research design, the design will fail to apply the medicine as practiced and thus to evaluate its potential benefit.

Combination Thera eutics: Effect, Size, and Sa ety

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Combination treatment is almost a rule among natural medicine practitioners, who use multiple remedies individualized for each case on the understanding that a disease is not a single entity but a complex expression of broad inputs. This practice complicates the design of clinical trials, yet the evaluation of combination interventions is critical to assessing an examined practice. Single natural agents may have a true effect small enough that a very large patient sample size is necessary to detect a treatment difference. However, the size of the effect of several agents acting together, especially if they act by different mechanisms, may be determined by cumulative or synergetic interactions. Larger effects are more readily

detectible in a clinical trial. Combination treatment also may afford the practitioner latitude in choosing the correct remedies for a patient’s condition, thereby increasing the treatment responder rate. Another strategy in choosing elements of combinations is tailoring them to a case to efficiently address multiple conditions simultaneously, and thereby achieving better global outcomes. Yet another is to use some agents as governors to ameliorate potential side effects of primary remedies. The possibility of adverse events could theoretically rise with combinations. Although the problems of additive and synergetic actions, inhibition, and toxicity associated with multiple synthetic and novel pharmaceuticals in combination are both formidable and ubiquitous, the history of use of natural remedy candidates and the experience of clinicians in using combinations of natural products in various clinical populations mitigate these problems in everyday practice. For example, when whole botanicals are used at a traditional-use dose, early toxicity is most likely to result in nausea and vomiting or diuretic action. More serious adverse events (e.g., anaphylactoid reactions) are rarer with nutrients and botanicals of traditional medicinal use than with novel drugs of a single molecular species. Modem practitioners of natural medicine also combine modalities (e.g., homeopathy and counseling, or manipulation and herbs) that are extremely unlikely to lead to a deleterious interaction but that, if successful, could each stimulate improvement by a completely different route. Because of the breadth of options in affecting a condition, a skilled practitioner can avoid remedies that pose a risk in a particular case while still attaining the targeted pharmacologic action. There is no systematic study of the safety of combinations, but data from licensing authorities and professional liability companies for practices covered show modest levels of adverse experience.

Nonspecific Healing Effects A confounder in a clinical trial is an apparent therapeutic effect that can be attributed not to the test treatment but to a factor associated with the treatment, disease, or population studied. This is a risk inherent to all research and is the reason why randomization, blinding, and “hard” objective measures are valuable in distinguishing true differences in effect among medications. The most honest scientists may have conscious or unconscious behaviors that could bias study results if differentially applied to study groups. Yet similar behaviors are at work in everyday clinical practice to induce affiliation, confidence, commitment, and satisfaction in patients and are, in fact, the responsibility and sine qua non of skilled healers. An important confounder that may be integral to treatment is intentionality. The potential therapeutic action of pure intention, which is not mediated by language or any well-known material force, might be

espoused explicitly by only a minority of holistic practitioners, although actually it may be widely practiced among them. This may be called "psychic healing" or simply "healing." If the intent is to determine whether these techniques have effect on disease, surprisingly, there may be no particular difficulties in conducting studies than are already addressed here. Trials of intercessory prayer may provide a model.I8Design differencesmay be versus ordicalled for if the therapists are special (Ged) nary people, or if the healing energy is directed or willed versus invoked (as from God or spirits). Little has been written on the capacity of intention to influence physical outcomes; in fact, there is implicit rejection of the idea based on Cartesian mind-body duality. Nevertheless a number of studies indicate its existence.l9J0Studies of the effect of prayer or other spiritual practices also may be relevant here and raise the possibility that specific kinds of intentionality may make a difference.2I Intuition is a similarly nebulous practitioner-associated quality that may have an influence on outcome. It might be thought to bear on diagnosis as a source of data or on therapeutics as a guide among possible alternative strategies. Although intentionality and intuition are not typically listed in the educational catalogs of natural medicine academic institutions as requisite health care skills to be acquired, they may be common concepts in the culture of the institutions. Generally they are not considered antiscientific concepts that should be expunged from the awareness of students. Indeed they might be acknowledged and even honored as possible sources of data and therapeutic direction as long as their "discoveries" are not contradicted by harder evidence. The informality of the inclusion of intention and intuition in practice compounds the difficulty of including these concepts in some reproducible way in research protocols. Health care is practiced within a culture whereby practitioners and patients have roles and expectations that reinforce belief in expected outcomes. Some studies have indicated that good practitioner-patient communication results in better health outcomes. Thus some of the magnitude of effect may depend on the setting in which care is offered. Differences in outcome between medical practices may also hinge on the difference between research and nonresearch settings. For example, it is possible that subjects who refuse random assignment have a psychological orientation that may work synergistically with the physical effects of the practices of a medical culture that they prefer or to which they are native. If this is true, the evaluation of systems of practice relative to each other would preclude simple randomization. Trials that should be of real interest to policy-makers are those that determine not simply whether a practice works for anyone to whom it is applied but whether it works (and is cost effective) among those who choose it. A study design that could determine the added value of

the availability of some form of natural health care in those who choose would be one that randomly assigns patients to either a group that undergoes further randomization to strict assignment of alternative or conventional care or a group offering them a choice of alternative or conventional care.= Such a four-group trial including randomization with choice would compare the effect of the different practices among those patients who discriminatively select among them versus those who are simply assigned to them. Natural medicine has little language for placebo and other nonspecific healing effects despite the fact that many conventional scientific authorities think this is an area in which there is much to offer. Both unintentional nonspecific healing effects and intentional psychospiritual medicine are areas in which the discovery and definition of important memes, especially those that may serve research, are poorly evolved not only for natural medicine but also for Western biomedicine.

Outcomes and Measures Because natural medicine is holistic, it is expected by practitioners to have broad benefit (e.g.' correcting deficiencies, strengthening and balancing metabolic processes, and "removing the obstacles to cure"). If a natural medicine intervention for a particular disease is shaped and delivered, a benefit is likely to affect more than one disease condition at a time. The RCT, as it is usually but not necessarily performed, tends to overlook effects on diseases other than the target disease and neglects effects on the entire constitution of the patient. Clients expect to see positive results not only in objective disease parameters but also in general body functions (e.g., fatigue and energy, pain, inflammation, digestion, mental and emotional function) at a perceptible level. Thus methods to assess the efficacy of the medicine should use holistic measures accounting for effects throughout the body systems and over the life cycle, if possible. Beyond the effectiveness of medicine for the individual patient, measures of an entire holistic practice may reasonably be expected to address public health as well as environmental, social, and economic outcomes. Of course, this is ideally the way conventional medicine also should be assessed. When consistentlyapplied to both, a comparison of the practices' comparative virtues might be performed. In the past 25 years, substantial strides have been made in the development of measures that assess individual health globally. There has been progress with the development and wide adoption of instruments such as the Medical Outcomes Study 36-item Short Form questionnaire (SF-36) and of measures such as "qualityadjusted years of life saved." However, there continues to be a lack of sensitivity to changes in disease at the upper levels of function in which the burden of human suffering is great, given the number of "walking

Research in Natural Medicine

wounded,” and which has enormous societal costs, both medical and nonmedical, in life quality, functional impairment, and missed opportunity. The lack of sensitivity in the upper levels of function relates to the general absence of health measures in clinical trials as opposed to disease measures. Gentle natural treatments may show smaller more gradual improvements than may be expected from carefully engineered pharmaceutical and surgical interventions, and instruments sensitive to change are needed if trials are to be relatively short. Ultimately the possibility of the superiority of natural health care in a few areas, such as longevity, the incidence of chronic disease in aging, and the incidence and prevalence of disease in progeny, ideally will require multidecade evaluation.

Controls and Blinding The choice of appropriate comparison controls is an important issue because every alteration of control answers different questions. The different questions in the comparison of a test intervention with placebo, a specific standard of care, usual care (the patient’s baseline care), or time-attention-behavior controls are all of interest. Sometimes ethical constraints may prevent a natural medicine therapy from being evaluated without a concomitant conventional therapy. Some cases of special interest are whether natural health care leads to lower overall morbidity and mortality (1)in patients who are randomly assigned to it compared with those who are not, (2) in patients to whom it is equally available on the basis of cost and access compared with those to whom is not, and (3) in patients who would actively pursue it in the presence of health system structural resistance (e.g., devoted consumers) compared with those who would choose it only if it were equally available or with those who would explore it only under special circumstances. The answers to these questions involve belief, motivation, cost, the restraint of use because of cost (from the consumer’s side), the restraint of access because of cost (from the provider’s side), and compliance. These answers may be fundamental to determining both the efficacy and efficiency of the inclusion of various forms of natural medicine in a rationally structured health care delivery system. Treatments can be categorized simply into substances (drugs, remedies), procedures, and interactions (verbal and behavioral medicine). The double-blind RCT test system is mostly easily applied with the evaluation of substances. Nonmaterial process interventions, such as manipulation, exercise, acupuncture, other forms of point work, and psychological and spiritual treatment, are more methodologically problematic in the RCT desideratum of blinding. Blinding is likely to prove difficult for most dietary manipulations, psychospiritual practices, and any whole practice intervention. In these

cases, blinding often may be at least partially maintained by separating evaluation from treatment and blinding the evaluator. In considering the value of blinding one should remember that studies that blind the practitioner and patient decrease or eliminate the possibility that intentionality will contribute to a positive outcome. Yet, CAM theories explicitly accommodate bonding and expectation as contributors to outcome.23

Whole Practice Models Given that individualized combinationsof modalities and remedies generally are the rule in natural medicine and that their selection is guided by a health system’s own principles and guidelines, evaluation of models of whole practices is most likely to reveal their potential health benefit. The main difficulty that arises is in attaining replicability of the intervention. Although they remain both innovative and challenging, a number of intervention models are possible in approaching the ideal. The simplest is a fixed combination of remedies, although this approach abandons individualization. If it is applied in trials with specific inclusion and exclusion criteria, however, the loss of individualization may be tolerable. A slightly more ambitious approach to whole practice is a menu of choices applied, say, to several possible etiologies in a symptom manifestation (disease) under study. As alternative medicines have been studied in recent years, ”pragmatic” trials have been increasingly explored to treat the practitioner at some specified level of qualification as the unit of intervention. This may be understood as treating the practitioner as a ”black box.” A further step in sophistication is the intervention driven by an algorithm. Such algorithms may be derived through expert practitioner panels. The design and replicability of best practice protocols are just beginning to be studied in naturopathic and Chinese medicine. The complexity of the models that have resulted may well require a manual for the guidance of practitioners, who must be well trained to assess patients and deliver a standardized intervention flexibly.“ A manualized practice would also provide the documentation necessary for ethical and regulatory reviews. A new question that would arise in such studies of manualized practice is the degree of adherence by the provider to the protocol.

Observational Studies There are essentially two components to scientific research observation and experimentation. Observation describes existing reality and the natural history of clinical concepts within medicine. It is where ideas of association are formed and hypotheses are generated. Observation requires focus; therefore the context for observation is the choice of focus. Operating questions that are preliminary to experimentation include: Does

Philosophy of Natural Medicine the phenomenon (or a relationship) exist? and What are its characteristics (description)?Experimentation in medicine is more about influencing future reality. Experimentation tests hypotheses, presumes a focus, and goes on to the context problem of how to model the experimental conditions to reflect a current or potential reality. In medicine, the operating question often concerns causing a desired outcome by manipulating the independent input variables. The input variables are discovered ultimately through observation, as are the models in which to study them. Both observation and experimentation are needed to validly evaluate medical practices. The challenge to results observed in evaluation of clinical practice is determining whether the observed association reflects a causative relationship. Observational studies (quantitative or qualitative) have been considered low on the hierarchy of validity in evaluation of medical practices. Effect sizes found in observational studies are often considered inflated. Yet recent work has shown effect sizes from clinical trials and observational studies to be ~ i m i l a r . ~ , ~ ~ Observational studies, in particular outcomes research, have some unique advantages in the study of natural medical practice. Outcomes research involves cohort studies wherein repeated health status evaluations in ordinary care settings compare outcomes of spontaneously arising variations of care, such as standard care and alternatives to it. Variations may be specific remedies, treatment approaches, or even whole professional practices. Advantages include the lack of ethical conflicts about withholding conventional treatment because the patients choose their practitioner. The effect of intention on the part of patient and practitioner is not abrogated. The medicine is implemented fully individualized with no constraint on the combinations considered best for a patient. The cost of research per case is a lesser constraint than in randomized trials if patients (or third parties) cover the cost of care. Cost-effectivenesscan be incorporated in design as an outcome. More early observational studies will help to guide future trials. Even best-case series, a very simple approach to observational study in CAM, are having a n effect on research directi~ns.~’ The slowly growing coverage of CAM practitioners by third-party payers in health delivery systems over the past 20 years has generated a surfeit of data on use and cost for currently licensed natural medicine practitioners that can be used for comparison with outcomes of standard therapy, although these data remain largely unexplored. Other observational studies have been undertaken, although most have been preliminary and unpublished. Daniel Cherkin’s study of the model of the National Ambulatory Care survey is remarkable in ascertaining the content of practice of state-licensed naturopaths, acupuncturists, chiropractors, and massage therapists.28The care of patients currently using natural

medicine is a valuable source of data for evaluating and monitoring health outcomes over time or against different forms of practice. Observationalstudies in general and in such studies in natural medicine in particular suggest that large amounts of data are generated in the course of well-designed studies. The complexities of natural medicine, with its multiple inputs (patient characteristics and combination individualized treatments), broad measures, standardization data, complex control conditions (e.g., ”usual” care), and early descriptive work, all imply data for specification and exploration. To plan studies, including single-agent trials, and to understand results, natural medicine research would benefit greatly from dedicated infrastructure for data management and quantitative analysis. The NIHNCCAM has recognized the need and value of developing such infrastructure at CAM institutions that have clinical expertise in the practices.29

Basic Science Studies Data from the basic sciences ensure the causal chain linking a happy clinical observation and an intervention. They help the community understand and use the natural medicine professions’ knowledge. All of the natural medicine practices would benefit from greater exposure to the entire array of laboratory pharmacology and might, in turn,inform pharmacology of their own useful strategies. In the exploration of natural medical theory and in refining remedies, it would be useful to have access to a range of basic science techniques from analytic chemistry to classical microbiology to advanced molecular biology. Thousands of natural products have been screened for numerous laboratory outcomes. However, new understandings of human biology and advances in technology have made many more types of studies possible in areas such as combinatory pharmacodynamics, gene expression, proteomics, glycobiology, and immunology. Practitioners could guide the refinement of study questions from their best clinical judgment for future investigation. One continuing need is in standardization of materia rnedicu, not only on chemical constituents but also on biologic activity. Other needed in vitro work includes combination effects and safety, and high dilutional effects. Mechanistic studies of natural treatments with substantial clinical evidence may provide knowledge useful across medical cultures. Recently, NCCAM explicitly turned toward the basic sciences in future CAM research centers to be funded. Animal studies present their own complexities for the practices of interest. On one hand, acupuncture and homeopathic veterinary are common, and demonstration of the concepts of the animal study practices seems a reasonable route to improving practice. On the other, some CAM institutions have policies prohibiting animal

Research in Natural Medicine research on the basis of cruelty. Many vitalists and holistic practitioners hold that neither animal studies nor in vitro work appropriately reflects the human being. Their arguments may bear legitimate scrutiny. However, when animal work is the most fruitful way to pursue an important clinical goal, some natural medicine academic centers are willing to collaborate with animal laboratories. Considering the salugenic rather than disease-oriented goals of most natural medicine practices, it may prove a valuable direction for natural medicine institutions to improve collective understanding through the basic science of normal and optimal physiology and the effects and mechanisms in which they are most likely to be expert. Alternative practitioners may in fact be well suited to contribute knowledge in the measurement of overall health.

CRITERIA FOR A PRIORITIZED RESEARCH PROGRAM The entire array of research designs has a place in natural medicine research. There is a wide range of discussions in the literature and many currently ongoing studies spurred by substantial funding from the NIH. Methodologists have covered many problems in evaluation of different expressions of natural medicine, and the approaches and methods have been well s u m m a r i ~ e d . However, ~~,~ resources are always limited; thus research should be prioritized. Some major criteria to consider in developing programs of research to be considered are the following: 1. Focus on diseases with the highest burden of human suffering and the greatest public health significance as well as those in which standard therapy falls short of cure and effective management.

1. Jonas W, Levin J, eds. Essentials of complementary and alternative medicine. Philadelphia: Williams & W h , 1999. 2. Emst EM, Pittler MH, Stevinson C, et al, eds. Complementary and alternative medicine: a desktop reference. St Louis: Mosby, 2001. 3. Jellii JM, ed. Natural medicines: comprehensive database, ed 3. Stockton, CA: Therapeutic Research Faculty, 2000. 4. Jonas WB, Linde K. Conducting and evaluating clinical research on complementary and alternative medicine. In Gallin I, ed. Principles and practice of clinical research. San Diego: Academic Press, 2002. 5.Bell IR, Caspi 0, Schwartz GE, et al. Integrative medicine and systemic outcomes research issues in the emergence of a new model for primary health care. Arch Intern Med 2002;162:133-140. 6. Goldberger AL. Non-linear dynamics for clinicians: chaos theory, fractals, and complexity at the bedside. Lancet 1996;3471312-1314. 7. Eisenberg DM, Cohen MH, Hrbek A, et al. Credentialing complementary and alternative medical providers. Ann Intern Med 2002; 137965-973. 8. Dumoff A. New codes for CAM: HHS review could make them a reality. Altern Ther Health Med 2002;832-33,35-36. 9.Engel GL. The need for a new medical model a challenge for biomedicine. Science 1977;196129-136.

2. Evaluate first the treatments that have the greatest likelihood of reducing the burden of suffering-the low-hanging fruit among natural medicine therapeutics and preventives. There are two sources for targeting decisions in this regard: the evidence already present in the scientific literature, particularly systematic reviews, and the opinions and data of experienced natural medicine practitioners. 3. Attend to methodologic evolution and the necessary sequencing of studies to achieve long-range goals and to explore for and validate positive clinical experiences. Some research questions require methodologic innovation because we do not yet know exactly how to answer them (e.g., in evaluating the whole-systemsapproach to disease, long-term safety, ultradilution and combinatorial effects, and spiritual practices). Important questions may call for complex designs that combine observational and experimental research. Clinical research often requires preclinical preparation. The confidence of investigators and funders and the clarity of their direction improve with preliminary data from pilot studies and observational outcomes studies. 4.Attend to questions that are fundable and for which infrastructure exists or can be quickly built. This requires attending to the issues that four funding sources-the NIH, foundations, commercial interests, and philanthropy-are prepared to act on.

Finally, we must prepare and build for the long run when husbanding and developing research resources. There is no ultimate proof in medicine, only evidence that inclines us in the right direction for a time but that can be superseded at any moment.

10. Freeman LW, Lawlis GF, eds. Mosby’s complementary and alternative medicine: a research-based approach. St Louis: Mosby, 2000. 11. Kaptchuk TJ.The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann Intern Med 2002;136:817-825. 12. Russo E. The biological basis of the placebo effect: imaging technologies bring empirical rigor to the study of a mysterious medical phenomenon. Scientist 2002;1630-33. 13. Swanson CS. A spirit-focused conceptual model of nursing for the advanced practice nurse. Issues Compr Pediatr Nurs 1995;18: 267-275. 14. Roberts KT, M a l l A. Serenity as a goal for nursing practice. Image J Nurs Sch 1996;28:359-364. 15. Goddard NC. Spirituality as integrative energy: a philosophical analysis as requisite precursor to holistic nursing practice. J Adv NUS 1995;22:808-815. 16. Dyson J, Cobb M, Forman D. The meaning of spirituality: a literature review. J Adv Nurs 1997;261183-1188. 17. Pehler SR. Children’s spiritual response: validation of the nursing diagnosis spiritual distress. Nurs Diagn 1997;8:55-66.

18. Harris WS, Gowda M, Kolb JW, et al. A randomized, controlled trial of the effects of remote, intercessory prayer on outcomes in patients admitted to the coronary care unit. Arch Intern Med 1999;1592273-2278. 19. h o r DJ. Healing research: holistic energy medicine and spirituality. Munich: Helix Verlag, 1993. 20. schlitz M, Braud W. Distant intentionality and healing: assessing the evidence. Altern Ther Health Med 1997;3:62-73. 21. Targ E. Research methodologies for studies of prayer and distant healing. In Lewith G, Jonas WB,Walach H, eds. Clinical research in complementary therapies: principles, problems and solutions. New York Churchill Livingstone, 2002. 22. Institute of Medicine, National Academy of Sciences, Committee on the Use of Complementary and Alternative Medicine Use by the American Public. Complementary and alternative medicine in the United States. Washington, Dc: National Academies Press, January 12,2005. 23. Wirth DP. The signhcance of belief and expectancy within the spiritual healing encounter. Soc Sci Med 1995;41:249-260. 24. Schnyer R, Allen JJ. Bridging the gap in complementary and alternative medicine research manualization as a means of promoting

standardization and flexibility of treatment in clinical trials of acupuncture. J Altern Complement Med 2002;8:623-634. 25. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342: 1878-1886. 26.Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2OOO;3421887-1892. 27. Nahin RL, Straw SE. Research into complementary and alternative medicine: problems and potential. BMJ 2001;322:161-164. 28. Cherkin DC,Deyo RA, Sherman KJ, et al. Characteristics of visits to licensed acupuncturists, chiropractors, massage therapists, and naturopathic physicians. J Am Board Fam Pract 2002;15: 463-472. 29. Lewith G, Jonas WB, Walach H. Clinical research in complementary therapies: principles, problems and solutions. New York Churchill Livingstone, 2002. 30. Nahin RL. Use of the best case series to evaluate complementary and alternative therapies for cancer: a systematic review. Semin 0nc0l 200229:552-562.

Women in the History of Medicine Jennifer L. Booker, ND CHAPTER CONTENTS Introduction 127 From Ancient Greece to Thirteenth-Century Rome 127 The Fourteenth through Seventeenth Centuries 128 The Witch Hunts 129 Discrediting the Midwives 130 Conclusion 130 The Battle of the Sects in Nineteenth-Century America 130

INTRODUCTION Traditionally women have been the healers, caring for their families and neighbors and helping one another through childbirth. Over centuries women developed and used herbal remedies, poultices, diet therapies, water treatments, and techniques for bone setting and the suturing of wounds. Their methods were passed down to form not only the basis of naturopathic medicine but also much of what is allopathic medicine. Women always have been at the forefront in providing humane health care, from the venerated women healers of ancient Greece, to the persecuted medieval women lay healers, to the pioneering women of North America. The witch burnings of medieval Europe; the persecution of midwives in the eighteenth, nineteenth, and twentieth centuries; and the discrimination experienced by women in medicine today are all part of the history and development of medicine. To be unaware of women’s role in medical history is to be ignorant of half the story of medicine. Today health care is primarily in the hands of men, with women playing helpmate roles. The history of women as primary health care givers has been almost completely obliterated. Information about women healers is not part of mainstream knowledge; the interested reader must seek out books specifically about women healers that, until recently, have been generally unavailable. Indeed, women are excluded from history books

Rise of the Medical Establishment 130 Upheaval of the Feminist and Popular Health Movements 132 The Threat of Women Doctors 134 Hydrotherapy:A Haven for Women 135 Victory for a Male Profession 136 Midwives:The Last of the Women Healers to Fall 137

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138

Conclusion 140

generally, not only those concerned with medicine (see Spender for further discussion).’ This dearth of information is a reflection of the pervasive sexism of civilization. It is the author’s intent to reclaim here part of the history of women in medicine. At the original writing of this chapter in 1988,93% of medical doctors (MDs) or allopathic physicians were men. Throughout the industrialized world there were still only few women physicians: England with 24%* and Canada with Statistics from 1997 indicated that 40%of allopathic medical school graduates were women, making up 21.3% of MDs.4 This underrepresentation of women in medicine is the culmination of events that date back to early Greece. This chapter investigates the chronologic events that have resulted in a medical system dominated by white, middle-class and upper-class men.

FROM ANCIENT GREECE TO THIRTEENTH-CENTURY ROME Trotula lived in the eleventh century and studied and taught in Salerno, Italy. Her gynecologic work, De Mulerium Passionibus (On the Sufming of Women), the earliest known compendium of women’s health care, includes the treatments used by Greek, Roman, and Arab physicians. This text was used across most of Europe during the ensuing 300 years. First typeset in 1544, it was reprinted many times in several languages?

127

Unfortunately, Italy was an exception in allowing women into medical schools and careers. The faculty of medicine at the University of Paris absolutely opposed female physicians. In 1220, the law strictly prohibited anyone who was not a faculty member from the practice of medicine, and women were effectively eliminated. There was little need to enforce the law until 1322 when Jacoba Felicie, along with several other women, was charged with examining sick persons, prescribing remedies, curing patients, and receiving fees without a license. Although many of Jacoba’s patients testified in her favor, and she demonstrated that her procedures were the same as those used by licensed physicians, she was stiU charged and fined. This discrimination continued in France, without remittance, until 1868 (600 years later), when the first woman was allowed entry into the Paris Medical School. Generally the tradition of women healers, which had begun in the ancient world, continued until approximately the thirteenth century. Surgery was commonly undertaken by nuns at the local convents or by the ”lady of the manor” in wealthy homes as a charitable duty. Some women healers received payment for their skills. Queen Phillippa, wife of Edward I11 (1327-1377), employed Cecelia of Oxford, who was the designated wise woman of the village, as court surgeon. In the thirteenth century, contact with Arabian scholars stimulated a revival of interest in learning that resulted in two major developments that led directly to the exclusion of women from the healing professions: the appearance of medical schools in universities and the formation of barber-surgeon guild^.^ With the incorporation of medicine into universities, only licensed doctors were given the legal right to practice with the title of physician. With the exception of Italy, all European universities were closed to women. Official recognition of their medical skills was no longer available. The development of universities and medicine was strictly controlled by church doctrine, and innovation was suppressed. Medical students studied Plato, Aristotle, and Christian theology. Medical theory was restricted to Galen and the study of the “complexions” and “temperaments” of men. Students rarely, if ever, saw patients, and the church outlawed human dissection. Surgery was considered degrading and menial. Treatment consisted of bleeding, leeches, and quasireligious rituals. For example, the physician to Edward 11, an Oxford graduate, prescribed writing ”in the name of the Father, the Son and the Holy Ghost, Amen,” on the patient’s jaw for a toothache.6 In contrast, the women healers of this era, practicing illegally, followed the healing methods of Trotula and St. Hildegarde of Bingen, Germany. Hildegarde (10981179) wrote a compendium of natural healing methods

entitled Libw Simplicis Medicine. In it, at a time when male physicians had no use for such advice, she lists the healing properties of 213 plants and 55 trees and asserts the importance of cleanliness for proper treat~nent.~ Although the natural healing methods of these women resulted in their being persecuted and burned at the stake as witches in the Middle Ages, many of these methods continue to be used in naturopathic medicine today. Viewed from the perspective of the late twentieth century, church doctrine was disturbingly misogynistic. Pain in labor was perceived as the Lord‘s just punishment for Eve’s original sin. In the thirteenth century, St. Thomas Aquinas2wrote:

As regards the individual nature, woman is defective and misbegotten, for the active power in the male seed tends to the production of a perfect likeness according to the male sex; while the production of women comes from defect in the active power, or some material indisposition. . . . (Summa Teleologicn) This attitude toward women climaxed in the fifteenth century with the burning of witches or lay healers (discussed later). The second development of the thirteenth century that served to exclude women from the healing professions was the formation of barber-surgeon guilds. These guilds laid down regulations for apprenticeship and membership. In return for guaranteeing standards of practice, members were given exclusive rights to their home town’s needs for surgical care and could prosecute non-gculd members who dared to perform surgery. Those most affected were the midwives. Forceps, a surgeon’s invention, could be used legally only by guild members; therefore a midwife was required to call in a barbersurgeon during a difficult delivery. The surgeon would either remove the infant piecemeal by hooks and perforators or perform cesarean section once the mother was dead.6 Occasionally women were allowed admittance into barber-surgeon guilds through patrimony or apprenticeship, but their numbers were small. By the end of the fourteenth century, organized medicine had effectively excluded women. The church joined the witch hunts in the fifteenth century, and the long tradition of women healers was almost completely eradicated.

THE FOURTEENTH THROUGH SEVENTEENTH CENTURIES By the fourteenth century, professional, universitytrained physicians were in demand by the wealthy. Middle- and upper-class educated women healers were eliminated through being excluded from universities and licensing. This left only the women lay healers of the peasant class as competition. The medical profession appealed to the church for help, and the church

Women in the History of Medicine ~~

~

responded by persecuting women in one of the most vicious rampages in history. There were two reasons for this victimization: The witch healer was an empiricist in direct opposition to church doctrine, and women represented sexuality, a betrayal of faith through sensory awareness and alignment with the devil. The church believed women to be the conduit of all evil. All pleasure was condemned because the devil was considered its source. Women were associated with sex, and lust in either husband or wife was blamed on the woman. A male priest immediately baptized a newborn to ensure salvation of its soul, which had been exposed to the wickedness of the woman for 9 months while in the womb. It was believed that upon resurrection, all humans would be reborn as men? Women healers had sins to atone for other than their sex. The so-called witches relied on their senses and observation in treating their patients. The church believed that to trust one's senses was wrong: The senses were the devil's playground and were used by the devil to lure men into the conceits of the intellect and delusions of carnality, and away from the faith.9 The methods of the witch healer were based on years of experience. She maintained an attitude of active inquiry, learning through trial and error, and cause and effect. Her repertoire included herbal remedies such as clary, hyssop, lily, ergot, belladonna, and digitalis, many of which are still used by naturopathic physicians today. Codified in the written works of Hildegarde of Bingen and Trotula of Italy, her approach was scientific according to today's standards. Even established medicine referred to these works for ~enturies.~ The approach of MDs, deeply antiempirical, with no concern for the material world and empirical observation, was more consistent with church doctrine. They did not search for the natural laws governing physical phenomena but instead abided by the belief that the Lord created the world anew each moment, and hence there was no point in questioning one's surroundings.

The Witch Hunts During the fourteenth through seventeenth centuries, witch hunts spread across Europe. Thousands of executions, usually live bumings at the stake, were carried out, first in Germany and Italy and later in France and England. In 1484, a witch-hunting manual, the Malleus, was written by reverends Kramer and Sprenger, sons of Pope Innocent VIII. It contained specific instructions for conducting witch hunts and methods of torture for extracting confessions and names of other witches. Witchcraft was defined as political subversion, religious heresy lewdness, and blasphemy. Women were accused of every conceivable sex crime against men. They were accused of being organized, of having magical healing powers, and of harming with magic. According to the Malleus, "All

witchcraft comes from carnal lust which in women is insatiable. . . . And blessed be the highest who so far has preserved the male sex from so great a rime."^ Women often were charged and burned at the stake simply for possessing medical knowledge and obstetric skills. "If a woman dare to cure without having studied, she is a witch and must die" Of course, women could not officially study because they were not allowed into medical schools. English physicians complained to Parliament about the "worthless and presumptuous women who usurped the profession" and requested that fines and long imprisonment be the punishment for any woman "who dared to use the practice of Fisyk."lo King Henry VIII heard their plea and secured nationwide regulation of medicine and surgery with the Act of 1512,which installed a system of licensing that approved practitioners and punished and suppressed all others.8 In Europe, the church was given the responsibility of implementing the program to eliminate women healers and "witchcraft." In several German cities, approximately 600 burnings occurred each year, two each day except Sundays. More than 900 "witches" were executed in 1 year in the Wiirzburg area, and more than 1000 in the area of Como, Italy. In Toulouse, France, 400 women were put to death in 1 day. In the Bishopric of Trier in 1585, so many women were killed that two villages were left with only one woman each. It has been estimated that the total number of executed "witches" (85% of whom were women) was in the million^.^ The persecution of women healers greatly strengthened the relationship between the church and the medical profession. The doctor was considered the medical expert, giving an aura of authority to the witch hunt as he decided whether the accused was a witch and what afflictionswere the results of witchcraft. The dogma was that if a woman effected a cure, it was with the help of the devil, whereas if a male priest or doctor effected a cure, it was with the help of God. The Lord worked through male priests and doctors, not through women.2 The majority of witches were the general practitioners of the peasant population, and for 1000 years they were the only source of health care for the general population. The poor did not have access to hospitals or universitytrained physicians and were bitterly afflicted with poverty and disease. The church upheld a double standard in terms of who should receive health care. It was a given for the upper classes and nobility. For the poor, life experience in the world was considered fleeting and unimportant and so was their suffering. The peasants were offered little in the form of relief or even words of comfort from the church: "You have sinned and God is afflicting you. Thank him and you will suffer so much less the torment in the life to come. Endure, suffer, die. Has not the church its prayer for the dead?'r9

Philosophy of Natural Medicine The witch hunts deprived the peasantry of the only health care that was available to them and helped establish the dominance of a technologic and rather violent male-dominated medical profession by eliminating the last of their competition. Not only during the medieval period in Europe but also until about 1875, universitytrained doctors depended on blood-letting and purgatives. Calomel, a mercury salt and the most popular purgative and cure-all medical remedy, was used in large doses for acute problems.” Through the seventeenth century, doctors derived their prognoses from astrology and the theory of ”complexions and temperaments,’’ partially treating their patients with incantations and quasireligious rituals. A common treatment for leprosy, for example, was a soup made of black snake caught on dry land among stones? In contrast, the approach of the medieval woman healer emphasized the role played by the patient’s innate power of healing, a view still held in naturopathic medicine today. She regarded illness as part of the life process and an attempt on the part of the organism to regain homeostasis. Her methods included herbs, diet therapy, massage, water cures, poultices, and other gentle health-promoting approaches.12 Women healers used their extensive knowledge of physiology, anatomy, and herbs gained through experience and observation. Their superior healing abilities were acknowledged by Paracelsus, who in 1527burned his texts on pharmaceuticals, confessing he “had learned from the Sorceress all he knew.”5 However, the witch hunts branded women healers as superstitious and potentially malevolent and so thoroughly discredited women healers among the emerging middle class that, in the seventeenth and eighteenth centuries, devastating inroads were made into their last preserve, midwifery.

Discrediting the Midwives The English Act of 1512, which ultimately controlled the licensing of physicians, made no mention of midwives, probably on the basis that midwifery was considered part of surgery? The system of licensing that did develop for midwives was concerned mainly with social and religious functions, for there was no way for a woman to become educated and therefore no possibility that she could achieve legitimate status through government licensing. As already mentioned, medical schools and universities were closed to women everywhere in Europe except Italy. The majority of midwives were peasants who could not afford to travel abroad to study. As a result, midwives lacked the knowledge of Latin and Greek necessary to read texts or communicate their knowledge of female anatomy and physiology. The few midwives who did manage to educate themselves, by

witnessing dissections and reading medical works, still remained legally unqualified because they could not attain a university degree.E Midwives in England organized in the mideighteenth century to protest the Act of 1512 and the intrusion of male doctors into their realm. They charged doctors with commercialism,damaging infants’ skulls with dangerous overuse of forceps, and causing undue harm to mothers. But because midwives did not know proper medical terminology and many of their members were being burned as witches even as they spoke, their protests were easily dismissed as “old wives’ tales” based on ignorance and superstition. Their skill and tradition were so discredited that they lost claim to their own techniques. For example, when Ambroise Pare (1510-1590), surgeon to the King of France, developed an interest in childbirth, he laid claim to discovery of the podalic version, the method used and described by the woman physician Aspasia in secondcentury Rome.5The male medical profession could now boast of their superior obstetric methods. By the early 1600s, male “midwives” began to establish themselves in earnest. They were called in for difficult cases, often with disastrous results. Nevertheless, childbirth had become the province of male physicians throughout Europe by the end of the eighteenth century.*

Conclusion The persecution of witches was a major exercise in medical and social control, eliminating women healers and removing the peasants’ only source of health care. World views that conflicted with church doctrinefor example, that recognized the nature principle and the holistic quality of human life-were exorcised from the healing arts, not to be revived until the women’s movement in North America in the 1700s and 1800s. Perhaps most significant was the effect the witch hunts had on society’s perception of women, firmly establishmg the suspicion of evil, black magic, and the immoral sexuality of women in general, and women healers specifically.

THE BAlTLE OFTHE SECTS IN NINETEENTH-CENTURY AMERICA Rise of the Medical Establishment In early colonial America, the responsibility for healing was in the hands of women, as was general family care. University-trained physicians (allopaths) did not immigrate from Europe and Great Britain to the colonies until the late 1700s, and then only a few came. In the New World, formal education, including medicine, was not available at the university level. In New Jersey, for

Women in the History of Medicine

example, medical practice, except in extraordinary cases, was mainly in the hands of women as late as 1818.13 Colonial women brought centuries of healing lore with them, handed down from the ”witch” healers of medieval Europe. Knowledge of indigenous herbs learned from the Native Americans was combined with the European traditions of massage, hydrotherapy, botanicals, and midwifery. Medical practice was open to anyone who could demonstrate healing skills, regardless of formal training, race, or sex. Then, in the early lBOOs, American university-trained doctors, modeled after the established European allopaths, began to become available. The four medical schools established by the turn of the century were far below European standards, and programs were only a few months in length. Most schools lacked clinical facilities and did not require even high school diplomas for entry. As the number of formally trained doctors grew, it became clear that much needed to be done before they could achieve the prestige and economic status of European MDs. One of their first tasks was to distinguish themselves from lay healers. Allopaths already were easily identified: They were male, middle- and upper-class, and almost always more costly Their clientele consisted of middle- and upper-class citizens who could afford the prestige of being under their care. It was fashionableamong upper-class women, for example, to employ male doctors for obstetric care, much to the horror of the general populace, who considered it immoral for a woman to expose herself in such a manner to a man.I3 However, the allopaths had little to offer in terms of theory or practice that was superior to what was available through folk medicine. Women healers used gentle botanical medications, offered dietary advice based on generations of experience, and, perhaps most importantly, did little or no harm. Allopathic doctors distinguished themselves by doing a great deal of harm in the form of ”heroic medicine.” Benjamin Rush has been credited with playing a central role in establishing heroic medicine. Along with a small group of elite American MDs, he completed his medical education with a few years of study in Great Britain. Here the group developed the style of the genteel, highly paid European physician, and aspired to establish a similar medical model in the New World. To accomplish this, they had to persuade the general public that the allopaths were able to offer medical care superior to the inexpensive and efficacious care provided by women lay healers and midwives. An all-encompassingtheory and system of therapeutics was developed that had immediate, although extremely dangerous, results. The purpose was to produce the strongest possible visible response in the patient. The

stronger a drug or procedure, the greater its therapeutic value was purported to be. Bloodletting, purgatives, laxatives, enemas, and blistering were among the most common treatments. A patient was bled until either he fainted or his pulse was no longer palpable. In 1847, one physician, after observing that extensive blistering of children often led to convulsions, gangrene, or even death, concluded that blistering ”ought to be held in high rank” in the treatment of childhood diseases.” Not all physicians agreed with these methods, however. Douglas observed, “Frequently there is more danger from the physician than from the Distemper . . . but sometimes not withstanding the Male Practice, Nature gets the better of the Doctor and the patient recovers.”’l Aside from the lack of effective therapeutic techniques, there was a total void where medical theory should have been. Air was considered the carrier of disease, and getting wet was thought to enhance susceptibility to disease. Those who listened lived in fear of bathing, sunlight, and breezes. Drinking water was kept from the ill, and windows were kept shut and covered with heavy drapes. Women were advised to keep themselves covered from the sun at all times with parasols and veils. Heroic medicine gave regular doctors the appearance of being able to keep back disease, winning the ”battle” against disease even if it killed the patient. Some of these doctors became wealthy and gained much influence with statesmen and other powerful members of the upper classes. Politically this influence was essential to subsequent events in the development of allopathic medical dominance in North America. Professions are the creation of the ruling class. To become sole providers of health care and succeed with the sham of heroic medicine, allopaths needed patronage from the ruling class. According to sociologist Elliot Friedson, “A profession attains and maintains its position by virtue of the protection and patronage of some elite segment of society which has been persuaded that there is some special value in its work.”l Between 1800 and 1820, allopaths used their newly acquired influence to pressure 17 states into passing licensing laws restricting the practice of medicine to their own kind. In 10 states, practicing without a license meant imprisonment.l4 However, two major unforeseen political problems appeared to disrupt the allopaths‘ plans. First, the general populace and lower classes did not accept the hazards and pretensions of heroic medicine, preferring the more effective and much less painful and expensive health care provided by lay healers. The second problem was enforcement of licensing laws. The general populace was not prepared to persecute their own trusted healers, who often were the women of their own families or wellknown neighbors. The new laws incited public outrage.

Philosophy of Natural Medicine The popular health movement emerged, fanned by the labor rebellion against upperclass elitism and exploitation of burgeoning industrialization.

Upheaval of the Feminist and Popular Health Movements In the early 1800s, the industrial revolution created a deep economic division between the upper and lower classes. Factory employees and unskilled laborers lived in abject poverty on the edge of starvation while working long hours for ridiculously low wages. Single-family farmers and owners of small businesses were exploited by banks whose financial manipulations often pushed them into ruin. Upper-class industrialists flaunted wealth gained at the expense of the lower classes. The labor movement arose from this setting, with its membership of farmers, artisans, and factory workers. At the same time, the women’s movement began to take greater hold among working-class women. In early industrialized society, many women were thrown together, free of the company of men. Women were either confined to home and church or worked in all-female factories such as those in the New England mill towns. Discovering their common aversion to heroic male medicine, women began to develop alternative^.'^ Among the hundreds of benevolent associations, charitable institutions, and mutual support groups was the “Ladies Physiological Society,” a feminist health care group. At society meetings, women learned about female anatomy, physiology, and personal hygiene; oldtime home remedies were recultivated and exchanged; and the lore of botanical healing and other techniques used by the pioneer women healers were recovered. In opposition to the dangerous therapies of allopathic doctors, they emphasized preventive care-frequent bathing, loose-fitting clothing, whole grains, and fresh air-all in direct opposition to the medical dogma of the day. University-trained regular doctors were considered members of the parasitic, nonproducing classes. The women’s health movement was at the forefront of general social upheaval, a radical assault on medical elitism, and an affirmation of traditional ”people’s” medicine. Women’s outrage against allopathic medicine, shared by working-class men, resulted in a mass movement against medical professionalism and ”expertism” of all forms. It was a class war, and the allopathic doctors were on the side of the aristocraticupper class. Regular doctors, with their claim to educational superiority, were denounced, along with the universities that trained them. It was popularly believed that students learned in the universities to look on labor as “servile and demeaning.”’2 By the 1830s, the labor and feminist movements had converged into the popular health movement. According to historian Richard Shryock, “This crusade for women‘s health was related both in cause and effect to the demand for women’s rights in general and the

health and feminist movement became indistinguishable at this point.”” The health movement was concerned with women’s rights, and the women‘s movement was concerned with health care and access to medical training for women. However, it took a male voice to repeat what women had already said and done before any change took place. Samuel Thomson is credited with laying the foundation of a theory (see Chapter 35) and practice of folk medicine for the working class and feminists. A poor New Hampshire farmer, he had watched his wife and mother die at the hands of allopathic doctors. Outraged by their violent methods, he began to reconstruct the folk medicine he had learned from a woman healer and midwife named Mrs. Benton. According to Thomson: The whole of her practice was with roots and herbs applied to the patient, or given in hot drinks, to produce sweating which always answered the purpose. . . . By her attention to the family, and the benefits they received from her skill, we became very much attached to her; and when she used to go out and collect roots and herbs, she would take me with her, and learn me their names, with what they were good

Thomson’s methodology systematized Mrs. Benton’s methods, which she in turn had learned from Native American Indians and the tradition of women healers before her. In 1822, he published A New Guide to Health, which basically described her entire healing system. His intention was to provide the public with self-sufficient health care and remove healing as a commodity from the marketplace. Although less toxic and more natural than the medical therapies of the day, Thomson’s treatments were not always particularly gentle. For example, lobelia was given as an emetic to cleanse the stomach and followed with capsicum to induce fever. He also used steam baths (his followers were often called ”steamers”) and sought to restore equilibrium through the use of Myrica cerifera (bayberry), Nympheu odoruta (pond lily), Pinus canadensis (spruce), and Rhus glabrurn (sumac).16 The Thomsonian Movement was in full swing by 1835, claiming just less than one fourth of the entire U.S. population. Five Thomsonian journals included articles concerned with health, women’s rights, and affronts to female health inflicted by “heroic” obstetric practices. Thomson held that women were natural healers and believed strongly that doctors, who graduated without ever having witnessed a delivery, should leave obstetrics to midwives. His son, John Thomson, wrote: We cannot deny that women possess superior capacities for the scienceof medicine, and although men should reserve for themselves the exclusive right to mend broken limbs and fractured skulls, and to prescribe in all cares for their own sex, they should give up to women the office of attending upon women.15

These ideas were in direct opposition to those of regular doctors, who believed that women had no place in

Women in the History of Medicine medicine and continued to put much effort into keeping them out. Women were still not allowed into regular medical schools, and the new licensing laws forbade anyone who was not licensed and university educated from practicing the healing arts. Perhaps an extreme example of discrimination against women is that of Henrietta Faber, who studied and practiced medicine in Havana, Cuba, disguised as a man. When she revealed her true sex in 1820 so that she could marry, she was sentenced to 10 years in prison.17It was not until 1849that the first woman, Elizabeth Blackwell, entered a U.S. medical school. (When she was applying to the 42 all-male medical schools, a well-meaning professor at Jefferson Medical College recommended she attend classes disguised as a man.) Healing systems similar to Thomson's grew in the radical climate of the 1830s. Sylvester Graham founded a movement of physiologically based healing called the Hygienic Movement. The Grahamites were so antimedicine that they rejected the use of botanicals as well as drugs. Instead the system encouraged a vegetarian diet of raw fruits and vegetables and whole grains, whereas allopaths held that uncooked produce was injurious to health and white bread was a status symbol. Both the Thomsonians and hygienists upheld the belief that health care and healing skills belonged to the people and should not be a marketable commodity. Followers of Thomson and Graham fought the new licensing laws for physicians alongside the feminists and working-class activists: Any system that teaches the sick that they can get well only through the exercise of the skill of someone else, and that they remain alive only through the tender mercies of the privileged class, has no place in nature's scheme of things, and the sooner it is abolished, the better off mankind will be.18

(It should be noted, however, that although the Thomsonians and hygienists actively recruited women and strongly believed in the importance of women's improving their health and that of their families, they were not particularly supportive of feminism.) By the mid-l830s, every state with restrictive licensing laws had either softened or repealed them. Some states, like Alabama and Delaware, exempted Thomsonians and Grahamites from any re~tricti0ns.l~ Regular doctors now became recognized as just another sect and were revealed as the sect that had attempted to monopolize health care at the expense of the working class. Unfortunately, however, the popular health movement began to decline shortly after its greatest victory. By the late 1830s, some of the Thomsonian and Grahamian practitioners wanted professionalism and the establishment of schools and licensing for their graduates, seeking what they had fought so hard against and reversing some of the original tenets of the movement. Infighting began over the loss of basic principles.

Much competition developed between their schools for students, creating a larger rift. Along with these events occurred a loss of public support. Feminists turned away from health issues and refocused their efforts on women's rights in a world controlled by men. The radicalism of the working class trailed off toward Andrew Jackson's Democratic Party and away from socialist revolution. During the lull, allopaths began adopting enough of the principles of natural healing to appear credible. The reputation of MDs was in a terrible state. Their professionalism had been significantly undermined, and uncontrollable growth of their ranks, from a few thousand in 1800 to more than 40,000 in 1850, resulted in decreased medical fees and lowered economic status.I4 Many of the graduates, unable to make a living from their practice, chose to open schools of their own. Allopaths were also experiencing stiff competition from herbalists, hydropaths, midwives, homeopaths, and the eclectics who mixed natural healing with allopathy. Each healing art had its own schools, journals, and dedicated following. Homeopaths were particularly threatening because they appealed to the upper class, the patient population most coveted by allopathic physicians. In 1847, a small group of allopathic doctors formed the American Medical Association (AMA). On surveying their affairs, they concluded, "NOwonder the profession of medicine has measurably ceased to occupy the elevated position which once it did; one wonders that the merest pittance in the way of remuneration is scantily doled out even to the most industrious of our ranks."14 One of the first acts of the newly formed AMA was to extend the length of required study from 4 to 6 months and to require 2 years of approved preceptorship. However, practically all hospitals barred women from internship programs. In 1857, Elizabeth Blackwell, after being barred from all New York hospitals (despite her degree), opened the first woman-dominated hospital in the world, the New York Infirmary for Women. Internships for women continued to be limited (in the early 1940s, 607 of 712 hospitals would not accept women) until World War 11, when the shortage of male doctors opened the doors for women. The problems for women were further aggravated by the AMA's Consultation Clause, which barred women from membership in the AMA and prohibited members from providing consultations for irregular doctors. Although the Consultation Clause was effective, it was not until the early 1900s that allopathic medicine was able to establish supremacy and essentiallyeliminate women allopaths and natural healers of both sexes from the field. This was accomplished through the adoption of the new religion of "science" and the infusion by the chemical and drug industry (primarily through the Rockefeller and Carnegie foundations) of millions of dollars into their drug-oriented schools.

Philosophy of Natural Medicine

The Threat of Women Doctors From the 1850s through the turn of the century, allopathic doctors relentlessly attacked their competition: the sectarian or irregular and women practitioners. The natural healing-riented groups were attacked for allowing women among their ranks, and women doctors were attacked for their sectarian methods. But the worst was yet to come. By midcentury, middle- and upper-class women were aspiring to become regular doctors. They too were motivated by reform, as were the women of the popular health movement, but their spirit of reform was moral rather than social. Middle- and upper-class women were outraged by the implicit indecency of a male doctor’s treating a female patient. Catherine Beecher, a wellknown doctor and journalist of her time, publicly raised charges of seduction and sexual abuse by male doctors.I9 A women’s society in Philadelphia made it quite clear that “the Bible recognizes and approves only women in the sacred office of midwife.”2”A popular women’s magazine, Godey‘s Lady’s Book, argued strongly in favor of women physicians: “We would, in all deference, suggest that, first of all, there will be candor in the patient to the female physician, which would not be expected when a sense of native delicacy and modesty existed to the extent of preferring to suffer rather than divulge the symptoms.“2o Women began to force their way into allopathic medical schools. Elizabeth Blackwell gained admission into Geneva Medical College in upstate New York in 1849 after having been tumed down by 16 other schools. After her graduation, the college quickly passed a resolution barring entry of women.20In the same year, Harriet Hunt was admitted to Harvard Medical College, but the decision was reversed when the all-male student body threatened to riot. Instead, she attended and graduated from an irregular Emily Howard Jennings returned to Canada from the New York Medical College for Women in 1867 to become the first recognized Canadian woman doctor.21Ironically the first woman doctor to practice in Canada was actually James Barry, who posed as a man right up to her death. Even in death her sex went unreported by the embalmer; only when her grave was exhumed did her sex become known. The truth had been too embarrassing for the male embalmer to reveal, because women were not believed to have the intellect necessary to study, let alone become physicians,” yet Barry had become the chief military doctor for the country. Through the efforts of the sisters Augusta Jennings Kimball and Ella Jennings, the second and third Canadian women doctors, and those who followed, there were approximately 5000 women doctors in the United States and Canada by 1900. More than 1500 women were enrolled in medical colleges exclusively for women, seven in the United States20and

two in Canada2I(Toronto Women’s Medical College and Queens Women’s Medical College). One of the strongest women physicians at the turn of the century, both as a feminist and as a leader of the natural health movement, was Aloysia Stroebele. In the early 1890s, Stroebele, originally from Sigmaringen, Germany, opened the Bellevue Sanitarium in Butler, New Jersey, a nature cure retreat. As the personal aide to Lady Cooke, the famed suffragist leader, she became a strong advocate of “feminine independence and the emancipation of women.’’22During the several years she spent with Lady Cooke, she made three trips around the world, and in the process met with several natural healers, one of whom, Rickli, influenced her greatly. Her accomplishments were many: cofounding the first naturopathic college, cofounding the famed Yungborn sanitarium, funding the journal Nut uropufh, and writing several articles and books. She married Benedict Lust, the founder of naturopathic medicine, in 1901and changed her name to Louisa Lust. Her most telling contribution, besides her famous cures at “the Bellevue” through her integration of diet therapy, hydrotherapy, and the Rickli air cure, were the funds she contributed to fight 17 legal actions taken against practitioners of naturopathy.23 The male medical profession understood all too well the economic threat of these women physicians. Any middle- or upper-class woman who found the idea of revealing herself to a male doctor too repulsive could turn to a woman who was a regular, allopathic physician, still the preferred healer of the upper classes. She no longer had to quibble over going to see ”irregular”women physicians. Male physicians fought back with all the misogynous slander they could muster. They argued that women were too frail to practice medicine, incapable of operating while menstruating, and unable to survive the vulgarities of anatomy class or the shocking truths of reproduction.2°The idea that women were too delicate and modest to survive medical training, let alone desire it, meant that women who insisted on their rights were not really women at all. Alfred Stille, president of the AMA in 1871, explained the phenomenon of women in medicine in his presidential address: Certain women seek to rival men in manly sports . . . and the strange-minded ape them in all things, even in dress. In doing so they may command a sort of admiration such as all monstrous production inspires, especially when they tend towards a higher type of their own.ll

The editor of the Bufulo Medical Journal was more explicit: If I were to plan with malicious hate the greatest curse I could conceive for women, if I could estrange them from the protection of men, and make them as far as possible loathsome and disgusting to man, I would favor the so-called reform which proposes to make doctors of them.18

Women in the History of Medicine In other words, women who became physicians, or even desired to become physicians, were not only less than women, they were less than human. In addition to public slander, male MDs and students did all they could to make the lives of women aspiring to medical careers as miserable as possible. In class they were harassed with insolent and offensive language, and missiles of tobacco quid and garbage were thrown at them. Anatomy teachers often refused to lecture if women were present.20An 1848 obstetrics textbook explained how: “She (woman) has a head almost too small for intellect but just big enough for love.”” Once graduated, women doctors were allowed into few hospitals, and internships were almost nonexistent. Nor were women doctors allowed to join medical societies or publish in medical journals. The AMA did not admit its first female physician until 1915. The entry of women into medicine was fiercely resisted by male doctors, not only because of their deeply rooted misogyny, dating from the beginnings of Christianity and the economic threat they posed, but also because of their association with the popular health movement. The integrity of allopaths had been assaulted by the general public and by the popular health movement in which women and feminism had played a central role. The irregular schools of nature cure continued to welcome women students, and many of the irregular doctors were women providing a gentle and viable alternative to the dangers of regular health care. During the late eighteenth and early nineteenth centuries, women applying to medical school were considered guilty by association of being in opposition to regular medicine and of being feminists.2

Hydrotherapy: A Haven for Women In terms of women’s liberation and medical thought, the most revolutionary alternative system of healing was the hydrotherapy movement, or “hydropathy” as it was known in nineteenth century America. The original system consisted of using hot and cold water for bathing, wrapping, douching, and spritzing (spraying all or parts of the body). Allopathic medicines were excluded. Instead, a vegetarian diet, fresh air, exercise, regular bathing with cold water, and drinking numerous glasses of pure water were considered the pathways to health. Later the principles of hydrotherapy were combined with those of the hygienic, Grahamian, and eclectic systems to form naturopathic medicine. The formal practice of hydrotherapy began with Vincent Priessnitz, who opened a water cure clinic in Graefenburg, Germany, in 1829.24An MD, Joel Shew, and his wife, Mary Louise Shew, introduced hydrotherapy to the United States in 1843, where the cause was most visibly carried forward by Mary Gove Nichols and Russell Thatcher Tra11.24

Women played a major role in hydrotherapy as practitioners, educators, and leaders in health reform and women’s rights. Many women worked alongside husbands or male professionals, specializing in the care of obstetric and gynecologic patients. Most prominent was Mary Gove Nichols, who in 1846 opened her own water cure establishment in New York.” In 1851, she and her physician husband Thomas Nichols opened a medical school in New York based on water cure principles. Other prominent water cure partners were Racheal Brooks Gleason and her physician husband Silas Gleason, James Jackson, Thodoria Gilbert (who opened the Glen Haven Water Cure), and Harriet Austin, who later worked with Jackson.24 The concept of women as protectors of the family’s health and morality was one of the major tenets guiding the hydrotherapist’s insistence that women take control of their own health and personal power. They believed that by developing a healthy lifestyle and independence, women could work alongside men to improve society. These ideas were in direct opposition to the dominant social ethics and medical thought of the day. Allopaths viewed puberty, menses, pregnancy, childbirth, and menopause as a series of potentially dangerous pathologic events. Women were relegated to the domestic sphere because of their supposed weak physical and intellectual nature. In the home, they could be protected by men.25 In contrast, the hydropaths viewed women’s physiology and reproductive functions as normal, healthy processes. Water cure establishments provided a haven where women could receive sympathetic care, find relief from constant pregnancies, and receive psychological and emotional support.25 Women were inspired to achieve beyond the domestic realm, and many went on to become hydropaths themselves. Taking the cure at the hydrotherapy establishments became fashionable among the wealthy during the late nineteenth century. Between 1843 and 1900, 213 water cure sanitariums opened.” Numerous journals, books, and magazines devoted to the tenets of water cure and a natural lifestyle were published during this time. They became forums for disseminating hydropathic ideals of the perfect society in which women no longer wore tight corsets or long dresses, or suffered the ill effects of the allopaths’ overmedication with mercury (for postpartum hemorrhage), lead (for dyspepsia), opium, leeches, and bloodletting. Women were encouraged to avoid the meat-, salt- and stimulant-rich diet of the day. In the vision of the hydropaths, women were free to pursue any career they chose, with hydrotherapy and medicine being the most Thomas Nichols’s statement in the Water Cure Ioumal clearly describes their intent: “Never has woman had such an opening for usefulness and influence as this.No water

Philosophy of Natural Medicine

cure establishment is complete without a qualified woman phy~ician.”~’ Mary Gove Nichols, in her inaugural address at the opening of the American Hydropathic Institute, professed, ”Women are peculiarly fitted to the art of healing because of their tenderer love, the sublime devotion, the never to be wearied patience and kindness of woman.”28 Women composed 30% to 50% of the graduates from the hydrotherapy schools. They worked diligently as the heads of the ladies’ departments of the water cure establishments, attending to all facets of women’s and children’s health care. They provided prenatal care, for which allopaths had little to offer, recommending a diet of fruit, vegetables, whole grains, and milk. Loose clothing, daily exercise, and cold baths were recommended to tone the body in preparation for ~hildbirth.2~ After the birth, women were encouraged to get out of bed within days, if not the same day, thus decreasing the risk of postpartum blood clots and pulmonary embolism. Women were taught to experience childbirth as an empowering, natural, and holy function, rather than as an event to be dreaded because it risked imminent death. Hydrotherapy, more than any other nineteenth century medical sect, had the strongest connection with the women’s movement.

Victory for a Male Profession Until the early twentieth century, allopaths had little to offer that was superior to the other types of health care practices. They had neither economic dominance nor elevated social status over the irregular or natural health care practitioners. In spite of the AMA’s valiant attempts to establish allopathy as the only legitimate form of healing, only 8000 out of 125,000 doctors in the United States were members of the AMA at the turn of the century.29 European allopaths had better success in establishing themselves among the upper class. With the introduction of the germ theory by French and German scientists came the first scientifically demonstrablebasis for disease prevention and treatment. European medical men were the first to adopt scientific methodology into medical practice and education. This served to further enhance their already elevated status. Science had become the new religion of the general public and was held up as the answer to all social, economic, and health problems. The new religion was received in North America with tremendous enthusiasm. Science became a national moral value in North America; any discipline that wanted to justify its existence had to adopt scientific doctrine. Social work, philanthropy, housekeeping, childrearing, business management, public administration, law, and medicine all began to search for a scientific basis. The adoption of scientific principles was synonymous with reform?

In the late nineteenth century, a small group of American doctors traveled to German and French medical universities for further training and retumed determined to install a n elite medical educational system that would elevate their professional status. In 1893, they founded Johns Hopkins University, the first medical school in North America with laboratories and full-time professors. Eight years later, the Rockefeller Institute for Medical Research was opened. The institute was, and is still today, solely concerned with pure research and helped to exalt the mystery of European scientism. One of the founders of the institute and a close friend of the Rockefellers described the place as “a theological seminary, presided over by the Reverend Simon Flexner, M.D.”30 Having finally created a credible academic and research model for medical education, the AMA began to effectively use economic and political pressure to ensure that all schools providing a medical education either ascribed to the model provided by the Rockefeller Institute and Johns Hopkins University or were closed. This was accomplished through a cooperative effort between the AMA’s Council on Medical Education (made up of faculty from the medical schools modeled on the Johns Hopkins prototype) and the Camegie and Rockefeller foundations. The Carnegie Foundation ostensibly agreed to conduct a study of the educational institutions found in the various healing professions. The results were then used to determine which schools and sects were to receive a portion of $150 million in endowments. The study was conducted by Abraham Flexner, brother of the director of the Rockefeller Institute, Simon Flexner, a graduate of Johns Hopkins University. In the survey, schools such as Harvard were seen to be conforming to the new scientific model quite well. They had the money (granted by the foundations) to employ fulltime professors and install expensive laboratories. These schools were given large endowments. The smaller, poorer schools, which provided medical education for women, nonwhites, and people interested in natural healing, did poorly in meeting allopathic requirements and hence received no funds from the Rockefeller and Camegie foundations. According to Flexner ’s report, these schools were not worth saving and their closure would be no loss. Even though 10 medical colleges at the time that provided medical education solely for women, Flexner also decided that few women doctors were needed. He perceived a lack of “any strong demand for women physicians or any strong ungratified desire on the part of women to enter the profe~sion”!~~ Flexner did deduce that some nonwhite doctors were needed, but only enough to check the spread of disease from nonwhite to white neighborhoods, because ”ten millions of them live in close contact with sixty million whites.”31For both

Women in the History of Medicine

economic and philosophical reasons, the irregular schools, which had been havens for women, and women’s medical colleges did not conform to the new allopathic model and were discredited by the Flexner report. From 1904 to 1915, of the 92 schools closed or merged: Five out of seven nonwhite medical schools closed, seven out of 10 medical schools for women shut their doors, and the majority of the alternative medical schools were eliminated. As a direct result, the number of women graduates from allopathic medical schools dropped from 4.3%to 3.2%.In the meantime, from 1910 to 1930, more than $300 million was poured into the medical schools that ascribed to the Johns Hopkins Not only women and nonwhites were affected by these events; scientism became the domain of the upper classes. The reforms that ruled the existence of medical schools included an entrance requirement of 2 years of university training. This effectively made a medical career impossible for all but the middle and upper classes because of the expense. Medical schools that had been economically accessible to the working class ceased to exist, and the entrance of blacks into medical schools was limited by racial discrimination. Women suffered sex discrimination in their attempts to enter the remaining medical colleges,2 with percentages of women students steadily shrinking until the 1970s and the resurgence of feminism.33The medical profession had become an institution composed almost entirely of white, middle- and upper-class men confirmed in their opposition to women and natural healing methods. It is true that turn-of-the-twentieth-century medicine needed some form of standardization of education and health care. However, in the fervor of scientism, sexism, racism, and the allopaths’ rush for economic control, the alternatives to allopathic medicine were effectively eliminated. Despite the new reforms, the quality of medical care was not necessarily improved. The new system of lengthy scientific training did not guarantee that physicians were any more effective or humanely empathic than the irregular healers they replaced. In fact quite the opposite appears to have been the case (see Ivan Illich, Limits to Medicine and elsewhere in thisbook).34Although the scientific method has much to offer, it is arguable that, in the context of the stifling, one-dimensional philosophy and male elitism of the medical profession, the use of the banner of scientism to establish political and economic protection from competing ideas actually inhibited the development of health care in this country.

Midwives: The Last of the Women Healers to Fall In 1900, approximately 50% of all births in North America were attended by midwives? The babies of

middle- and upper-class women were delivered by licensed MDs. Lower-class blacks and European immigrants could not afford MDs, nor did they want them. Midwifery was a respected tradition held in high esteem, particularly by Africans and Europeans. This meant fewer obstetric cases for teaching medical students, because upper-class women certainly did not want a room full of men, medical students or not, witnessing their birthing efforts. Therefore it was said that midwives, by providing affordable and readily available obstetric care to the lower class, were depriving medical students of valuable learning experiences. To remedy the situation, medical schools began to associate themselves with local charity hospitals, offering medical trainees as staff in return for patients they could learn on. In the meantime, the medical profession put considerable energy into making midwifery illegal. An editorial in the Journal of the American Medica2 Association by Charles Ziegler stated the situation as follows: “It is at present impossible to secure cases sufficient for the proper training in obstetrics, since 75%of the material otherwise available for clinical purposes is utilized in providing a livelihood for midwives.”12The “material,” of course, was the bodies of pregnant women. A campaign was launched to rally support among members of the profession to outlaw midwifery by appealing to their sense of what was best for medical education and by portraying midwives as ”hopelessly dirty, ignorant and incompetent relics of a barbaric past” who could do only harm to mother and child: They may wash their hands, but oh what myriads of dirt lurk under their fingernails. Numerous instances could be cited and we might well add to other causes of pyosalpinx “dirty midwives.“ She is the most virulent bacteria of them all and she is truly a micrococcus of the most poisonous kind.26,35 An obvious solution to the problem of the “dirty and ignorant midwives” would have been to educate them in hygiene, the use of an eyedropper to prevent gonococcal eye infections in the newborn, and the use of forceps in difficult births. However, the medical profession wanted obstetrical ”material,” not to train midwives to further improve their effectiveness and legitimacy. Through cooperation with midwives, the MDs could have learned much about childbirth and improved their own reputations. The MDs version of childbirth was dangerous. If the labor was going too slowly for his schedule, he used forceps and cesarean section with considerable risk to mother and child.6 In teaching hospitals, there was a definite bias in favor of surgery to provide experience for students in abnormal deliveries.12 In fact, a 1912 study by Johns Hopkins University found the majority of American doctors less competent than the midwives they had replaced. According to the study, they were

Philosophy of Natural Medicine

less experienced, less observant, and less likely to be present at the critical moment.% It appears that the MDs realized they could not fill the void of service left if midwives were eliminated. One obstetrician in 1915 admitted that of all births in New York State, 25% would be entirely deprived of assistance once midwifery was eliminated.%Yet between 1900 and 1930, midwives were almost totally eliminated from North America. With the demise of the midwife, American women lost their last independent role as healers. More than one historian has referred to the years from 1900 to 1965 as the Dark Ages in terms of the progress of women in the healing arts.37 Although there were women allopathic physicians, their numbers were small. In 1900, women composed 5% of all physicians of all sects, but by 1926 they made up only 2%. Not until the 1970s, with the resurgence of feminism, did the number of women in allopathic medical schools approach even 6%.32 The remaining irregular schools had continued accepting women students without discrimination, although the numbers were not as high as they are now. In the early 1970s, the naturopathic student body was approximately33%female.

WOMEN IN MEDICINE TODAY Today’s dominant form of medicine is a refined form of the heroic techniques of tum-of-the-twentieth-century allopaths, and women have only recently begun to make real progress in entering the ranks of male-dominated technologic medicine. From 1968 to 1978, the number of women enrolled in regular medical schools rose dramatically, from 7% to 25%. Because of federal legislation instituted between 1964 and 1974 that rendered racial and gender discrimination illegal in education and employment, as well as the pressures of threatened lawsuits, the numbers of women enrolled in medical schools increased sigruficantly. At McMaster Medical School in Hamilton, Ontario, more than 50%of the 1978 graduating class were women. This represented the first time in North America that the number of women in an allopathic medical school was greater than that of men.%Data from the year 2000 indicate that women made up 43% of all allopathic medical students, 37%of all residents, and 23%of MD practitioners. In comparison, women composed more than 50%of naturopathic medical school students and 50% of practitioners of naturopathic medicine.* Discussion of the disparity between the numbers of women allopathic students and the number of women who go into practice has included barriers to mentoring and internship positions,

‘Schools surveyed include Bastyr University, Southwest College of Naturopathic Medicine, and University of Bridgeport College of Natumpathic Medicine.

lack of parental leave of absence, lack of on-site child care, and financial and family responsibilities to children and s p ~ u s eHowever, .~ discrimination against women in medicine persists. According to a 1985-1986 survey conducted by the AMA, women eamed 62% of the salary of their male c0lleagues.3~As of 1987, women filled less than 3% of administrative positions in medical schools and only two American allopathic medical colleges had a female dean. Data from 1998 indicated that only 6%of all medical schools’ department chairs were women, an average of one per medical school.4oAs of September 1999, six of the 125 U.S. allopathic medical schools’ deans were women. A survey of three U.S.naturopathic medical schools (see earlier footnote),’ however, showed that 30% to 50% of academic deans were women. Academic ranking for 1987 also shows discrimination, because women compose 23.6% of assistant professors but only 6% of full professor^.^^,^^ Data for the year 2000 indicated that fewer than 11% of full professors at allopathic schools were women, 19%were associate professors, 50%were assistant professors, and 17% were instructors. For men, the numbers were 31% full professors, 25% associate professors, 35% assistant professors, and 8% instructors.40Men are more equally distributed among the rankings of teaching positions. Factors affecting the upward mobility of women are similar for all professions, including medicine. US. culture allows a narrower band of acceptable behaviors required for competition for jobs and positions of authority. What is seen as appropriately goal oriented and competitive in men is perceived as “harsh and “confrontational”in women. Competency and femininity are still perceived as conflicting q u a l i t i e ~This .~~ discrimination among rankings of women is evident in naturopathic medical schools, although to a lesser degree. Barriers to admitting women into medical schools have been lowered considerably for several reasons: The adoption of civil rights and affirmative action legislation, and resolutions on equal opportunity in the United States and Canada. The women’s movement has encouraged women to seek nontraditional careers and assert their rights to pursue them.O Although the number of women in medicine is growing, sexist attitudes seem to have changed little since the tum of the twentieth century. Ramey, referring to the scarcity of women in administrative positions, commented in 1980 that “women are prone to emotions, verbosity, pettiness and pregnancy.”pq In this author’s opinion, the final proof of the continued existence of discrimination against women in allopathic medicine is this statistic: Women account for only 10%of practicing allopathic physicians; in contrast, 40% of practicing naturopathic physicians are women.

Women in the History of Medicine

Continuing discrimination against women in medicine has manifested itself in many There is no school-supported recruitment of women such as there is for minority students. There is a reluctance to admit married women because they may become pregnant and, if they have families, may not use their education. There is overt discrimination in the classroom, including baiting, hostility, and derogatory comments. It has been documented that lecturers, in dealing with problems in medical practice, direct all of their questions and comments to male student^!^,^^ The prevalence of stereotyping women as sex objects within the profession is exhibited by the number of female students who have been sexually embarrassed, harassed, or abused by their male instructors. Reports of such incidents at a conference on women in medicine in Toronto in 1985 were too frequent to be considered extraordinary.& A 1988 study of the gender climate in medical school found that 80% of women students reported discrimination by faculty and other physicians, with faculty displaying subtle to blatant sexism.4’A later study at a Midwest medical school found that gender discrimination increased in intensity as women moved closer to graduation and li~ensing.4~ The types of discrimination reported included sexual remarks, jokes, and innuendoes relegating women into stereotyped roles, sexual advances by married mentors, and blatant sexual manipulation.48The same study also found that two thirds of practicing male physicians admitted that they did not accept women as professional peers. A prevalent argument used to justify reluctance in allowing women into allopathic medical school is that women MDs are less p r o d ~ c t i v eHowever, .~~ evidence suggests that the opposite is true. The January 1976 Bulletin of the Professional Corporation of Physicians of Quebec indicated that although women doctors work only 66% of the hours that male doctors do, they provide 92% of the patient care that male doctors provide. Although it is true that not all women physicians continue to practice throughout the entire span of their potential working years, it is also true that women doctors are still expected to carry on with traditional family roles, a continuing societal problem. A study of women doctors in Detroit indicated that only 59% had worked without interruption since graduation and that 76% of women physicians are still doing all of the cooking, shopping, housekeeping, and child care.40,48Women’s advancement within the profession is inversely related to marital status and family size.37As a direct result of carrying the lion’s share of family responsibility, and the discrimination they experience in obtaining an education and competing for career opportunities, women allopathic physicians are severely underrepresented in private practice, surgical

specialties, and administrative and policymaking positions. Still, the future of women in allopathic medicine looks brighter because their numbers are increasing. It was predicted in 1985 that women will make up 35% of the medical profession within the next decade or two.& Data from the year 2000 indicate that 43% of allopathic medical students are women. As to the types of medicine women will be practicing, it seems that women are returning to their traditional role of providing preventive health care. According to Spiro, ”The long-standing interest of women in preventive medicine, and the current public dissatisfaction with crisis-oriented care have led still others to predict that one contribution of women may be a more ’health-oriented’ medical practice.”MHis statement is irrefutable when one considers the percentage of women in naturopathic medicine. The return of women to their role as primary providers of humane, holistic health care can be attributed to the following events: The resurgence of irregular and naturopathic medicine in North America and Europe as indicated by the increasing number of colleges and institutions providing training in massage, herbal medicine, midwifery, acupuncture, homeopathy, and naturopathy The revival of the feminist movement since the late 1960s Women‘s growing interest in self-health care, as reflected by the rising number of women’s organized health information groups The growing dissatisfaction of the general public with allopathic medicine, who recognize it as expensive and potentially dangerous to one’s health. (For further discussion, see Illich,34Mendelsohn,51and M c K e o ~ n . ~ ~ ) These events and social conditions have created an atmosphere similar to the one in which the popular health movement became successful in the early 1800s. Feminism of the 1960s and 1970s resulted in the growth of women’s self-help groups that taught female anatomy and principles of health and self-care, the publication of Our Bodies Ourselves by the Boston’s women’s movement, and the springing up of clinics devoted solely to women’s health and run by women practitioners. Now, as during the early 1800s, there is considerable public discontent with a “heroic” medicine emphasizing laboratory results and procedures with little attention to wellinformed patient relationships. A recultivation of “folk” medicine with emphasis on the whole person, including emotional, physical, and spiritual well-being, has become a public revolution in thinking. Today’s health care consumer feels empowered to question any health care he or she is receiving. Also similar to the 1800s is the increasing use of “alternative” or ”unconventional” approaches to health care considered nonallopathic

Philosophy of Natural Medicine ~~

because they are not mainstream for MDs. These methods include herbal medicines, treatment diets, nutritional supplements, massage, emotional counseling, acupuncture, and hydrotherapy. Eisenberg and published a landmark study in 1993 indicating that the use of such medicines was common to 34% of the U.S. population. Subsequent studies have put this figure at more than 65%.History is indeed repeating itself with women at the forefront of the revolution in health care. Today, women make up close to or more than 50% of the student bodies at Bastyr University, Canadian College, Southwest College, University of Bridgeport, and National Colleges of Naturopathic Medicine. Much of the philosophy and therapeutic approach of naturopathic medicine has been derived from the work of women healers dating back to ancient Greece and the Roman Empire. In allopathic medicine women physicians are highly valued by women and men patients alike, because they are perceived as less intimidating and more caring, empathic, and willing to listen.

CONCLUSION The history of women in medicine is not well known outside their traditional roles as helpmates and nurses

1. Spender D. Man made language. London: Routledge and Kegan Paul, 1985. 2. Ehrenreich B, English D. Witches, midwifes and nurses: a history of women healers. Old Westbury, NY: The Feminist Press, 1973. 3. Avery ME. Women in medicine, 1979: what are the issues? J Am Med Womens Assoc 1981;36:79-81. 4. More ES, Greer MJ. American women physicians in 2000 a history in progress. J Am Med Womens Assoc 2OOO;55:6-9. 5. Hurd-Mead KC. A history of women in medicine from the earliest times to the beginning of the nineteenth century. Haddam, CT: Haddam Press, 1938. 6. Szasz TS.The manufacture of madness: a comparative study of the Inquisition and the mental health movement. New York Harper & Row, 1970. 7. Thorndike L. A history of magic and experimental science, vol II. New York Macmillan, 1923. 8. Donnison J. Midwifes and medical men: a history of interprofessional rivalries and women‘s rights. New York Schocken Books, 1977. 9. Michelet J. Satanism and witchcraft, a study in medieval superstition. Secaucus, NJ: Citadel Press, 1939. 10. Hughes MJ. Women healers in medieval life and literature. Freeport, Ny: Books for Libraries Press, 1943. 11. Shryock RH. Medicine and society in America: 1660-1860. Ithaca, NY Great Seal Books, 1960. 12. Ehrenreich B, English D. For her own good: 150 years of the expert’s advice to women. Garden City, Ny: Anchor Press, 1978. 13. Kett J. The formation of the American medical profession: the role of institutions. New Haven, C T Yale University Press, 1968. 14. Rothstein WG. American physicians in the nineteenth century: from sects to science. Baltimore: Johns Hopkins University Press, 1972.

to male physicians. It is not generally known that women have been primary health care providers from ancient Greece through the beginning of the nineteenth century. Many factors have created the low percentage of women in the medical profession today. Throughout the ages, women have been intensively persecuted for practicing medicine: Aspasia by Roman law, women folk healers of medieval times who were burned as witches, English midwives who were legislated out of practice in 1512, and women healers of all kinds in early America who were virtually barred from entering allopathic medical schools in North America until the end of the nineteenth century, and then allowed in only very limited numbers. Today, women have made substantial progress in breaking into the allopathic medical profession despite continuing discrimination. The real changes for women in medicine may come with recent trends toward natural therapies and preventive health care, and the resurgence of midwifery and naturopathic medicine. Along with increasing public interest in irregular medicine and the resurgence of colleges providing credible training in alternative health care, a growing number of primary health care givers once again are women.

15. Ryan MP. Womanhood in America: from colonial times to the present. New York New Viewpoint, 1975. 16. Kaufman M. Homeopathy in America: the rise and fall of a medical heresy. Baltimore: Johns Hopkins Press, 1971. 17. Miscellany. Women in medicine. JAMA 1901;371403. 18. Bums D, ed. The greatest health discovery: natural hygiene and its evolution past present and future. Chicago: Natural Hygiene Press, 1972. 19. Beecher C. On female health in America. In: Cott N, ed. Roots of bitterness: documents of the social history of American women. New York EP Dutton, 1972. 20. Woody T. A history of women’s education in the United States, vol II. New York Octagon Books, 1974. 21. Hacker C. The indomitable lady doctors. Toronto, Ontario: Irwin, 1974. 22. Lust-Boyd A. Yungbom: the life and times of Dr. Benedict Lust, founder and father of naturopathy. Self published, 1997. 23. Kirchfield F, Boyle W. Nature doctors: pioneers in naturopathic medicine. Portland, OR Medicina Biologica, 1994. 24. Donegan JB. Hydropathic highway to health: women and watercure in antebellum America. New York Greenwood Press, 1986. 25. Cayleff S. Wash and be healed: the water-cure movement and women’s health. Philadelphia: Temple University Press, 1987. 26. Weiss HB, Kemble HR. The great American water cure craze, a history of hydropathy in the United States. Trenton, NJ: The Past Times Press, 1967. 27. Nichols TL. Medical education. The American hydropathic institute. Water-Cure J 1851;1266. 28. Gove Nichols MS. Woman the physician. Water-Cure J 1851;1274. 29. Berliner HS. A larger perspective on the Flexner Report. Int J Health Sew 1975;5:573-592.

Women in the History of Medicine 30. Brown RE. Rockefeller medicine men: medicine and capitalism in America. Berkeley, CA. University of California Press, 1979. 31. Flexner A. Medical education in the United States and Canada: a report to the Camegie Foundation for the advancement of teaching. New York Amo Press, 1972 (c. 1910). 32. Markowitz G, Rosner DK. Doctors in crisis, a study of the use of medical education reform to establish modem professional elitism in medicine. Am Q 1973;25:83. 33. Walsh MR. Doctors wanted no woman need apply. New Haven, CT Yale University Press, 1977. 34. Illich I. Limits to medicine, medical nemesis, the expropriation of health. New York Penguin, 1977. 35. Barker-Benfield GJ. The horrors of the half-known life: male attitudes toward women and sexuality in nineteenth-century America. New York: Harper & Row, 1976. 36. Kobrin FE. The American midwife controversy: a crisis of professionalization. Bull Hist Med 1966;40:350-363. 37. Morantz RM, Pomerleau CS, Fenichel CH, eds. In her own words: oral histories of women physicians. Westport, C T Greenwood Press, 1982. 38. Carver C, Berlin S. Proposal for study on productivity of women doctors. Toronto, Ontario: Women's Research and Resource Center, The Ontario Institute for Studies in Education, 1978. 39.Donaghue GD. Eliminating salary inequities of women and minorities in medical academia. J Am Med Womens Assoc 1988; 43:28-29. 40. Bickel J. Women in academic medicine. J Am Med Womens Assoc 2000;5510-12,19.

41. Bartlik BD, Smith CA. Women doctors meet to map working strategies. J Am Med Womens Assoc 1981;3623&238. 42. Valian V. Why so slow? The advancement of women. Cambridge, MA: MIT Press, 1998. 43. More ES, Greer MJ. American women physicians in 2000 a history in progress. J Am Med Womens Assoc 2000;556-9. 44. Braslow JB, Heins M. Women in medical education: a decade of change. N Engl J Med 1981;304:1129-1135. 45. Lain BM. Women in medicine. Metuchen, NJ: ScarecrowPress, 1980. 46. Proceedings of symposium on murmurs of the heart: issues for women in medical training, Toronto, Ontario, 1985. 47. Grant L. The gender climate of medical school perspectives of women and men students. J Am Med Womens Assoc 1988;43: 109-110,115-119. 48. Coombs RH, Hovanessian HC. Stress in the role constellation of women resident physicians.J Am Med Womens Assoc 1988;43:21-27. 49. Campbell MA. Why would a girl go into medicine? Medical education in the United States. A guide for women. Old Westbury, Ny: Feminist Press, 1973. 50. Spiro HM. Myths and mirths: women in medicine. N Engl J Med 1975;292:354-356. 51. Mendelsohn RS.Confessions of a medical heretic. Lincolnwood, IL: Contemporary Publications, 1987. 52. McKeown T. The role of medicine: dream, mirage, or nemesis? London: Nuffield Provincial Hospital Trust, 1976. 53. Eisenberg DM, Kessler RC, Foster C, et al. Unconventional medicine in the United States: Prevalence, costs, and pattems of use. N Engl J Med 1993;328:246-252.

Supplementary Diagnostic Procedures 11 Apoptosis Assessment 145 12 Bacterial Overgrowth of the Small Intestine Breath Test 153 13 Cell Signaling Analysis 161 14 Comprehensive Digestive Stool Analysis 2.0 165 15 Erythrocyte Sedimentation Rate 179 16 Fantus Test 185 17 Fatty Acid Profiling 189 18 Folic Acid Status Assessment 199 19 Food Allergy Testing 203 20 Hair Mineral Analysis 209 21 Heidelberg pH Capsule Gastric Analysis 21 7 22 Immune Function Assessment 221 23 Intestinal Permeability Assessment 241 24 Laboratory Tests for the Determination of Vitamin Status 251 25 Lactose Intolerance Testing 255 26 Metal Toxicity: Assessment of Exposure and Retention 263 27 Mineral Status Evaluation 275 28 Oral Manifestations of Nutritional Status 281 29 Rapid Dark Adaptation Test 283 30 Urinary Organic Acids Profiling for Assessment of Functional Nutrient Deficiencies, Gut Dysbiosis, and Toxicity 285 31 Urinary Porphyrins for the Detection of Heavy Metal and Toxic Chemical Exposure 299 32 Urine Indican Test (Obermeyer Test) 305

Over the past 50 years, tremendous progress has been made in the development of laboratory procedures for the diagnosis of

disease. However, this work has focused primarily on pathologic processes-little has been done to help the physician recognize physiologic abnormalities before they progress to the pathologic stage. The problem is further aggravated for doctors of preventive and natural medicine, who need to evaluate in an objective manner the nutritional status, lifestyle, physiology, and health of their patients. The few widely available tests that exist tend to be oriented to measuring absolute values rather than functional indices and generally indicate abnormal values only after serious dysfunction develops. We have compiled a number of useful procedures that we believe will greatly aid physicians who would like to utilize more objective tests in their evaluation of the pathophysiologic status of their patients. These are not meant to replace the standard, pathologically oriented, diagnostic procedures but rather to supplement them and aid in the early diagnosis of disease susceptibility and the quantification of the processes that usually precede clinical disease. Where possible, preference is given to tests that measure function rather than abstract absolute values. In keeping with the metabolic and scientific orientation of this textbook, emphasis has been placed on those procedures that have good support in the scientific literature for the evaluation of nutritional status. Most of these laboratory procedures are on the cutting edge of our understanding of the assessment of the physiologic function of metabolically unique individuals. Because it is an emerging field, few experts exist and most are employed by the commercial laboratories performing and providing the procedures. A list is given on the copyright page (p. iv) of chapter authors for whom such a potential conflict of interest exists.

143

Apoptosis Assessment AristoVojdani, PhD, MT CHAPTER CONTENTS Introduction 145 Measurable Features of Apoptosis 145 Different Stages of Apoptosis 146 Apoptosis Is Induced by Chemicals to Control Malignancy 146 Clinical Applications 147

INTRODUCTlON Apoptosis is a distinct form of cell death controlled by an internally encoded suicide program. It is believed to occur in the majority of animal cells. It is a distinct event that triggers characteristic morphologic and biologic changes in the cellular life cycle. It is common during embryogenesis, normal tissue and organ involution, and cytotoxic immunologic reactions and occurs naturally at the end of the life span of differentiated cells. Apoptosis can also be induced in cells by the application of a number of different agents, including physiologic activators, heat shock, bacterial toxins, oncogenes, chemotherapeutic drugs, various toxic chemicals, and,ultraviolet and gamma radiation. When apoptosis occurs, the nucleus and cytoplasm of the cell often fragment into membranebound apoptotic bodies, which are then phagocytized by neighboring cells. Alternatively, during necrosis, cell death occurs by direct injury to cells, resulting in cellular lysing and release of cytoplasmic components into the surrounding environment, often inducing an inflammatory response in the tissue. A landmark of cellular selfdestruction by apoptosis is the activation of nucleases and proteases that degrade the higher-order chromatin structure of the DNA into fragments of 50 to 300 kilobases and subsequently into smaller DNA pieces of about 200 base-pairs in length. Using fluorescent-labeled reagents, it is possible to tag the DNA break and identify the percentage of apoptotic cells with a high degree of accuracy.’4

Measurable Features of Apoptosis One of the most easily measured features of apoptotic cells is the breakup of the genomic DNA by

Apoptosis in Autoimmune Diseases 147 Apoptosis during Viral Infection 148 Apoptosis in Acquired Immunodeficiency Syndrome 149 Apoptosis in the Heart and Brain 149

Conclusions

150

cellular nucleases. These DNA fragments can be extracted from apoptotic cells and result in the appearance of DNA laddering when the DNA is analyzed by agarose gel electrophoresis. The DNA of nonapoptotic cells, which remains largely intact, does not display this laddering on agarose gels during electrophoresis. The large number of DNA fragments appearing in apoptotic cells results in a multitude of 3’-hydroxyl termini of DNA ends. This property can also be used to identify apoptotic cells by labeling the DNA breaks with fluorescent-tagged deoxyuridine triphosphate nucleotides (F-dUTP). The enzyme terminal deoxynucleotidyl transferase (TdT) catalyzes a template-independent addition of deoxyribonucleotide triphosphates to the 3’-hydroxyl ends of double- or single-stranded DNA. A substantial number of these sites are available in apoptotic cells, providing the basis for the single-step fluorescent labeling and flow cytometric method. Nonapoptotic cells do not incorporate significant amounts of the F-dUTP owing to the lack of exposed 3’-hydroxyl DNA ends. Apoptosis can also be characterized by changes in cell membrane structure. During apoptosis, the cell membrane’s phospholipid asymmetry changes-phosphatidylserine (PS) is exposed on the outer membrane, while membrane integrity is maintained. Annexin V specifically binds phosphatidylserine (PS), whereas propidium iodide (PI) is a DNA-binding fluorochrome. When a cell population is exposed to both reagents, apoptotic cells stain positive for annexin V and negative for PI; necrotic cells stain positive for both, and live cells stain negative for both.3 This process of apoptosis and its analysis by flow cytometry are shown in Figures 11-1and 11-2. 145

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THE EXECUTIONER IL,+ converting enzyme Granzymes

Figure 11-1 Detection of apoptosis using damaged membrane or DNA single-strand break and flow cyiometry.

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Figure 11-3 Various stages of "inside out" cell death or apoptosis.

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ANNEXIN V Figure 11-2 Separation of cells by flow cytometry and detection of apoptotic population.

Different Stages of Apoptosis The process of apoptosis is divided into three different stages: Induction Sensing or triggering Execution These stages of apoptosis are depicted in Figure 11-3. Induction represents the initial events that signal a cell so that apoptosis may begin. This induction phase may be induced by various physical agents such as toxic chemicals, radiation, chemotherapy agents, hormones, and CD95 or Fas ligation. However, in a series of experiments, I and my colleagues demonstrated that this induction stage of apoptosis is prevented by many antioxidants (vitamin C, beta-carotene, and vitamin E)

and also by various biologic response modifiers, including lentinan, thymic hormones, viral antigens, and cytokines. The induction stage is followed by a decision on whether or not the cell will undergo apoptosis. The decision to die is under the control of a number of different pathways or cellular sensors that induce the apoptosis signal, which then triggers the central mechanisms. During this stage, enzymes such as ILI-p converting enzymes, serine protease, cysteine protease, granzymes, and cyclin-dependent kinases become activated. Once activated, these enzymes dismantle the cell and trigger the cell surface changes that cause direct cell recognition and engulfment of the dying cells by phagocytes. These central events are prevented by various antioxidants and biologic response modifiers.

Apoptosis Is Induced by Chemicals to Control Malignancy Many chemicals have the capacity to bind to DNA, form DNA adducts, or cause DNA single-strand breaks, possibly leading to cancer. However, the body is equipped with many factors, enzymes, suppressor genes, and cellular sensors, all with the capacity to prevent this action of chemicals on DNA by activating apoptosis-inducing signals. The role of apoptosis in regulating tissue growth is readily apparent in the simple equation in which the rate

Apoptosis Assessment

of growth is equal to the difference between the rates of cell proliferation and cell death. Thus tissues expand if the rate of proliferation exceeds the rate of cell death. This is one of the reasons for suggesting that defects in apoptosis may contribute to the transformed state. An important prediction of the relevance of apoptosis to malignancy is that the rate of apoptosis versus mitosis should influence the behavior of a tumor. Recently, the relationship between the apoptotic and mitotic indices in a tumor was demonstrated predictive of outcome: Higher ratios correlate with positive prognosis. Further, it was found that this is not simply a function of cell death per se. Tumors with a high incidence of necrosis rather than apoptosis were correlated with poor prognosis. It therefore follows that treatments or conditions that favor apoptosis should have desirable effects, and that defects in the pathways leading to apoptosis are likely to play important roles in the process of oncogenesis.45 Many reactive chemicals and drugs such as acetaminophen, diquat, carbon tetrachloride, quinones, cyanide, polyhydroxyl polyether, methyl mercury, and organotin have been implicated in apoptosis (programmed cell death) and necrosis (toxic cell death).7-14 Most research on chemical induction of apoptosis is carried out with primary cultures of cell lines (e.g., neurons, thymocytes, carcinoma cells, leukemia cells, neuroblastoma, breast cancer cells, lymphoma); little has been published on the in vivo effects of chemicals on apoptotic cells in animal models and none in humans. Therefore it was of interest to examine the effects of exposure to low levels of benzene, as well as through drinking water concentrations of up to 14 ppb on the apoptotic cell population, as well as to examine possible changes in the cell-cycle progression.' Evidence is suffiaent for the carcinogenicity of benzene in humans; therefore there is no safe level of exposure to this chemical or its metabolites. Published case reports, a case series, epidemiologicstudies, and both cohort and case-control studies have shown statistically sigruficant associations between leukemia and occupational exposure to benzene and benzene-containing s~lvents.*~J~ It is indicated that possibly 800,000 persons are exposed to benzene from coke oven emissions at levels greater than 0.1 ppm, and 5 million may be exposed to benzene from petroleum refinery emissions at levels of 0.1 to 1ppm. Since then, numerous chemicals have been implicated in apoptosis (or programmed cell death), which arises from damage to DNA. We hypothesized that in individuals with a certain genetic makeup, benzene or its metabolites act as haptens, which may induce programmed cell death. The study involved a group of 60 male and female subjects who were exposed to benzene-contaminated water (at concentrations up to 14 ppm for a period of 3 to 5 years). For comparison, we recruited a control group consisting of 30 healthy males

and females with a similar age distribution and without a history of exposure to benzene. Peripheral blood lymphocytes of both groups were tested for percentage of apoptotic cell population, using flow cytometry. When exposed individuals were compared with the control group, statistically sigruficant differences between each mean group were detected (27.5 f 2.4 and 10 f 2.6, respectively),indicating an increased rate of apoptosis in 86.6% of exposed individuals (p c 0.0001, Mann-Whitney U-test). Flow cytometry analysis of apoptosis in a healthy control and a patient with chronic fatigue syndrome is shown in Figure 11-4. We have already shown that benzene induction of apoptosis is caused by a discrete block of the cell cycle progression. Because it was shown that the ratio of apoptosis to mitosis is predictive of tumor growth, with increased apoptosis favoring positive prognosis. We analyzed their data and expressed them in terms of this ratio? As shown in Table 11-1, about 10%of the chemically exposed individuals demonstrated a rate of mitosis greater than that of apoptosis, which is predictive of cancer development. Therefore the tendency of normal cells to commit suicide when deprived of their usual growth factors, or of physical contact with their neighbors due to chemical exposure, is probably a built-in defense against metastasis. Prompt activation of apoptosis in tumor cells that leave their native tissue presumably eradicates many metastatic cells before they have a chance to proliferate. In cancer, it is tumor cells that neglect to sacrifice themselves or forget to die. Indeed, researchers increasingly describe cancer as a disease involving both excessive proliferation of cells and abandonment of their ability to die. Cancer develops after a cell accumulates mutations in several genes that control cell growth and survival. When a mutation seems irreparable, the affected cell usually kills itself rather than risk becoming deranged and potentially dangerous. But if the cell does not die, it or its progeny may live long enough to accumulate mutations that enable it to divide uncontrollably and metastasize, to break away from the original tumor and establish masses at distant sites. In many tumors, genetic damage apparently fails to induce apoptosisbecause the constituent cells have inactivated the gene that codes for the P53 protein. This protein, it will be recalled, can lead to activation of the cell's apoptotic machinery when DNA is injured by environmental agents such as benzene or its metabolites. Thewfore it is important to study cell suicide in health and diseases.

CLINICAL APPLICATIONS Apoptosis in Autoimmune Diseases In cancer, it is the tumor cells that forget to die-in autoimmunity, immune cells fail to die when they are

Supplementary Diagnostic Procedures Negative control

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Figure 11-4 Enhanced apoptotic cell population in benzene-exposed chronic fatigue syndrome individuals. Flow cytometry analysis of apoptotic cell population in negative mntrol cells (HL-60 leukemic cell line), positive control cells (HL-60 leukemic cells treated with the m e n camptothecin), control subjects, and benzene-exposed individuals. Peripheral blood leukocytes were isolated. cultured for 12 hours paraformaldehyde-fixed, F-dUTP-labeled, and analyzed for apoptosis by flow cytornetry.

supposed to. Virtually all tissues harbor apoptotic cells at one time or another. Damaged cells usually commit suicide for the greater good of the body; when this does not occur, disease may develop. Autoimmunity occurs when the antigen receptors on immune cells recognize specific antigens on healthy cells and cause the cells bearing those particular substances to die. But true autoimmune diseases that involve apoptosis do exist. Under normal conditions, the body allows a certain number of self-reactive lymphocytes to circulate. These cells normally do little harm, but they can become overactive through several processes. For instance, if these reactive lymphocytes recognize some foreign antigen such as microbes on food and haptenic chemicals, then exposure to that antigen causes them to become excited. If, due to molecular mimicry, these antigens are similar to normal tissues, the activated cells may expand their numbers and attack the healthy tissue, thus causing an autoimmune disease.'J7Js Autoimmune reactions usually are self-limited-they disappear when the antigens that originally set them off are cleared away. In some instances, however, the autoreactive lymphocytes survive longer than they should and continue to induce apoptosis in normal cells. Some evidence in animals and humans indicates that extended survival of autoreactive cells is implicated in at least two chronic autoimmune syndromes-systemic

lupus erythematosus and rheumatoid arthritis. In other words, the lymphocytes undergo too little apoptosis, with the result that normal cells undergo too

Apoptosis during Viral Infection Disturbance in the regulation of apoptosis participates in various diseases. Viral illnesses are among the diseases caused by apoptosis dysregulation. After entering a cell, viruses attempt to shut down the cell's ability to make any proteins except those needed to produce more virus. This act of stalling host protein synthesis is enough to induce many kinds of cells to commit suicide. If the host cell dies, the virus is also eliminated. Therefore certain viruses have evolved ways to inhibit apoptosis in the cells they infect. Epstein-Barr virus, which causes mononucleosis and has been linked to lymphomas in humans, uses a mechanism that has been seen in other viruses. It produces substances that inhibit apoptosis. Other viruses, such as P53, inactivate or degrade the induced apoptosis. Papillomavirus, a major cause of cervical cancer, is one example. Cowpox virus, a relative of which is used as the smallpox vaccine, is another. Both elaborate a protein that prevents proteases from carrying out the apoptotic program. Investigators interested in antiviral therapy are now exploring ways to block the activity of the antiapoptotic molecules manufactured by viruses.19

Apoptosis Assessment -

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(benzene). In patients 11 and 14, the rate of mitosis is twice that of apoptosis, yielding a ratio of apoptosis to mitosis close to 0.5. Others present ratios

Sample no.

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34 29 48 47 20 42 23 26 35 44 18 19 32 19 27 29 28 24 7 10

18.3 25 46 52 18 17 17 19 13 19 33 15 12 35 16 19 27 19 6 11

Apoptosis in Acquired Immunodeficiency Syndrome Induction of apoptosis by viruses in healthy cells is believed to contribute to the immune deficiency found in patients with acquired immunodeficiency syndrome (AIDS). In these patients, infection with human immunodeficiency virus (HIV) causes T-helper cells to die. As T-helper cells gradually disappear, cytotoxic cells, such as natural killer (NK) cells, perish as well through apoptosis, since they cannot survive without the growth signals produced by T-helper cells. When the number of T-cells dwindles, so does the body’s ability to fight infections, especially viral and parasitic. Researchers have shown that many more helper cells succumb than are infected with HA? It is also highly probable that a large number of the cells probably die through apoptosis. Apparently, Fas plays a crucial role in this process. Normally, T cells make functional Fas only after they have been active for a few days and are ready to die. But helper cells from AIDS patients may display high amounts of functional Fas even before the cells have encountered an antigen. This display of Fas would be expected to cause the cells to undergo apoptosis prematurely whenever they encounter Fas ligand on other cells (such as on T cells already activated against HIV or other microbes).

Ratio of apoptosidmitosis

1.9 1.2 1.05 0.9 1.1 2.5 1.35 1.37 2.7 2.3 0.54 1.26 2.66 0.54 1.68 1.52 1.03 1.26 1.16 0.9

In addition, if the primed cells encounter the antigen recognized by their receptors, they may trigger their own death. It is also possible that oxygen-free radicals trigger the suicide of virus-free T cells. These highly reactive substances are produced by inflammatory cells drawn to infected lymph nodes in HIV patients. Free radicals can damage DNA and membranes in cells. They will cause necrosis if they do extensive damage, but they can induce apoptosis if the damage is more subtle. In support of the free-radical theory, researchers have found that molecules capable of neutralizing free radicals prevent apoptosis in T-cells obtained from AIDS patient~.l~,*~ Therapies with antiapoptotic medication, such as Trolox, a water-soluble analog of vitamin E that prevents oxidative stress, and pyrrolidine dithiocarbamate, a potent inhibitor of nuclear factor kB (NF-KB),are now the focus of AIDS and autoimmune disease studies.21”

Apoptosis in the Heart and Brain In contrast to cancer, where cells forget to die and insufficient apoptosis occurs, excessive apoptosis accounts for much of the cell death that follows heart attacks and strokes. In the heart, vessel blockage decimates cells that were fully dependent on the vessel. Those cells die by

Supplementary Diagnostic Procedures necrosis, partly because they are catastrophically starved of the oxygen and glucose they need to maintain themselves and partly because calcium ions, which are normally pumped out of the cell, rise to toxic levels. Over the course of a few days, cells surrounding the dead zone-which initially survive because they continue to receive nourishment from other blood vessels-can die as well. Later, however, many cells die by necrosis after being overwhelmed by the destructive free radicals that are released when inflammatory cells swarm into the dead zone to remove necrotic tissue. The less injured cells commit suicide by apoptosis. If the patient is treated by restoring blood flow, still more cells may die by necrosis or apoptosis because reperfusion leads to a transient increase in the production of free radicals. Similarly, in strokes due to inflammation, release of such neurotransmitters as glutamate lead to necrosis and apoptosis. Understanding of the factors that lead to the tissue death accompanying heart attack, stroke, and reperfusion has led to new ideas for treatment. Notably, cell death might be limited by drugs and other agents that block free-radical production or inhibit proteases. Apoptosis also accounts for much of the pathology seen in such diseases as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis (Lou Gehrig disease), which are marked by the loss of brain neurons. Elevated apoptosis in these neurologic diseases seems to be related to lack of production of the nerve growth factor and to free radical damage. It seems likely that a combination of such factors could cause many cells to destroy themselves. Manipulation of this process of cell killing may help in treating these neurologic diseases. In fact, studies in animal models imply that long-term delivery of nerve growth factors could protect against programmed cell death in these conditions. Therefore a greater understanding of the mechanisms involved in cell death should greatly enhance those important step^."*^',^

Figure 11-5 Balance or imbalance between the rate of apoptosis and mitosis determines tissue homeostasis,atrophy, cell proliferation, and development of cancer.

Apoptosis and cell proliferation play an important role in development, differentiation, homeostasis, and aging2” The balance established between these two processes depends on various growth and death signals that are influenced by diet, nutrition, lifestyle, and other environmental factors.

When the equilibrium between life and death is disrupted by aberrant signals (e.g., low levels of antioxidants in the blood or tissue cells), either tissue growth or atrophy occurs. Under normal conditions with optimal nutritional factors, tissue homeostasis is sustained by balancing the effects of mitosis and apoptosis. The importance of this balance can clearly be seen when one of these processes becomes predominant (Figure 11-5). During viral or chemical exposure and in preneoplastic tissue, the number of cells undergoing apoptosis increases, possibly to compensate for an increase in proliferation. As the cell loses functional tumor-suppressor genes (the P53), the propensity to undergo apoptosis decreases and the population of tumor cells grows. Inefficient immune function such as low NK activity due to stress or antioxidant deficiencies may contribute further to this mitosis and apoptosis imbalance, which results in additional tumor cell growth.

1. Wyllie AH,Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol 1980;68:251. 2. White E. Life, death and the pursuitof apoptosis.Genes Dev 1996;lOl. 3. Jarvis WD, Kolesnick RN, Fomari FA, et al. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci U S A 1994;91:73.

4. Green DR,Martin SJ.The killer and the executioner:how apoptosis controls malignancy.Curr Opin Immunol 1995;7694. 5.Arends MJ,McGregor AH, Wyllie AH. Apoptosis is inversely related to necrosis and determines net growth in tumors bearing constitutively expressed myc, ras and HPV oncogenes. J Pathol 1994;144:1045.

CONCLUSIONS

Apoptosis Assessment 6. Marchetti P, Hirsch T, Zamzami M, et al. Mitochondrial permeability triggers lymphocyte apoptosis. J Immunol1996;1574830. 7.Vojdani A, Mordechai E, Brautbar N. Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water. Human Exp Toxic01 1997;16485-494. 8. Walker PR, Smith C, Youdale T, et al. Topoisomerase 11-reactive chemotherapeutic drugs induce apoptosis in thymocytes. Cancer Res 1991;51:1078-1085. 9. Brown DB, Sun Xh4, Cohen GM. Dexamethasone-induced apoptosis involves cleavage of DNA to large fragments prior to internucleosomal fragmentation. J Biol Chem 1993;268:3037. 10. Reynolds ES, Kanz MF, Chicco P, Moslen MT. 1.1-Dichloroethylene: an apoptotic hepatotoxin? Environ Health Perspect 1984;57313. 11. Aw TY, Nicotera P, Manzo L, Orrenius S. Tributyltin stimulates apoptosis in rat thymocytes. Arch Biochem Biophys 1990; 28346. 12. Rossi AD, Larsson 0,Manzo L, et al. Modification of Ca2+signaling by inorganic mercury in PC12 cells. FASEB 1993;71507. 13. Kunimoto M. Methyl mercury induces apoptosis of rat cerebellar neurons in primary culture. Biochem Biophys Res Commun 1994; 204:310. 14.Vivian 8, Rossi AD, Chow SC, Nicotera P. Organotin compounds induce calcium overload and apoptosis in PC12 cells. Neurotoxicology 1995;1619.

15. Ledda-Columbano GM, Coni P, Curto M, et al. Induction of two different modes of cell death, apoptosis and necrosis in rat liver after a single dose of thioacetamide. Am J Pathol1991;139:1099. 16. ATSDR (Agency for Toxic Substances and Disease Registry). Toxicologicalprofile for benzene, draft report. Atlanta: Department of Health and Human Services, Agency, 1987. 17. National Institute of Environmental Health Sciences. Sixth annual report on carcinogens. Benzene Case No. 71-43-2: 35. Research, 1991. Triangle Park, NC: National Institute of Environmental Health Sciences, 1991, 18. Golstein P, O~ciusDM, Ding-E Young J. Cell death mechanisms and the immune system. Immunol Rev 1991;121:29. 19.Cohen JJ, Duke RC, Fadok VA, Sellins KS. Apoptosis and programmed cell death in immunity. Ann Rev Immunol 1992; 10:267. 20. Duke RC, q c i u s DM, Ding-E Young J. Cell suicide in health and disease. Sci Am 1996;275:80. 21. Martin SJ, Green DR. Protease activation during apoptosis: death by a thousand cuts. Cell 1995;82:349. 22.Forrest VJ, Kang Y, McClain DE, et al. Oxidative stress-induced apoptosis prevented by Trolox. Free Radic Biol Med 1994;16: 675-684. 23. Schreck R, Meier B, Mannel DN, et al. Dithiocarbamates as potent inhibitors of nuclear factor kB activation in intact cells. J Exp Med 1992;175:1181.

Bacterial Overgrowth of the Small Intestine Breath Test Mary James, ND CHAPTER CONTENTS Introduction 153 Frequency of Small Intestinal Bacterial Overgrowth 153 Pathophysiology 153 Diagnosis 154 Laboratory Assessment Endoscopy 155 Breath Testing 155

155

INTRODUCTION Small intestinal bacterial overgrowth (SIBO)is an abnormal colonization within the small bowel by bacteria normally found in the colon, mouth, or pharynx.’ Also called BOSI (bacterial overgrowth of the small intestine), “bhd-loop,” or ”stagnant loop,”2 SIBO is a potentially serious disorder that leads to problems such as malabsorption, anemia and weight loss, malnutrition? increased intestinal permeability (”leaky gut”),“ and bone loss? Breath testing for hydrogen and methane provides a simple noninvasive means of detecting SIBO. Once SIBO has been identified, antimicrobials are typically administered to eradicate the bacteria. Further treatment then can be commenced to address the underlying causes of SIBO to prevent a recurrence.

Frequency of Small Intestinal Bacterial Overgrowth Bacterial overgrowth of the small intestine is a frequently overlooked contributing factor in several common disorders.6For example, irritable bowel syndrome (IBS), responsible for up to 40% of referrals to gastroenterologists? is frequently associated with SIBO. One study of more than 200 patients with IBS found that 78% tested positive for SIBO. Of those successfully treated for SIBO, 48% no longer met the Rome criteria for IBS.8 Patients with fibromyalgia9 and chronic fatigue syndromeS also have been observed to have a high rate of SIBO (78% and 77% of subjects, respectively).

Treatment of Bacaial Overgrowth 157 Bacterial Eradication 157 Antibiotics 157 Antibiotic Alternatives 157 Addressing the Underlying Cause 158 Restoration of Gastric Acidity 158 Normalization of Intestinal Motility 158 Supportive Measures 158

About half of such patients who tested positive for SIBO in one study experienced marked subjective improvement after antibiotic administration. Interestingly both of these disorders have been observed to overlap with IBS.’O Other groups of patients particularly prone to bacterial overgrowth of the small intestine include those with intestinal dysmotility syndromes associated with systemic disease (e.g., diabetes, scleroderma, and intestinal pseudoobstruction), prior intestinal surgery, and strictures of the small bowel. Both jejunal diverticulosis6and Crohn’s disease” have been associated with SIBO, particularly in patients with Crohn’s disease who have undergone previous intestinal surgery. Interestingly most patients with celiac disease whose gastrointestinal symptoms persist with a gluten-free diet have been shown to have SIBO, with amelioration of symptoms after bacterial eradication.I2 The incidence of bacterial overgrowth increases with age, particularly in people 80 years and 01der.I~It has been found that 64% of individuals older than 75 years with chronic diarrhea have colonic-type flora in their small bowels6and that SIBO is the most common cause of clinically sigruhcant malabsorption in elderly persons?

Pathophysiology Although the concentration of bacteria increases exponentially toward the distal end of the small intestine, particularly the ileum: far fewer bacteria normally 153

Supplementary Diagnostic Procedures inhabit the small intestine than the Two major factors control the numbers and kinds of bacteria found within the small bowel: intestinal peristalsis and gastric acid ~ecretion."'~Consequently SIBO has been associated Other with both intestinal stasis and hyp~chlorhydria.'~ factors that discourage small intestinal flora overgrowth are pancreatic enzyme secretion,'6 disaccharidase production by intestinal mi~rovilli,'~ the ileocecal valve,18 bile salts, luminal pH, and oxidation-reduction p~tential.'~ Intestinal immunoglobulinsecretion and a m u m bamer that prevents bacterial adherence are unproven mechanisms for limiting bacterial growth in humans.15 Alterations in any of these normal functions (whether endogenous or drug-induced) favor uncontrolled bacterial proliferation in the small inte~tine.'~ A variety of anatomic and motor disorders of the small bowel may also lead to SIBO, such as surgical loops, diverticula, strictures, adhesions, tumors, fistulas? s~leroderma,'~ intestinal pseudoobstruction,2°and diabetic enteropathy2' All have as a common feahm the stasis of small bowel contents, which allows bacterial concentrations increasingly to resemble those of the large intestine (Box 12-l).14*15 The composition of small bowel flora varies among individuals with SIBO; however, the concentration of organismsis always higher than normal. The predominant flora is composed of coliform organisms and strict anaerobes (both rare in the small bowel), such as Bacteroides, Clostridium, and Bifid~bacterium.'~ To have clinical consequences, SIBO appears to require an adequate concentration of organisms with particular metabolic properties within specific locations of the small intestine. For example a heavy concentration of strict anaerobes and coliforms in the proximal small intestine is more likely to be associated with malabsorption than a flora consisting of fewer strict anaerobes or coliforms or when strict anaerobes or coliforms are located in the distal small inte~tine.'~ For this reason SIBO may be asymptomatic in some individuals, whereas in others

Gas, bloating, or diarrhea, usually after eating Unexplained weight loss Evidence of malabsorption Chronic hypochlorhydria or achlorhydria Use of acid-blocking medications Prior intestinal surgery, chronic constipation, or other causes of intestinal stasis Intolerance of disaccharides (lactose) Unexplained vitamin BI2 deficiency, weight loss, or bone loss Unexplained nutrient insufficiencies(e.g., calcium, magnesium, fat-soluble vitamins) Elevations of fecal short chain fatty acids Unexplained "leaky gut"

Achlorhydria, hypochlorhydria, drug-induced hypoacidity Chronic constipation Stasis resulting from structural changes (e.g., diverticulosis, blind loops, radiation damage, stricture, fistulas, intestinal pseudoobstruction,adhesions resulting from prior surgery) Chronic pancreatic insufficiency Disaccharidase deficiencies (lactase) Damaged ileocecal valve Immunodeficiency (especially of secretory immunoglobulin A) Diabetes mellitus Scleroderma Crohn's disease

Gas, bloating, and flatulence Diarrhea Abdominal cramping Steatorrhea Lactose intolerance Megaloblastic anemia

it may produce a variety of signs and symptoms. Box 12-2 outlines clinical signs and symptoms that alert the practitioner to consider testing for SIBO.

Diagnosis Signs and Symptoms Although many of the bacteria found in SIBO play beneficial roles within the colon, these same microorganisms may have deleterious effects within the delicate environment of the small intestine. The classic SIBO syndrome is characterized by megaloblastic anemia resulting from vitamin BI2 deficiency, and weight loss and diarrhea secondary to fat malab~orption.'~ However, many patients present with nonspecific symptoms such as bloating, flatulence, and abdominal pain resulting from bacterial fermentation of intraluminal sugars and associated gas production

(BOX12-3).'J2 Via secretory and osmotic processes, diarrhea may o c m even in the absence of sigruficant steatorrhea. Unabsorbed fats and bile salts are modified by bacteria in the colon to hydroxylated fats and free bile acids, respectively, which stimulate colonic secretion of water and electr01ytes.l~ Bile salts, which are essential to emulsification and assimilation, must be conjugated with either taurine or glycine to function properly. In SIBO, bacteria in the proximal small intestine (predominantly anaerobes such as Bacteroides, B$dobacteriurn, VeilloneZla, enterococci, and CZ~stridiurn)'~ are capable of deconjugating bile salts

Bacterial Overgrowth of the Small Intestine Breath Test

l e v e l ~ . ~Although J~ intrinsic factor is not altered by to form free bile acids.14 This deconjugation can have anaerobic bacteria, these microbes are capable of detachtwo major clinical repercussions: (a) the free bile acids ing vitamin B12 from intrinsic factor as well as directly may become concentrated enough to cause mucosal using Bl2.l8Either mechanism has the effect of rendering damage (Figure 12-l),resulting in reduced brush-border the vitamin unavailable to the host. Vitamin B12bound to enzyme activities (especially lactase)?’ defects in bacteria also may be partially metabolized to inactive mucosal uptake of sugars and amino acids, enteric blood analogues that compete with normal vitamin B12binding loss, and protein-losing enteropathy, or (b) the conjuand absorption.” Paradoxically, serum folate values gated bile salt concentration may fall below the concenusually are normal or even elevated in SIBO, a result of tration necessary for effective micelle formation, leading the ability of bacteria to synthesize the vitamin.= to fat malabsorption and steatorrhea (fecal fat).I4J5This Hypoproteinemiaalso may occur in SIBO, secondary to fat malabsorption may lead to insufficiencies of fatprotein-losing enteropathy and protein malab~orption.~,’~ soluble vitamins (e.g., E, A, K, and D).3 In addition bacteria may metabolize proteins to ammonia Electron microscopy research also has revealed the and fatty acids, thereby rendering them unavailable to presence of a pseudomembrane that mechanically the host.= interferes with the absorption of fats in many cases of SIBO. This pseudomembrane is thought to represent a maladaptive defense mechanism against the bacterial LABORATORY ASSESSMENT Thus, two possible mechanisms appear to o~ergrowth.’~ The composition of the bacterial populations contamibe involved in fat malabsorption in patients with SIBO, nating the small bowel is complex and variable.’ In deconjugationof bile acids and maladaptive pseudomemone study, the main bacteria recovered from patients branes that block the absorption of fats. with SIBO consisted of the microaerophilic bacteria Intraluminal fatty acids from fat malabsorption may Strqtococcus, Escherichia coli, Staphylococcus, Micrococciis, form insoluble soaps with calcium and magnesium, thus rendering them unavailable for a~similation.~ KkbsieIla, and Proteus and the anaerobic bacteria Lactobacillus, Bacteroides, Clostridium, Veillonella, Osteomalacia, night blindness, hypocalcemic tetany,’ Fusobacteriurn, and Peptostreptococcus.’ However, the and metabolic bone disease5 have been known to diagnosis of SIBO tends to be oriented less to the identidevelop as a consequence of lipid malabsorption in fication of specific microorganisms and more to overall patients with SIBO. Although rare, iron deficiency bacterial concentrations? anemia may result from blood SIBO may lead to vitamin B12 deficiency, with associEndoscopy ated megaloblastic anemia and low serum cobalamin Culture of a small bowel aspirate via endoscopy is considered the most direct method for diagnosing SIBO. High bacterial counts (exceeding 104organisms/ml from the jejunum or lo7 organismslml from the ileum) confirm the diagn0~is.l~ This method offers good sensitivity, although fairly low specificity. Because the aspirate is typically taken from only one location, overgrowth located in the more distal end of the small bowel or concentrated in a large diverticulum or blind loop may be missedF6 Intubation methods are also time consuming, uncomfortable, and expensive.

Breath Testing

Ffgure 12-1 In small intestinal bacterial overgrowth, free bile acids can damage the brush border, resulting in reduced enzyme activity and maldigestion. (Courtesy Great Smokies Diagnostic Lab, Asheville, “2.)

Breath tests were devised as less invasive alternatives to endoscopy and intubation. Breath tests have good sensitivity:’ are simple to administer, and offer greater patient comfort and convenience compared with intubation and culture. Most breath tests are based on the ability of intestinal microbes to ferment carbohydrates,producing hydrogen or methane in the process. A fraction of these gases naturally diffuses from the bowel to the circulation and is excreted with expired air. Because there is no other metabolic production of hydrogen and methane, the

hydrogen or methane. One study found that individuals pulmonary excretion may be used as a measure of bactewho produce higher amounts of H2 relative to CHI rial fermentation during the passage through the gasreported significantly increased bloating and cramping trointestinal tractF8 after carbohydrate ingestion, whereas individuals who The lactulose breath test is commonly used for the produce high CH4reported no significant increase in diagnosis of SIBO. Typically the patient ingests a chalthese symptoms.35Patients with IBS have been found to lenge dose of lactulose (a synthetic, nonabsorbed disaccharide) after 2 days of a fiber-restricted diet and a excrete significantly more H2 than healthy controls, although the total volumes of hydrogen and methane 12-hour fast.29Glucose has also been used as a challenge produced by the two groups did not differ.% Still other agent, although the sensitivity is reduced for distal ileum researchers observed associations between breath gas bacterial overgrowth because of rapid absorption of the values and specific IBS symptoms; methane production and the agent clearly is not suitable for patients with diabetes, hypoglycemia, or other blood sugar disorwas associated 100% with constipation-predominant ders. Other compounds that have been used in breath IBS, whereas hydrogen production was associated with testing are '4C-glycocholic acid and D-xylose (fermented diarrhea.37 to C02),2both of which have some l i m i t a t i ~ n s .No ~ ~ , ~ ~ Correlations between breath CHI values and colon cancer have been reported in the but subsematter which agent is used, intestinal bacteria modify the quent studies failed to substantiate the correlation?y challenge substance in such a way that an early peak in Interestingly, in vitro research suggests a possible role breath gas value is produced in patients with SIBO. In the for bile acids in the accumulation of hydrogen gas in the case of lactulose, which offers the advantage of traveling intestine; bile acids were found to inhibit methanogenesis the full length of the small intestine, the early hydroin a dose-response fashion.4O gen/methane peak is typically followed by a prolonged peak representing colonic bacterial a~tivity.2~3 Interpretation In the lactulose breath test, breath specimens are collected by having the subject exhale into a special mouthLactulose is not fermented in a healthy subject until it piece that is connected to a vacuum-sealed collection tube. reaches the colon. As a result the typical fasting breath sample contains less than 20 ppm of hydrogen or A fasting (prechallenge)breath sample is collected, 10 g of lactulose is ingested (lesser amounts for small children), methane. An increase in breath gas levels in the fifth or and then five more breath specimensare collected at timed sixth breath specimen (90 and 120 minutes, respectively) intervals over a 2-hour period. Breath levels of hydrogen usually reflects colonic bacterial fermentation and is and methane are plotted over time; early rises in breath considered normal. Lack of the expected colonic peak gas values are thought to correlate with more proximal may result from antibiotics or an acidic colonic pH.33,41 However, this should not affect results for the small portions of the small intestine. Hydrogen appears in the breath about 8 minutes after lactulose comes into contact intestine.29 with gut bacteria.3l This speed of response allows one to In patients with SIBO, the lactulose is fermented in the small intestine. This process leads to an earlier peak distinguish between small bowel bacterial overgrowth in breath gas values followed by a larger, more prolonged and the normally dense colonic flora, the latter of which peak reflecting colonic f e r m e n t a t i ~ n . ~ ~ typically gives a later, more prolonged yield of breath gas levels (roughly 90 minutes into the collection process). A positive test result (indicating SIBO) is defined by either (a) the presence of a total hydrogen/methane gas Hydrogen versus Methane peak more than 15 ppm above baseline levels, occurring within 90 minutes of lactulose ingestion or (b) an elevated Many studies using carbohydrate challenges have measured only breath hydrogen (H2).However, 30% to 50% baseline (fasting)breath gas concentration, even if there is of H2 producers also produce methane (CHJ,32 most not a large rise from baseline over the next few samples." likely because "methanogenic" bacteria consume H2and Elevated fasting values occur in up to one third of cases33 and are thought to relate to the fermentation of endogeproduce CH, in the process.2yIndividuals who harbor methanogenic bacteria (primarily Methnnobrevibncter nous brush-border glycoproteins in patients with SIBO.@ ~ r n i f h i iin ) ~ their ~ intestines typically produce greater In some cases of slow transit, high levels of gases in amounts of breath CH4during the breath test; thus those the fifth or sixth breath specimens may indicate SIBO in the distal ileum rather than the usual colonic peak, thus with SIBO may be missed by a test that examines only HPMConsequently the addition of methane to the analy- complicating the interpretation. sis provides a more thorough assessment of bacterial False-Positive and False-Negative Results overgro~th.~~,~~ Various researchers have noted clinical correlations Various factors may interfere with the lactulose breath between various disorders and the production of test, resulting in false-negative or false-positive results.

Bacterial Overgrowth of the Small Intestine Breath Test

Detailed instructions for breath collection are aimed at minimizing this interference and must be followed carefully.

False-Positive Results The following factors may account for a false-positive result on a breath test: Failure to fast for at least 12 hours before the test or to avoid dietary fiber the day before collection may result in a high "background noise" that contributes significantly to the overall concentration of breath gases.28 Sleeping, smoking, or eating shortly before or during sample collection can increase concentrationsof breath gases4 Fermentation by mouth and oropharyngeal flora may lead to early, transient elevations in breath gases after carbohydrate ingestion.45As a result, thorough teeth and tongue brushing before specimen collection is recommended.

False-Negative Results False-positive results on a breath test can be caused by the following factors: Diarrhea or the recent administration of antimicrobials can temporarily reduce the concentration of gut bacteria,& leading to a false-negative result. Laxatives and enemas may have a similar effect." It is recommended that the patient wait at least 1 week after antibiotic therapy before performing the test. SIBO that is confined to the distal ileum may go undetected if the breath gas peak produced in the ileum merges with the breath gases produced by the colonic Rapid intestinal transit time may cause delayed increases in breath gases, leading to a rise only after the lactulose has already reached the cecum.&This is particularly relevant for patients with SIBO who have undergone small bowel resection.

TREATMENT OF BACTERIAL OVERGROWTH Bacterial Eradication More often than not, addressing only the contributing factors to SIBO fails to adequately resolve the bacterial overgrowth; therefore the primary treatment of SIBO is directed at altering the intestinal flora with antibiotics.l5 Most patients with clinically significant SIBO host an intestinal flora consisting largely of anaerobes; however, some patients harbor a predominance of gram-negative

aerobes, such as Escherichiu coli, Klebsiella, and Pseudomon~s.4~ Therefore it is generally agreed that the most effective antimicrobial agent is one that targets both aerobic and anaerobic microorganisms.2

Antibiotics The first-line antibiotic for SIBO has traditionally been tetracycline (250 mg QID)? However, the high prevalence of bacterial resistance to the drug (up to 60% of patients with SIB0)2 has led to the use of alternative antibiotics. The most effective alternative agents, shown either empirically or by clinical trials, are the quinolones (e.g., ciprofloxacin or norfloxacin), amoxicillin with clavulanic acid (Augmentin), clindamycin, and metroni d a ~ o l e .Other ~ ~ , ~antibiotics ~ that have been reported to be effective in SIBO are ampicillin, erythromycin, lincomycin, oral aminoglycosides, cephalosporins (Keflex), and chloramphenicol. Antibiotics that show poor activity against anaerobes probably should be avoided in the treatment of SIBO (e.g., penicillin, ampicillin, and the oral aminoglycosides kanamycin and neomycin).2 The use of more poorly absorbed antibiotics may help minimize the risk of side effects. Rifaximin, a nonabsorbable rifamycin derivative, compared favorably with tetracycline in one study; a 7-day course of rifaximin at 400 mg TID normalized breath hydrogen excretion in 70% of patients with SIBO, whereas tetracycline normalized breath hydrogen excretion in only 27% of patients.52 In most patients, a single course of antibiotic therapy (7 to 10 days) is adequate; in others, cyclic therapy (1 week out of every 4) or continuous therapy (1 to 2 months) may be needed? Prolonged antibiotic therapy significantly raises the risk of diarrhea, Clostridium dificile infection, and bacterial resistance? The administration of probiotics usually helps to minimize such side effects.17 A poor response to antibiotics may indicate slowly reversible or irreversible mucosal disease, antibiotic resistance, antibiotic-associated diarrhea, or an incorrect diagno~is.'~,~~

Antibiotic Alternatives Aromatic oils have been shown to be effective antimicrobials. Peppermint oil, which has been used successfully in patients with IBS, has demonstrated antimicrobial properties in vitro.%In a case study, enteric-coated peppermint oil (dose of 0.2 ml tid) was seen to dramatically reduce gastrointestinal symptoms in a patient with SIBO?5 Follow-up breath testing indicated some persistent bacterial overgrowth; the addition of an established antimicrobial agent such as berberine may help to improve the results.% Research on the effectiveness of other botanical agents in SIBO is clearly needed.

A small double-blind study examined the effect of oral probiotics (combined Lactobacillus acidophilus and L. cusei strains) on SIBO. A significant decrease in breath hydrogen concentration was noted as early as 1 week into treatment, providing evidence that LactobacilIus strains may be effective in the treatment of bacterial o~ergrowth.~~

addressed. When not resulting from anatomic or organic causes, reduced motility may be improved with measures such as increased dietary fiber, water, probiotics, stress management, and exercise. Surgical correction of anatomic causes of intestinal stasis, such as small bowel diverticula, may be ~ a r r a n t e d . 5 ~

Addressing the Underlying Cause

Patients may become lactose intolerant secondary to an acquired disaccharidase deficiency caused by SIBO.*l Avoiding lactose as well as other disaccharides such as sucrose, maltose, and isomaltose (concentrated in grains) may help to “starve” the excess bacteria and allow healing of the intestinal lining.6o Substituting more easily absorbed medium-chain triglycerides for most dietary fat may be helpful in patients with diarrhea and steatorrhea.z Probiotics and prebiotics are recommended to help restore normal balance of intestinal flora, especially in patients with a history of antibiotic use. Various strains of Lactobacillus and Bifidobacterum have been used successfully to treat SIB0.17,57

Bacterial overgrowth of the small intestine may recur easily if the root causes are not addressed.

Restoration of Gastric Acidity Because gastric acidity is an important deterrent to SIBO, the restoration of normal stomach pH in the patient with hypochlorhydria or achlorhydria is essential. This may include the use of betaine hydrochloride with meals or the discontinuation of antacid medications. SIBO has been found in both patients with ulcer and healthy subjects after even short-term (5-week) administration of omeprazole (a proton pump inhibitor). The bacterial overgrowth was associated with greater deconjugation of bile acids and fat malabsorption and was thought to be induced by a shift to neutral pH in the gastric juice.58

Supportive Measures

Acknowledgment Special thanks to Sharon Rock for her research assistance.

Normalization of Intestinal Motility Intestinal stasis, whether functional or anatomic, is another major contributing factor to SIBO that should be

1. Bouhnik Y, et al. Bacterial populations contaminating the upper gut in patients with small intestinal bacterial overgrowth syndrome. Am J Gastroenterol1997;94:1327-1331. 2. Toskes PP. Bacterial overgrowth of the gastrointestinal tract. Adv Intern Med 1993;38387-407. 3. Keusch GT, Solomons NW. Microorganisms, malabsorption, diarrhea and dysnutrition. J Environ Pathol Toxic01 Oncol 1985;5: 165-209. 4. Riordan SM, et al. Luminal bacteria and small-intestinalpermeability. Sand J Gastroenterol 1997;32:556-563. 5. Di Stefan0 M, et al. Small intestine bacterial overgrowth and metabolic bone disease. Dig Dis Sci 2001;46:1077-1082. 6. Thomas PD, et al. Guidelines for the investigation of chronic diarrhoea. Gut 2003;52(Suppl 5):vl-15. 7. Zaman A. Irritable bowel syndrome. Clin Cornerstone 2002;4:22-33. 8. Pimentel M, Chow EJ, Lm HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol2000;95:3503-3506. 9. Pimentel M, et al. Small intestinal bacterial overgrowth a possible association with fibromyalgia. J Musculoskelet Pain 2001;9:107-113. 10. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 2000;160:221-227. 11. Castiglione F, et al. Orocecal transit time and bacterial overgrowth in patients with Crohn’s disease. J Clin Gastroenterol2000;31:63-66.

12. Tursi A, Brandimarte G, Giorgetti G. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal. Am J Gastroenterol2003;98:839-843. 13. Riordan SM, et al. Small intestinal bacterial overgrowth in the symptomatic elderly. Am J Gastroenterol 1997;92:47-51. 14. Anonymous. Small intestinal bacterial overgrowth syndrome. Gastroenterology 1981;80834-845. 15. Kirsch M. Bacterial overgrowth. Am J Gastroenterol 1990;85: 231-237. 16. Hill M. Normal and pathological microbial flora of the upper gastrointestinal tract. Scand J Gastroenterol1985;111(Suppl):1-6. 17. Rolfe RD. The role of probiotic cultures in the control of gastrointestinal health. J Nutr 2000;130(Suppl):396SO2S. 18. King CE, Toskes PP. Small intestine bacterial overgrowth. Gastroenterology 1979;76:1035-1055. 19. Rose S, Young MA, Reynolds JC. Gastrointestinal manifestations of scleroderma. Gastroenterol Clin North Am 1998;27563-594. 20. Camilleri M. Small bowel motility disorders. Rev Gastroenterol Mex 1994;59:120-126. 21. Virally-Monod M, et al. Chronic diarrhoea and diabetes mellitus: prevalence of small intestinal bacterial overgrowth. Diabetes Metab 1998;24:530-536. 22. Sherman P,Lichtman S. Small bowel bacterial overgrowth syndrome. Dig Dis Sci 1987;5:157-171.

Bacterial Overgrowth of the Small Intestine Breath Test 23. Fagundes-Net0 U, et al. Studies of the small bowel surface by scanning electron microscopy in infants with persistent diarrhea. Braz J Med Biol Res 2000;331437-1442. 24. Murphy MF, et al. Megaloblastic anaemia due to vitamin BIZdeficiency caused by small intestinal bacterial overgrowth possible role of vitamin BI2 analogues. Br J Haematol 1986;62:7-12. 25. Camilo E, et al. Folate synthesized by bacteria in the human upper small intestine is assimilated by the host. Gastroenterology 1996;110991-998. 26. OLeary C, Quigley EM. Small bowel bacterial overgrowth, celiac disease, and IBS: what are the real associations?Am J Gastroenterol 2003;98:720-722. 27. Rhodes JM, Middleton P, Jewel1 DP. The lactulose hydrogen breath test as a diagnostic test for small-bowel bacterial overgrowth. Scand J Gastroenterol1979;14:333-336. 28. Brummer RJ, et al. The hydrogen (H2)breath test: sampling methods and the influence of dietary fibre on fasting level. Scand J Gastroenterol1985;201007-1013. 29. Hamilton LH. Breath tests and gastroenterology, 2nd ed. Milwaukee: QuinTron Instrument Company, 1998. 30. Cloarec D, et al. Breath hydrogen response to lactulose in healthy subjects: relationship to methane producing status. Gut 1990;31: 300-304. 31. Bond JH Jr, Levitt MD. Use of pulmonary hydrogen (H2) measurements to quantitate carbohydrate absorption: study of partially gastrectomized patients. J Clin Invest 1992;51:1219-1225. 32. Rumessen JJ, Nordgaard-Andersen I, Gudmand-Hoyer E. Carbohydrate malabsorption: quantification by methane and hydrogen breath tests. Scand J Gastroenterol1994;29:826-832. 33. Romagnuolo J, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol2002;971113-1126. 34. Corazza G, et al. Prevalence and consistency of low breath H2excretion following lactulose ingestion: possible implications for the clinical use of the H2breath test. Dig Dis Sci 1993;382010-2016. 35. Kajs TM, et al. Influence of a methanogenic flora on the breath H2 and symptom response to ingestion of sorbitol or oat fiber. Am J Gastroenterol1997;9289-94. 36. King TS, Elia M, Hunter JO. Abnormal colonic fermentation in irritable bowel syndrome. Lancet 1998;352:1187-1189. 37. Pimentel M, et al. Methane production during lactulose breath test is associated with gastrointestinal disease presentation. Dig Dis Sci 2003;48:86-92. 38. Haines A, et al. Breath-methane in patients with cancer of the large bowel. Lancet 1977;2(8036):481-483. 39. Pique JM, et al. Methane production and colon cancer. Gastroenterology 1984;87601-605. 40. Florin TH, Jabbar IA.A possible role for bile acid in the control of methanogenesis and the accumulation of hydrogen gas in the human colon. J Gastroenterol Hepatol 1994;9:112-117.

41. Vogelsang H,et al. Acidic colonic microclimate-possible reason for false negative hydrogen breath tests. Gut 1988;29:21-26. 42. Kerlin P, Wong L. Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology 1988;95:982-988. 43. Perman JA, Modler S. Glycoproteins as substrates for production of hydrogen and methane by colonic bacterial flora. Gastroenterology 1982;83388-393. 44. Solomons N. Evaluation of carbohydrate absorption: the hydrogen breath test in clinical practice. Clin Nutr J 1984;3:71-78. 45. Thompson DG,OBrien JD, Hardie JM. Influence of the oropharyngeal microflora on the measurement of exhaled breath hydrogen. Gastroenterology 1986;91:853-860. 46. Gilat T,et al. Alterations of the colonic flora and their effect on the hydrogen breath test. Gut 1978;19:602-605. 47. Solomons NW, et al. H2breath tests during diarrhea. Acta Paediatr %and 1979;68:171-172. 48. Caride VJ, et al. Scintigraphic determination of small intestinal transit time: comparison with the hydrogen breath technique. Gastroenterology 1984;86714-720. 49. Kocoshis SA, et al. Duodenal bile acids among children: keto derivatives and aerobic small bowel bacterial overgrowth. J Pediatr Gastroenterol Nutr 1987;6:686-696. 50. Meyers JS, Ehrenpreis ED, Craig RM. Small intestinal bacterial overgrowth syndrome. Curr Treat Options Gastroenterol2001;4:7-14. 51. Attar A, et al. Antibiotic efficacy in small intestinal bacterial overgrowth-related chronic diarrhea: a crossover, randomized trial. Gastroenterology 1999;117794-797. 52. Di Stefan0 M, et al. Rifaximin versus chlortetracycline in the shortterm treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther 2000;14551-556. 53. Bjomeklett A, Hoverstad T, Hovig T. Bacterial overgrowth. Scand J Gastroenterol1985;109(Supp1):123-132. 54. Shapiro S, Meier A, Guggenheim B. The antimicrobial activity of essential oils and essential oil components towards oral bacteria. Oral Microbiol Immunol 1994;9:202-208. 55. Logan AC, Beaulne TM. The treatment of small intestinal bacterial overgrowth with enteric-coated peppermint oil: a case report. Alt Med Rev 2002;7410-417. 56. Birdsall T,Kelly G. Berberine: therapeutic potential of an alkaloid found in several medicinal plants. Alt Med Rev 1997;294-103. 57. Gaon D, et al. Effect of Lactobacillus strains (L. casei and L. acidophilrts strains cereal) on bacterial overgrowth-related chronic diarrhea. Medicina (Brazil) 2002;62:159-163. 58. Shindo K, et al. Omeprazole induces altered bile acid metabolism. Gut 1998;42266-271. 59. Drude RB Jr, et al. Malabsorption in jejunal diverticulosis treated with resection of the diverticula. Dig Dis Sci 1980;25:802-806. 60. Gottschall E. Breaking the vicious cycle. Baltimore: Kirkton Press, 1994.

Cell Signaling Analysis Aristo Vojdani, PhD, MT CHAPTER CONTENTS Introduction 161 The Cell Cycle 161

Clinical Application 162 Patients Exposed to Carcinogenic Chemicals and Patients with Chronic Fatigue Syndrome 162

Flow Cytometry to Assess Cell Cycle Status 162

INTRODUCTION Signaling pathways in normal cells consist of growth and controlling messages from the outer surface deep into the nucleus. In the nucleus, the cell cycle clock collects different messages, which are used to determine when the cell should divide. Cancer cells often proliferate excessively because genetic mutations cause induction of stimulatory pathways and issue too many "go ahead" signals, or the inhibitory pathways can no longer control the stimulatory pathways.' Over the past 5 years, impressive evidence has been gathered with regard to the destination of stimulatory and inhibitory pathways in the cell. These pathways converge on a molecular apparatus in the cell nucleus that is often referred to as the cell cycle clock. The clock is the executive decision maker of the cell; apparently, it runs amok in virtually all types of human cancer. In a normal cell, the clock integrates the mixture of growth-regulating signals received by the cell and decides whether the cell should pass through its life cycle. If the answer is positive, the clock leads the process.

THE CELL CYCLE A scheme of the classical cell cycle is shown in Figure 13-1. The cell cycle compartments are drawn such that their horizontal position reflects their respective DNA content. Cells that contain only one complement of DNA from each parent (2C) are referred to as diploid cells. Cells that have duplicated their genome, and thus have 4C amounts of DNA, are called tetraploid cells.

The cell cycle is classically divided into the following phases: Go

G1 *S G2

*M The cell cycle phase of G1 was historically considered to be a time when diploid (2C) cells had little observable activity. Since this time precedes DNA synthesis, the term Gap 1 ( G I )was coined. Now it is known that there is quite a bit of transcription and protein synthesis during this phase. At a certain point in the cell's life, the DNA synthetic machinery turns on. This phase of the cell's life is labeled "S" for synthesis. As the cell proceeds through this phase, its DNA content increases from 2C to 4C. At the end of S, the cell has duplicated its genome and now is in the tetraploid state. After the S phase, the cell again enters a phase that was historically thought to be quiescent. Since this phase is the second gap region, it is referred to as G2. In the G2phase, the cell is producing the necessary proteins that play a major role in cytokinesis. After a highly variable amount of time, the cell enters mitosis (M). DNA content remains constant at 4C until the cell actually divides at the end of telophase. The enlarged parent cell finally reaches the point where it divides in half to produce its two daughters, each of which is endowed with a complete set of chromosomes. The new daughter cells immediately enter GI and may go through the full cycle again. Alternatively, they may stop cycling temporarily or permanently? 161

Supplementary Diagnostic Procedures

CLINICAL APPLICATION Patients Exposed to Carcinogenic Chemicals and Patients with Chronic Fatigue Syndrome To determine whether peripheral blood lymphocytes (PBLs) isolated from chronic fatigue syndrome (CFS) individuals and chemically exposed patients represent a discrete block in cell cycle progression, PBLs isolated from CFS and control individuals were cultured, harvested, fixed, PI-stained, and analyzed by flow cytometry. The nonapoptotic cell population in PBL isolated from CFS individuals consisted of cells arrested in the late S and G2/M boundaries, as compared with healthy controls. The arrest was characterized by increased S and G2/M phases of the cell cycle (from 9% to 33% and from 4% to 21%, respectively) (Table 13-1, Figure 13-2) at the expense of Go/GI. Such an abnormality in cell cycle

Phase

Healthy controls

Chemically exposed

GdGi

88.6f 1.4 8.6f 1.2 3.6f 0.82

51.7k 2.4 33.2k 4.3 21 .O k 2.6

S GdM

,

Figure 13-1 Stages of cell cycle (Go, G,, S.GZ,and M phases) (A) and DNA histogram (6)generated by flow cytometry.

FLOW CYTOMETRY TO ASSESS CELL CYCLE STATUS Flow cytometry is a method of measuring cell properties as they “flow” through a detector while being illuminated with intense light. Tissues are generally disaggregated into single-cell suspensions and stained with one or more fluorescent dyes. The cells are forced to flow within a sheath of fluid, eventually being intersected and interrogated by an intense light source such as a laser beam. As the cell enters the laser beam, it scatters light in all directions. The measurement of light scattered in the forward direction yields information on the particle’s size. Scattered light at right angles to the incident light beam provides information on the internal granularity of the cell. If the cell has been stained with one Or more fluorescent a ‘Orrelated measurement Of more than one cellular parameter can be achieved.

Figure 13-2 Cell cycle analysis of peripheral blood lymphocytes from healthy controls (A) and patients exposed to benzene (B). Note that in patients’ samples, the majority of cells switched from GJG, to S and GJM phases.

Cell Signaling Analysis

progression is an indication of abnormal mitotic cell division in patients who have been exposed to chemicals and who suffer from CFS. From these results, we concluded that PBLs of patients with chemical exposure and CFS grow inappropriately, not only because the signaling pathways in cells are perturbed, but also because the cell cycle clock becomes deranged and stimulatory messages become greater than the inhibitory pathway^.^,^

However, in order to limit cell proliferation and avoid cancer, the human body equips cells with certain back-up systems that guard against runaway division. One such back-up system present in lymphocytes of CFS patients provokes the cell to undergo apoptosis. This programmed cell death occurs if some of the cell's essential components are deregulated or damaged. For example, injury to chromosomal DNA can trigger a p o p t o s i ~ . ~ , ~ , ~

1. Weinberg RA. How cancer arises. Sci Am 1996;275:62. 2. Wheeless LL, Coon JS, Cox C, et al. Precision of DNA flow cytometry in inter-institutional analyses. Cytometry 1991;12405. 3. Wersto RE', Liblit RL, Koss LG. Flow cytometric DNA analysis of human solid tumors: a review of the interpretation of DNA histograms. Hum Pathol1991;22:1085. 4. Shankey TV, Rabinovitch PS, Bagwell 8, et al. Guidelines for implementation of clinical DNA cytometry. Cytometry 1993;14472.

5. Vojdani A, Ghoneum M, Choppa PC, et al. Elevated apoptotic cell population in patients with chronic fatigue syndrome: the pivotal role of protein kinase RNA. J Intern Med 1997;242:465-478. 6. Vojdani A, Mordechai E, Brautbar N. Abnormal apoptosis and cell cycle progression in humans exposed to methyl tertiary-butyl ether and benzene contaminating water. Human Exp Toxic01 1997;16: 485494.

Comprehensive Digestive Stool Analysis 2.0 R.W. Watkins, MD, MPH, FAAFP CHAPTER CONTENTS Introduction 165 The GastrointestinalTract The Digestive Process Mouth 166 Esophagus 166 Stomach 167 Small Intestine 167 Large Intestine 167

165

166

Absorption of Nutrients 168 Carbohydrate Digestion 168 Lipid Digestion 168

Microbiology 169 Intestinal Microflora 169 Pathogens 169 Yeast 170 Dysbiosis 170 Using Comprehensive Digestive Stool Analysis 2.0 170 Digestive Function 170 Interpretation at a Glance 174 Conclusion

174

Digestive Abnormalities 168 Maldigestion 168 Pancreatic Exocrine Insufficiency 168 Malabsorption 168

INTRODUCTION Within the philosophy of natural medicine, sound nutrition and digestion are seen as fundamental to long-term health. Without proper digestive function to ensure adequate breakdown and assimilation of nutrients, even the most nutritious diet may be ineffective for optimizing health. Moreover, incomplete or faulty digestive processes, left undiagnosed and untreated, are believed to raise the risk of many diseases and may lead to a variety of chronic disorders. Problems related to the gastrointestinal (GI) tract are among the most common symptoms experienced by patients.' One study reported that during a 3-month period, nearly 70% of American households had at least one person who experienced GI symptoms.2 Problems with digestion, absorption, and inflammatory processes--even imbalances in gut flora and ecologyoften underlie the most common GI complaints. Furthermore, these common symptoms may herald much more complex and serious clinical signs and illnesses.

The Comprehensive Digestive Stool Analysis (CDSA) 2.0 provides the physician with a critical noninvasive tool for evaluating the functional and clinical status of the GI tract (Figure 14-1). By measuring key markers of digestion/absorption, gut immunology, metabolism, and intestinal microflora, this in-depth analysis can help uncover the underlying causes of GI symptoms or disease states that may have originated in the intestine. This is accomplished by identifymg critical, previously unsuspected imbalances and important physiologic connections among diet, digestive function, mucosal integrity, and the etiology of diseases, such as colon cancer, inflammatory bowel disease (IBD), and type 2 diabetes.

THE GASTROINTESTINAL TRACT Most food molecules are complex polymers that cannot be absorbed or used by the body in their native state. The primary function of the GI system is to break down these complex lipids, proteins, and carbohydrates into 165

Figure 14-2 The healthy ecology and functioning of the gastrointestinal tract depend on a host of interdependent nutritional, biochemical, and microbial interactions.

Figure 14-1 The functional status of the gastrointestinal tract can be evaluated noninvasively with the Comprehensive Digestive Stool Analysis 2.0. (Courtesy Great Smokies Diagnostic Lab, Asheville, NC.)

simple absorbable nutrients (monomers), such as monosaccharides, monocyglycerols, fatty acids, amino acids, vitamins, minerals, and water. Once broken down into these monomeric building blocks, nutrients can be transported into interstitial fluids as they move across the inner layer, or mucosa, of the GI tract, to be distributed to cells throughout the body.3 Digestion is a chemical breakdown of food accomplished chiefly by enzymes secreted into the lumen of the GI tract by glandular cells in the mouth and stomach, by exocrine cells of the pancreas, and by enzymes in the brush-border membrane and cytoplasm of mucosal cells (enterocytes) of the small i n t e ~ t i n e .Its ~ ,proper ~ function relies on a series of interdependent nutritional, biochemical, and microbial interactions (Figure 14-2). While allowing the diffusion of life-sustaining nutrients, the mucosa must also act as a barrier to prevent the passage of potentially life-threatening bacteria and toxins into the systemic circulation. In this way the GI mucosa constitutes the body’s frontline defense against immune system attack and the arena in which the battle for healthy GI function, to absorb nutrients while excluding toxins, is fought.

THE DIGESTIVE PROCESS Mouth Homogenization of ingested food first occurs in the mouth via the grinding and mixing action of the teeth. Salivary glands provide hydration to form a bolus and protect the pharyngeal and esophageal mucosa, primarily with secretory IgA antibodies. The process of starch and fat hydrolysis is initiated with the release of lingual lipase, salivary amylase, and p t ~ a l i n . ~ , ~

Esophagus As the food bolus is swallowed, the epiglottis closes, providing a one-way valve that allows the food to pass into the GI tract and not the respiratory tract. Food is then transported down the esophagus in peristaltic waves past the lower esophageal sphincter into the stomach. Gastroesophageal reflux disease (GERD) can occur when there are transient lower esophageal sphincter relaxations, decreased lower esophageal sphincter resting tone, delayed stomach emptying, ineffective esophageal clearance, and diminished salivation. Factors that may exacerbate the symptoms of GERD in some patients include smoking, caffeine, chocolate, fatty foods, overeating with gastric distention, tight clothing, the presence of a hiatal hernia, and certain medications.

Comprehensive Digestive Stool Analysis 2.0

Small Intestine

of approximately 200 to 250 square meters, about the surface area of a tennis co~rt.3,~,8 Even after prolonged contact with pancreatic enzymes, a substantial portion of ingested carbohydrates and amino acids remains as dimers and oligomers. For final digestion, these compounds depend on hydrolytic enzymes (disaccharidases such as maltase, sucrase, lactase, enterokinase, and peptidases) produced by the brush-border membrane? For this reason, damage to the intestinal brush borderresulting from inflammation, trauma, disease, parasite infection, bacterial overgrowth, chronic nonsteroidal antiinflammatory drug use, and other factors-may interfere sigruficantly with the proper absorption of nutrients. Such damage also can disrupt the intracellular tight junctions that are vital to the protective barrier function of the gut mucosal layer, increasing the intestinal permeability of potentially harmful macromolecules, such as bacteria and toxins, into the systemic circulation. This syndrome, sometimes called "leaky gut," has been cited as an important contributory or causative factor in gluten enteropathy, Crohn's disease, food allergy, various arthritides and autoimmune diseases, chemotherapy complications, and many other conditions?-13

Most digestion and assimilation occur in the small intestine. Digestion is mediated chiefly by pancreatic enzymes, including proteolytic enzymes, nucleolytic enzymes, lipases, alpha-amylase, and phospholipase A2, which hydrolyze macromolecules to oligomers, dimers, or monomer^.^ Pancreatic enzymes are most active in the neutral pH rangePr4and bicarbonate begins the process of neutralizing stomach acid. Pancreatic proteases are secreted into the duodenum as inactive precursors, trypsinogen, chymotrypsinogen, and proelastase, and are activated by brush-border enzymes such as enterokinase to form trypsin, chymotrypsin, and elastase, respective1Y . ~ Bile secreted by the liver (about 700 ml/day) also plays a role in the solubilization and emulsification of lipids, enabling enzymatic hydrolysis. Bile is also critical for elimination of both endogenous byproducts, such as cholesterol, and exogenous xenobiotics, such as drugs and heavy metals. Bile acids (also called bile salts) are the major organic component of bile and compose about half of its solid content. From the small intestine, bile acids are absorbed into the portal blood and are taken up by hepatocytes, conjugated with taurine and glycine, and resecreted in bile, a process known as enterohepatic circulation." The digestive and absorption capacities of the small intestine are greatly enhanced by circular folds and fingerlike projections of the intestinal mucosa called microvilli. This region, dubbed the "brush border," increases the luminal surface area of the intestinal wall by about 600 times, creating a total absorptive surface

A primary role of the large intestine is to absorb water, about 1 liter daily. The large intestine also provides an environment for microbial fermentation of soluble fiber, starch, and undigested carbohydrates. Soluble fibers are more readily fermented than insoluble fibers.I4 Nondigestible carbohydrates (e.g., fiber), polysaccharides, and oligosaccharides contain chemical bonds that make them incapable of complete digestion by pancreatic or brush-border enzymes. As they move through the digestive tract, these undigested compounds play an important role in intestinal transport mechanisms. Once in the colon, they are cleaved and modified by enzymes produced by resident colonic bacteria to form shortchain fatty acids (SCFAs) and various gases, such as methane, hydrogen, and carbon dioxide.' The SCFAs, in combination with amines derived from protein degradation, provide fuel for colonocytes, act as buffering agents, and cause the pH of luminal contents to decrease. This pH decline is important because the bacterial enzyme 7-alpha-dehydroxylase, which triggers the formation of potentially carcinogenic secondary bile acids from primary bile acids, is active only above pH of 6.5.14 The epithelial layer of the colon is only one cell deep and, unlike the small intestine, has no villi. To form this layer, crypt cells located below it must differentiate. Although adequate differentiation of crypt cells is vital, excessive cell division (cell proliferation) of the epithelial layer is linked to tumorigenesis. Thus dietary agents that

Complications of GERD include esophageal erosion, esophageal ulcer, and esophageal stricture; replacement of normal esophageal epithelium with abnormal (Barrett's) epithelium; and pulmonary aspiration.

Stomach The stomach produces churning action and initiates protein and lipid hydrolysis. Peptides, amino acids, and fatty acids released in this process synchronize the release of pancreatic juice and bile into the small intestine? About 2 liters of gastric juice are produced each day, containing several important component^.^ Hydrochloric acid (secreted by the parietal cells) activates pepsinogen to convert to pepsin, which renders some minerals (e.g., calcium and iron) more absorbable. It also creates an essentially sterile environment to prevent bacterial overgrowth. Mucus forms an acid- and pepsin-resistant coating for the stomach lining. Gastric lipase secreted by gastric mucosa begins to hydrolyze triglycerols, producing 1,2-diacylglycerols and fatty acids. The optimal pH of gastric lipase is about 4, but the enzyme is active up to pH 6 or 6.5.7

Large Intestine

Supplementary Diagnostic Procedures

promote differentiation and apoptosis are believed to reduce colon cancer risk, whereas those that stimulate cell division are considered car~inogenic.'~

ABSORPTION OF NUTRIENTS Carbohydrate Digestion Digestible carbohydrates, such as sucrose, starch, and lactose, are the body's principal sources of energy? and their proper digestion is vital for adequately sustaining its energy needs. Dietary carbohydrates consist of monosaccharides, disaccharides, and polysaccharides. Monosaccharides are absorbed directly by sodium-dependent transport carrier mechanisms. Disaccharides require small intestinal surface enzymes for hydrolysis to monosaccharides; polysaccharides depend on pancreatic amylase and surface enzymes for this process. Final hydrolysis of disaccharides and oligosaccharides to monosaccharides is carried out by surface enzymes (e.g., sucrase, maltase, lactase) of the small intestinal epithelial cells.5

Lipid Digestion Lipid digestion is the most complex of the digestive and absorptive processes. The primary function of this process is to convert water-insoluble lipids, primarily triacylglycerols, phospholipids, and cholesterol esters, into soluble, absorbable forms. The absorption of lipophilic compounds, such as fat-soluble vitamins and certain drugs, depends on proper lipid digestion and ab~orption.~ Although a small amount of lipid digestion occurs in the mouth with the secretion of lingual lipase, the primary process of lipid digestion begins in the stomach. Gastric lipase is secreted by gastric mucosa to hydrolyze triacylglycerols, producing 1,2-diacylglycerolsand fatty acids. Optimal pH is about 4,but the enzyme is active at pH 6 to 6.5. After partial digestion in the stomach, the lipid emulsion moves to the small intestine, where further digestion of triacylglycerol is performed, primarily by pancreatic lipase. However, triacylglycerol lipid droplets covered in bile salts are not accessible to pancreatic lipase and require the action of colipase, which allows binding of lipase molecules to the lipid droplets to hydrolyze tria~ylglycerol.~ The digestion of lipids produces mainly monoacylglycerols, fatty acids, lysophosphatidylcholine, and cholesterol. Because these products have limited ability to dissolve in water, they have difficulty reaching the epithelial surface of the small intestine, which is covered by the unstirred water layer. To be more effectively absorbed, they must form aggregates (micelles)with bile acids (which act as biologic detergents) that can penetrate the unstirred water layer. Without bile acids, only a small number of lipid molecules permeate through the water layer to be taken up by the brush-border membrane

of the enterocytes. Mixed micelles increase the concentrations of fatty acids, cholesterol, and other lipids near the epithelial absorptive surface of the small intestine by a factor of 100 to iOO0.7

DIGESTIVE ABNORMALITIES Maldigestion Gastric acid secretion is a fundamental step in digestion and assimilation. Many clinical conditions may originate with decreased gastric acidity. It has been argued that chronic hypochlorhydria can lead to reduced mineral absorption, bacterial overgrowth, amino acid deficiency, GI symptoms, depression, and other s y n d r ~ m e s . ' ~ J ~ Maldigestion of carbohydrates can also cause chronic GI symptoms. Disaccharides, oligosaccharides, and polysaccharides not hydrolyzed by alpha-amylase or intestinal surface enzymes cannot be absorbed. Bacterial fermentation of these undigested carbohydrates in the lower intestine and colon increases the osmotic retention of water. This can lead to cramping, abdominaldistention, and diarrhea.45

Pancreatic Exocrine lnsufficiency Inadequate delivery of enzymes to the small intestine can lead to inadequate breakdown of fats, carbohydrates, or protein. The net effect is poor nutrition and an unhealthy environment for the flora of the large colon. It has been argued that even small decreases in exocrine pancreatic output can contribute substantially to maldigestion and may have far-reaching effects in chronically ill patients. Significant decreases in exocrine pancreatic secretion have been associated with the aging process and are theorized to play an important role in intestinal trophicity and pr01iferation.l~In addition, decreased exocrine pancreatic function has been associated with osteoporosis,'s diabete~,'~,*~ and numerous other chronic disease states! Excessive consumption of carbohydrates and lipids is increasingly becoming a common characteristic of the average Western dieP; this trend may promote cyclical, self-perpetuating imbalances that lead to maldigestion and chronic ill health (Figure 14-3).

Malabsorption Malabsorption can be characterized by abnormal fecal excretion of fat (steatorrhea);abdominal pain; and variable malabsorption of fats, fat-soluble vitamins, other vitamins, proteins, carbohydrates, minerals, and water. Common causes include the following: Bile salt deficiency, resulting in inadequate solubility of fatty acids7 Rapid transit, which does not allow adequate time for absorption

Comprehensive Digestive Stool Analysis 2.0 depends on substrate availability rather than neuronal or hormonal pathways.25 Because the oxygen content of the colon is low, roughly 99% of the colonic flora is composed of anaerobes, predominantly Bacteroides, Eubacterium, Bfidobacterium, and Peptostreptococcus.26 Bifidobacterium, Lactobacillus, and nonpathogenic Escherichia coli are the main strains of beneficial with bifid bacteria constituting about one fourth of the microbial flora found in adults.26These strains play pivotal roles in gut health, including: (a) control of potentially pathogenic organisms, (b) production and absorption of nutrients, (c) removal of toxins from the gut, and (d) stimulation of the intestinal immune system.25For this reason, they are employed as key indicators of eubiosis, or healthy overall gut flora. Stress can profoundly alter the microbial milieu, increasing gut permeability, enhancing bacterial adherence of gut pathogens, and reducing the luminal level of beneficial bacteria such as L a c t o b a ~ i l Z u s . ~ ~ ~ ~ ~

Figure 14-3 Chronic maldigestion can set off a cascade of gastrointestinal imbalances that synergistically trigger malnutrition, toxic overload, and poor health. (Courtesy Great Smokies Diagnostic Lab, Asheville, NC.)

Mucosal cell abnormality and inadequate surface area Pancreatic insuffi~iency~,~ Intestinal infection and bacterial overgrowth syndromes Malabsorption can arise from any condition that results in decreased gastric acidity and pancreatic insufficiency. Malabsorption often increases with agG3; atrophic gastritis is estimated to affect 10% to 30% of individuals more than 50 years old and often leads to inadequate absorption of key nutrients such as vitamin BI2.= General malabsorption syndromes are associated with many disorders of the intestinal tract, including celiac sprue, bacterial overgrowth, gluten enteropathy, IBD, giardiasis, cryptosporidiosis, lactose intolerance, and eosinophilic gastroenteritis.Because amino acids, carbohydrates, vitamins, and mineral are absorbed through different processes, individuals with malabsorption are at risk for development of a wide range of nutrient deficiencies.

MICROBIOLOGY Intestinal Microflora The human colon is host to more than 2 billion organisms per gram of stool, with 17 different bacterial families, 50 different genera, and almost 500 different species.” Therefore the bacteria in the gut exceed the total number of eukaryotic cells in the entire human body. Therefore the microflora can be perceived as an organ of the body in its own right. The key difference is that their metabolism

Pathogens In addition, bacterial cultures identify pathogens and potential pathogens. Pathogens are defined according to Koch’s postulates: The organism must be present in every case of the disease. It must be possible to isolate the organism from the disease host and grow it in pure culture. The pure culture of the organism, when inoculated into a new susceptible host, must produce the same symptoms of disease. The term potential pathogen can be used to indicate microbes that do not strictly meet Koch’s postulates for the definition of pathogen yet have the potential to be etiologic agents of disease in certain susceptible hosts (Box 14-1). These agents may be involved in the etiology of GI disorders; moreover, by triggering bacterial translocation and molecular mimicry, they may also be involved in various chronic or systemic diseases seemingly unrelated to GI function, such as arthritis and autoimmune disorders. For example, Klebsiella and Proteus are not routinely reported in conventional laboratories, but both have

Citrobacter Klebsiella Proteus Pseudomonas Morganella Enterobacter Enterotoxin-producingBacillus cereus (4+) Enterotoxin-producingStaphylococcus aureus (4)

demonstrated antigenic cross-reactivity to human leukocyte antigens (HLA antigens). KZebsieZlu has been associated with ankylosing spondylitis (AS) when crossreactivity occurs with the HLA-B27 antigen. Similarly, Proteus mirabilis has been associated with reactive arthritis and is known to cross-read with the HLA-DR4 antigen.3031 Other potential pathogens may cause clinical and subclinical malabsorption and increase bowel permeability to large molecules. Abnormalities of the immune or mechanical barriers can lead to enhanced uptake of inflammatory luminal macromolecules and pathogenic bacteria. Bacterial antigens are capable of inducing antibodies, which cross-react with host antibodies, forming systemic immune c o m p l e x e ~ This . ~ ~ ~process ~~ been linked with the etiology of chronic gut inflammation, systemic lupus erythematosus, and a r t h r i t i ~ . ~ 3 ~

Yeast Colonic yeast infections have attracted attention and controversy as a possible cause of chronic complex illnesses.36Investigators have suggested that an intestinal overgrowth of yeast such as Cundidu ulbicuns may be involved in the etiology of allergic disorders such as scleroderma and a ~ t h m a , 3 ~chronic 3 chemical sensitivity,%and other hypersensitivity conditions. The presence of large amounts of dead C. ulbicuns and other yeast in stool has also been reported in patients with irritable bowel syndrome (IBS); it is theorized that this overgrowth could underlie some of the sympt o m in IBS, such as recurrent diarrhea and abdominal cramping.40 Although these associations have been highly disputed, there is strong evidence that yeast overgrowth may have pathogenic potential in susceptible individuals, particularly in those with weakened immune systems. One large-scale review concluded that nearly all comparative studies have found significantly higher yeast counts in patients than in healthy controls.41Other studies have linked Candidu overgrowth to higher rates of death and neoplastic complications in patients with leukemia and of GI hemorrhage in renal transplant recipients.*,43 The GI tract in healthy individuals normally harbors small amounts of yeast. However, many conditions are known to promote the overgrowth of Cundidu sp. in the bowel, including diabetes, alcoholism, mucosal damage, neoplasms, and treatment with antibiotics, steroids, or antacids.%S4For this reason researchers have suggested that the interpretation of yeast levels in stool may be most valuable when carefully correlated with clinical conditions in the i n d i v i d ~ a l . ~ ~

Dysbiosis Dysbiosis is a state of disordered microbial ecology that may cause illness or disease. It can exist in the oral cavity,

Poor diethutritional status Stress Antibiotidother drug therapy Decreased immune status Decreased gut motility Maldigestion Intestinal infection Xenobiotics Increased intestinal pH Diabetes, scleroderma Gastrointestinaltract surgery

GI tract, or vaginal cavity. In dysbiosis, organisms of low intrinsic virulence, including bacteria, yeasts, and protozoa, may grow or migrate beyond their normal limitations. In the GI tract, this can result in intensified microbial competition for nutrients and damage to the mucosal layer, which alters the nutritional status and immune function of the host.& Major causes of dysbiosis are listed in Box 14--2.29,47-51 Published research has implicated intestinal dysbiosis as contributing to vitamin and amino acid deficiencies, malabsorption of carbohydrates, IBD, autoimmune arthropathies, and colon and breast cancer.37,38,49~50~2-54 One controversial theory posits that food allergy is not strictly an immunologic disease but instead is a chronic disorder of excessive bacterial fermentation in the colon. In this model, the combined mechanisms of reduced gut enzyme concentrations, imbalanced bacterial flora, and increased intestinal permeability act synergistically to trigger symptoms of food int~lerance.~~

USING COMPREHENSIVE DIGESTIVE STOOL ANALYSIS 2.0 The CDSA 2.0 provides an indepth noninvasive analysis of digestion/absorption, gut immunology and metabolism, microbial flora, and colon cancer risk.

Digestive Function DigestiodAbsorption Pancreatic Elastase 1 An enzyme produced exclusively by the human pancreas, pancreatic elastase 1 (PE1) is an extremely reliable and specific marker of exocrine pancreatic function.56 PE1 is concentrated fivefold to sixfold higher in feces than when it enters the duodenum. This reflects the stability of PE1 in the GI tract.57PE1 is not degraded during intestinal transit, nor is it significantly affected by increases or decreases in intestinal transit Unlike other pancreatic markers, such as chymotrypsin, PE1 results are not affected by pancreatic enzyme replacement

Comprehensive Digestive Stool Analysis 2.0 therapy.56 This feature makes it a valuable marker for monitoring and adjusting enzyme replacement.% Pancreatic function diminishes with Exocrine pancreatic insufficiency may result in inadequate nutrient metabolism, leading to nutrient deficiency states. Malabsorption of fats and proteins may be accompanied by a deficiency of vitamins, particularly lipid-soluble vitamins. Mineral deficiencies, including calcium depletion, may also occur. Problems with glucose control may be exacerbated in diabetics because of inadequate nutrient metabolism.20Nearly one third of patients with osteoporosis have reduced concentrations of PE1.I8 Vitamin D levels may also be significantly lower in these patients?" Pathologic conditions such as alcoholism, cholelithiasis, diabetes, IBD, autoimmune or connective tissues diseases, and pancreatic cancer are other well-known causes of pancreatic insufficiency.

ValeratelIsobutyrate Valerate and isobutyrate are produced exclusively by bacterial fermentation of polypeptides and amino acids. These SCFAs are putrefactive, and their presence suggests underlying maldigestion, malabsorption, or bacterial overgrowth in the small intestine. Other causes are GI disease (resulting from the fermentation of blood or mucosal cells delivered to the colon)61and rapid transit time (resulting from inadequate time for digestion and absorption of peptides and amino Short-Chain Fatty Acids SCFAs are produced by the anaerobic bacterial fermentation of primarily nonabsorbed dietary fiber.63SCFAs: Provide energy for the colonocytes and exert a trophic effect on the intestinal lining." Act as antidiarrheal agents by removing sodium and water from the ~0lon.6~ Improve colonic blood flow.& Deter the colonization of pathogens in the bowel." Provide 5% to 30% of systemic daily energy req~irements.6~ Reduce ammonia uptake from the intestine."

In general, the more slowly fermented forms of fiber tend to maintain low pH and raise SCFAs along the entire length of the bowel.

N-Butyra te Butyrate, the major fuel for colonocytes, assists in the maintenance of colonic integrity.@Because of its trophic effect on the colonic epithelium, butyrate protects against ulcerative colitis and colon ~ancer.6~ In Crohn's disease, butyrate decreases production of tumor necrosis factoralpha production and the activity of lipopolysaccharideinduced nuclear factor kappaB (NFKB)in intestinal cells,

both of which are key factors in its path~genesis.~" Low levels of N-butyrate are associated with slow transit time, antibiotic therapy, insufficient dietary fiber, and increased risk of adenomas and colorectal Levels of N-butyrate may be increased by dietary fiber, Larch arabinogalactan (Larix sp.), normalization of pH and transit time, probiotics/prebiotics, and butyric acid (oral or r e ~ t a l ) ? ~ , ~ ~ - ~

Gut Immunology Eosinophil Protein X Eosinophil protein X (EPX)is a glycosylated protein that serves a marker of eosinophil activation and degranulation. It has potent cytotoxic and neurotoxic properties and is released from the eosinophils after being activated and stimulated by cytokines. EPX can attack cell membranes, making the membranes porous, which in turn causes osmotic lysis.85 Accumulation of EPX in the GI tract is associated with chronic intestinal inflammation and tissue Elevations can occur in response to food allergy, proteinsensitive enteropathy, helminthic infection, IBD, cancer, allergic colitis, and gastroesophageal reflux.86100 Ca1proteetin Calprotectin belongs to a group of calcium-binding neutrophil-derived proteins. Calprotectin makes up about 5% of the total protein content of the neutrophil and about 60% of the cytosolic proteins. Fecal calprotectin is a direct and sensitive marker of gut inflammation and correlates closely with IBD activity.'"' Calprotectin enters the bowel lumen as part of an inflammatory process rather than through bleeding. Increased calprotectin levels in colorectal cancer are believed to be caused by the infiltration of white blood cells into the tumor, with subsequent shedding into the lumen. This explains why Tibble et a1.lo2reported that the sensitivity of calprotectin for identifying adenomas was 55%,compared with only 10% for fecal occult blood testing; they also estimated the sensitivity of calprotectin for detecting colorectal cancer at 90%, compared with 58% for fecal occult blood.lo2 The conundrum of trying to distinguish functional abdominal pain from serious or life-threatening conditions faces the clinician frequently. IBS accounts for up to 12%of primary care consultations and 28% of referrals to gastroenterologists.103,104 Because symptoms often overlap, early IBD is often misdiagnosed as IBS. In fact, more than 25% of patients with IBD (particularly those with Crohn's disease) are given the diagnosis of IBS in the prodromal stages of their disease.lo5 This misdiagnosis often leads to extensive and invasive radiographic and endoscopic testing to make a "diagnosis of exclusion" in patients with IBS.

Supplementary Diagnostic Procedures Laboratory markers used to assess disease activity in IBD, such as C-reactive protein, erythrocyte sedimentation rate, white blood cell count, and cytokines (e.g., interleukin-6, tumor necrosis factor-alpha, and interleukin-1), have achieved only limited This is because these markers may be affected by malabsorption, mechanical obstruction, poor nutrition, and drug therapy as well as other infective or inflammatory conditions. Calprotectin provides a much more convenient and sensitive noninvasive alternative for assessing inflammatory activity in IBD. Fecal calprotectin levels have been shown to correlate significantly with histologic and endoscopic assessment of disease activity in ulcerative colitis"' and with indium-111-labeled white blood cells (the gold standard for assessing gut inflammation) in patients with Crohn's disease.Il2Indeed, increased levels of fecal calprotectin have been found in more than 95% of patients with IBD and appear to correlate well with disease activity in IBD.Il3 A 2000 study has confirmed the usefulness of fecal calprotectin in predicting IBD relapse.l14This predictive ability is important for timing interventions to reduce gut inflammation before patients experience a recurrence of debilitating symptoms. In patients with clinically quiescent IBD, fecal calprotectin levels higher than 50 mg/L (pg/g) predicted the relapse of the disease within 3 months with more than 80% sensitivity. Another study showed that at a cutoff level of 50 mg/L (pg/g), the sensitivity of calprotectin for predicting IBD relapse was 90%, and the specificity was 83%.l15This evidence suggests that symptomatic relapse in IBD occurs when inflammation in the gut reaches a critical level of intensity. Calprotectin also can be used to evaluate treatment efficacy in IBD, allowing the patients to avoid prolonged, ineffective, and potentially harmful courses of corticosteroids and other medication fraught with side effects.l16 Other inflammatory conditions are also associated with elevated calprotectin levels (Box 14-3).

Metabolism PH Fecal pH is an indicator of the health or status of the colonic digestive process. Intestinal pH is affected by

Parasite, viral, or bacterial infection Nonsteroidal antiinflammatory drug enteropathy Inflammatory bowel disease activity Bowel polyps or neoplasia

fiber and food constituent intake,l17-l19fermentative processes, bacterial populations, antibiotics,n and transit time.62The pH serves as a useful biomarker for assessing colonic neoplasm risk,lz0malabsorptive syndromes, and the cause of diarrhea.lZ1Fiber (especially cellulose and resistant starch) decreases pH, whereas high-protein intake causes higher (more alkaline) pH.

Beta-Glucuronidase Beta-glucuronidase is an inducible enzyme elaborated by anaerobic E . coli, Peptostreptococcus, Bacteroides, and Clostridi~rn.'~~J~~ By uncoupling glucuronides (xenobiotics and endogenous compounds detoxified via the glucuronidation pathway), this enzyme can deconjugate potential toxins, enhancing the formation of local carcinogens in the boweP4 and promoting the enterohepatic recirculation of toxins, hormones,125and various drUgslZ6 in the body. For this reason, excess amounts of the enzyme may promote higher risk of colon cancer. Both the incidence of colon cancer and levels of betaglucuronidase tend to be higher in individuals consuming Western diets (high in saturated fat, low in fiber) than in individuals consuming diets high in fiber and low in saturated fat.127 However, an adequate amount of beta-glucuronidase activity is probably important to maintain normal enterohepatic recirculation of endogenous compounds such as vitamin D,128thyroid hormone,lZ9and estrogen.53 In addition, the bioavailability of the cancer-protective isoflavone glycosides genistein and daidzein depends on initial hydrolysis by intestinal beta-glucuronidase and sulfatase enzymes. Abnormally low levels of beta-glucuronidase may reduce the efficacy of these

compound^.'^^ Bile Acids The relationship between dietary fat and increased risk of colon cancer is believed to hinge on the excess production of bile acids and the bacterial conversion of conjugated primary bile acids to potentially dangerous unconjugated secondary bile acids.l3I Studies have found that a higher ratio of secondary bile acids, specifically, an elevated ratio of lithocholic acid to deoxycholic acid (LCA/DCA ratio), is associated with higher susceptibility to polyps and colorectal c a n ~ e r . ~ Increased ~~J~ secondary bile acid excretion and a rise in the LCA/ DCA ratio have also been observed in patients with gallstones.lM Bacterial overgrowth markedly increases the concentration of unconjugated bile acids, and this mechanism may play an important role in the pathophysiology of gut mucosal injury.135 Probiotic treatment with Lactobacillus reiiteri has been demonstrated to lower the bioavailable concentration of toxic bile acids.131

Comprehensive Digestive Stool Analysis 2.0

Microbiology Beneficial Bacteria Analysis of stool samples provides a window for viewing the distal colonic flora population. Levels of growth reflect the density of colony formation on the primary culture performed at the laboratory and can indicate the need for supplementation. Adequate amounts of lactobacilli, bifidobacteria, and E. coli are essential for the maintenance of a healthy digestive system. These beneficial flora help protect against overpopulation of potentially pathogenic organisms, enhance nutrient production, and stimulate the immune system. For example, the lactic acid and acetic acid produced by lactobacilli and bifidobacteria reduce intestinal pH, which in turn can restrict the growth of bacterial toxins.26 Many factors are thought to affect the composition of the colonic flora, including diet, transit time, stool pH, age, microbial interactions, colonic availability of nutrients, bile acids, sulfate, and the ability of the microbes to metabolize these s ~ b s t r a t e s . ~ ~ Additional Bacteria Bacteriology also cultures for additional bacteria that are nonpathogens, potential pathogens, and pathogens. These include alpha-hemolytic Streptococcus, beta-hemolytic Streptococcus,Citrobucterfreundii, and Klebsiellu pneumoniae. Serotyping for E. coli and Cumpylobucter cultures is performed on diarrheal specimens. Because the microflora is influenced by environmental factors and the competitive ecosystem of the organisms in the GI tract, the clinical interpretation of these bacterial findings should be based on patient symptoms and reproducibility of bacterial recovery.

Mycology The CDSA 2.0 includes a mycology culture that identifies and quantitates fecal yeast. Some of the more commonly identified species are Cundida albicans, Cundida tropiculis, Rhodotorula, and Geotrichum. Broth dilution sensitivity analyses are performed on all yeast cultures yielding scores of 2+ or greater for natural and pharmaceutical substances. Quantitative minimum inhibitory concentration (MIC) sensitivity analysis determines the relative potency of various antimycotic agents. This procedure provides information on the effective agents and doses that may be used to treat yeast growth. MIC analysis is available by request for cultures with yeast scores below 2+.

Additional Tests The additional tests included in the CDSA 2.0, described here, can be helpful in diagnosing and monitoring diseasespecific infections or conditions.

Helicobacter pylori Stool Antigen Helicobacter pylori remains a highly prevalent infection, with infection rates in middle-aged adults reaching more than 80% in areas of low socioeconomicstatus and 20% to 50% in most industrialized countries.'36 H. pylori is the major cause of peptic ulcer disease. For those infected, the lifetime risk for development of H. pylori-associated peptic ulcer is estimated to be 10% to 20%.137 H. pylori infection also increases the risk of gastric adenocarcinoma, with clinical sequelae of gastric atrophy, intestinal metaplasia, and, ultimately, gastric carcinoma.'38 H. pylori stool antigen (HpSA) testing provides a simpler alternative to urea breath testing. This U.S. Food and Drug Administration-approved marker is a measure of H . pylori antigens shed directly into the stool. Sensitivity is 89% to 98% and specificity exceeds 90%. HpSA testing is appropriate for diagnosis and follow-up of infection, and can be used 7 days after eradication (versus 4 weeks for breath te~ting).'~~-l~l Because HpSA testing performs well in children of all ages, it may be the noninvasive procedure of choice for this group.'37 Shiga Toxin-Producing E. coli Shiga toxin-producing Escherichiu coli (STEC)is a group of bacterial strains that have been identified as a worldwide cause of severe GI disease and life-threateningillnesses.lq STEC may produce Shiga-like toxin I or Shiga-like toxin 11, both of which are similar to the toxins expressed by Shigellu d y s e n t e r i ~ e . ' ~These ~ - ~ ~ ~toxins destroy the colonic epithelium and may cause small blood vessel damage in various tissues, including the kidney. Red blood cells passing through the damaged vessels can fragment as result, causing anemia and thrombocytopenia.'" STEC is believed to reside primarily in the intestinal tract of animals, most commonly dairy and beef cattle. Foods associated with infection include ground beef, sausage, salami, roast beef, raw milk, mayonnaise, apple cider, and raw vegetables. Because the organism has a low infective dose, food outbreaks may affect a large number of people.144J46 Campylobacter jejuni Cumpylobucter jejuni is a gram-negative, microaerophilic, thermophilic rod first identified as an important human pathogen in the late 1970s. Both C. jejuni and Cumpylobucter coli have been recognized as primary agents of GI infe~tion.'~'J~ Clinical and epidemiologic studies have identified C. jejuni as the most common cause of bacteria-induced diarrhea. The isolation rate exceeds the rates of both Salmonella and Shigellu combined. In the United States, the infection rate has been reported as high as 1000 per 100,000 population. The prevalence is even greater in developing c ~ u n t r i e s . ' ~ ~ - ' ~ ~

Supplementary Diagnostic Procedures The highest incidence of C. jejuni infection occurs in infants and young children younger than 5 years; daycare centers frequently harbor the organism. Adults 20 to 40 years old are the next most commonly affected segment of the population.*B3 Possible sources of infection include fecal-oral transmission, ingestion of contaminated animal-based foods (e.g., poultry, red meat, milk), and consumption of untreated surface water.

Clostridium diflicile Clostridium dificile is an anaerobic, spore-forming, grampositive bacterium that can be part of the normal intestinal flora. After a disturbance of the gut flora (usually caused by antibiotics) colonization with C. dificile can o c m . Toxigenic C. dificik produces two toxins, A and B, which are the main virulence factors. Human infection with C. di’cile can take many forms. Some infected individuals may be ”carriers” and appear clinically healthy. Some may have recurrent, mild to moderate diarrhea and other symptoms resembling those of IBS.Others may have recurrent severe cramps and diarrhea, with or without flatulence, and may be misdiagnosed as having IBD.152 C. di’cile also may manifest as a condition indistinguishable from colitis, with cramps, diarrhea, urgency, mucus, and blood. However, severe, fulminant pseudomembranous colitis accounts for less than 3%of cases.153 Unless it is clearly diagnosed by testing for both toxins A and 8, infection with C. dificile may be misdiagnosed as IBS or IBD.

the stool sample because of blood loss somewhere in the GI system. This could be caused by conditions such as ulcers, polyps, diverticulosis, IBD, and colorectal cancer.154 Vitamin C should be avoided before stool sample collection and, ideally, a high-roughage diet (e.g., bran cereal, nuts, popcorn, raw fruits or vegetables) should be started 2 days before the test and maintained for the duration of the testing period. These preparations help to uncover “silent” lesions, which may bleed only intermittently.

Interpretation at a Glance For ease of interpretation, the CDSA 2.0 report consists of an aggregate of abnormal indicators arranged by clinical significance. This allows the practitioner to quickly assess how the composite test results may be interpreted in relation to digestive deficiency, inflammation/IBD, dysbiosis, and neoplastic risk.

CONCLUSION

Fecal Occult Blood A monoclonal antibody technology is used to detect fecal occult blood. Fecal occult blood can be present in

Abundant evidence underscores the importance of maintaining optimal functioning and ecology of the GI tract as a fundamental strategy for improving human health and wellness. The CDSA 2.0 is a comprehensive noninvasive analysis that provides advanced clinical insight into digestion/absorption, gut immunology, metabolism, and microflora balance. Test results allow practitioners to optimize nutritional and lifestyle interventions; diagnose, treat, and monitor prevalent GI disorders; and prevent the potential ”ripple effect” whereby gut dysfunction spirals into chronic poor health and systemic disease states.

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Erythrocyte Sedimentation Rate Michael T.Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 179 Erythrocyte Aggregation

179

Procedures 180 Westegren Method 180 Wintrobe Method 180 Results 180

INTRODUCTION The erythrocyte sedimentation rate (ESR), the rate at which erythrocytes settle out of nonclotted blood in 1 hour, has been one of the most widely performed laboratory tests in the past 55 years. Used primarily to detect occult processes and monitor inflammatory conditions, the ESR test has undergone little change since 1918 when Fahraeus discovered that erythrocytes of pregnant women sedimented in plasma more rapidly than they did in nonpregnant women. Since its incorporation into standard laboratory diagnosis, the ESR has been shrouded with medical myths and is often misinterpreted or misused. This chapter provides a rational guideline for its use as a nonspecific measure of inflammatory, infectious, neoplastic, and cardiovascular diseases.14

ERYTHROCYTE AGGREGATION Normally, erythrocytes settle quite slowly, as the gravitational force of the erythrocyte's mass is counteracted by the buoyant force of the erythrocyte's volume. However, when erythrocytes aggregate, they sediment relatively rapidly because the proportional increase in their total mass exceeds the proportional increase in their volume.14 Therefore the major determinant in the sedimentation rate of erythrocytes is erythrocyte aggregation, which usually occurs along a single axis (rouleaux formation). The aggregation of erythrocytes is largely determined by electrostatic forces. Under normal circumstances, the erythrocytes have a negative charge and therefore repel

Interpretation 180 Elevated Erythrocyte Sedimentation Rate 180 Decreased Erythrocyte Sedimentation Rate 182 Monitoring of Disease Activity 182 Summary 182

each other. However, many plasma proteins are positively charged and neutralize the surface charge of erythrocytes, thereby reducing repulsive forces and promoting aggregation The relative contribution of the various "acute-phase" reactant proteins to aggregation is shown in Table 15-1. One protein that has no direct effect on the ESR in physiologic concentrations, but which is associated with certain inflammatory, degenerative, and neoplastic diseases, is the C-reactive protein. Its major function is facilitation of the complement system. Like the ESR, measurement of the C-reactive protein is used in the monitoring of patients with chronic inflammatory conditions.' An elevated C-reactive protein provides evidence of an inflammatory process despite a normal ESR. Therefore when used in conjunction with the ESR, it greatly increases the sensitivity in detecting inflammatory/infectious processes, especially when variables such as anemia confound the ESR. The ESR is also elevated in patients with proteinemias (myeloma, macroglobulinemia, cryoglobulinemia, and cold agglutinin disease).l-" Disorders of erythrocytes such as anemias alter the ESR and may interfere with accurate interpretation.I4 Since the ESR is directly proportional to the mass of the erythrocyte and inversely proportional to its surface area, large erythrocytes sediment more rapidly than smaller cells. Therefore in macrocytic anemia there is an increased ESR, and in microcytic anemia there is a decreased ESR. Although the usefulness of ESR determination has decreased as new methods of evaluating disease have been developed, it remains quite helpful in the diagnosis 179

Relative contribution of acute-phase reactant proteins to erythrocyte aggregation Blood constituent

Relative contribution

Fibrinogen

10

Beta-globulin

5

Alpha-globulin

2

Albumin

1

of some diseases, such as temporal arteritis and polymyalgia rheumatica. Perhaps more useful is its use in monitoring these conditions and others including chronic inflammatory diseases such as rheumatoid arthritis and Hodgkin's disease and other cancers. Although the use of the ESR as a screening test to idenhfy patients who have serious disease is not supported by the literature, it does provide a general gauge of inflammatory process in the body. It is well accepted that an extreme elevation of the ESR is strongly associated with serious underlying disease, most often infection, collagen vascular disease, or metastatic malignancy. Recently, there has been a growing appreciation of the value of the ESR as a marker for atherosclerosis and coronary artery

PROCEDURES Various methods for determination of the ESR have been developed. Currently the Westegren method is recommended by the International Committee for Standardization in Hematology.

Westegren Method In the standard Westegren method, the following procedure is used: 1. Dilute venous blood 4:l with anticoagulant sodium citrate. 2. Put in a 200-nun long, 2.5-mm internal diameter, glass tube (Westegren tube). 3. Allow to stand in a vertical position for 1 hour. 4.At the end of 1hour, the distance from the meniscus to the top of the column of erythrocytes is recorded as the ESR.

The modified Westegren method uses edetic acid (EDTA) rather than sodium citrate as an anticoagulant and is more convenient, since the same tube of blood can be used for other hematologic studies. The standard and modified methods give identical results.'"

Wintrobe Method The second most commonly used method is the Wintrobe method. This method is performed with a

Westegren (normal results) Men: 0-10 mm/hr Women: 0-15 mm/hr Children: 0-10 m d h r Wintrobe (normal results) Men: 0.3 mg/dl 30 pg/l O8 WBCs 0.3-2.0 mg/hr in control 24-49 mg/hr after 500 mg

Biotin

Beta-hydroxyisovalerate

QO pg/mg creatinine (overnight urine)

Folate

RBC folacin Neutrophil hypersegmentation Serum homocysteine CBC

>160-650 ng/ml ~30% with five or more lobes c10 pmol/L Macrocytic anemia

Niacin

Urinary Kmethylnicotinamide RBC NADlNADP

>1.6 mag creatinine >1.o

Pantothenic acid

Urinary pantothenic acid

>1 mg/day

Pyridoxine

Serum level Tryptophan load EGOT EGPT Plasma pyridoxal Serum homocysteine

>50ngml 8 ng/ml 4 0 pmoWL

RBC glutathione reductase FAD effect

4 0 % increase

Thiamine

RBC transketolase

4 5 % increase

Vitamin B12

Serum B12 Urinary methylmalonic acid Serum homocysteine

20 >30 >20

Plasma carotene: 0-5months 6-11 months 1-17 years Adult Pregnancy

80-400 pg/dl: >10

Fat-soluble Vitamin A

>150 pg/ml

>30 9 0 >40 >80 10-80 ng/ml 21-45 paml

Vitamin D

Cholecalciferol (D3) 1,25-dihydroxycholecalciferol

Vitamin E

Serum tocopherol RBC hemolysis in H202 Serum tocopherol/triglyceride

>0.7mg/lOO dl

Abnormal prothrombin antigen assay

4 0 ng/ml

Vitamin K

40% 35-120

Data from references 1-5. 'EGOS; Erythrocyte glutamic oxaloacetic transaminase; EGPS; erythrocyte glutamic pyruvic transaminase; FAD, flavin adenine dinucliotide; NAD, nicotinamide adenine dinucleotide; NADF: nicotinamide adenine dinucleotide phosphate; RBC, red blood cell; WBC. white blood cell.

involved in some 60 enzymes, so deficient activity of these enzymes can be measured as a functional assessment of pyridoxine.

Riboflavin The most common measure of riboflavin is red blood cell (RBC) glutathione reductase activity. The enzyme is stimulated in vitro by the addition of flavin adenine

dinucleotide. Elevation of activity greater than 20% is suggestive of a functional deficiency. Blood riboflavin levels are not reliable because of technical difficulties in measurement.

Thiamine The most common measure of thiamin is RBC transketolase activity. The enzyme is stimulated in vitro by the

Laboratory Tests for the Determination of Vitamin Status

addition of thiamine pyrophosphate. Elevation in activity greater than 15% indicates a functional deficiency. The test is not reliable in patients with diabetes mellitus, pernicious anemia, or a significant negative nitrogen balance. More recently, measurement of amino acids and their ketoacid analogues that are excreted in thiamine deficiency is being used. (See Brally and Lord4for a more complete discussion.)

Vitamin BI2 Serum levels of vitamin BI2 are of value, though they do not track cerebrospinal fluid levels very well. Erythrocyte cell size is also not reliable, as neurologic signs and symptoms can precede macrocytosis by 6 to 12 months. Measurement of urinary methylmalonic acid is sensitive and accurate, especially when expressed as a ratio with the urinary creatinine measurement. Elevated homocysteine concentrations can be of same value as well.

Fat-Sohble Vitamins Vitamin A Although liver biopsy is the most accurate method of vitamin A assessment, other less invasive and less expensive methodologies are more appropriate. As with most other nutrients, serum levels of vitamin A fall significantly only after tissue reserves have been depleted. Fortunately, the dark adaptation test detects early deficiency of this nutrient (see Chapter 29).

1. Tiemey LM, McPhee SJ, Papdakis MA. Current medical diagnosis and treatment. Stamford, CT Appleton & Lange, 2001:1239-1244. 2. Rubenstein E, Federman DD. Scientific american medicine. New York

Scientific American, 2004:1-15. 3. Werbach MR Textbook of nutritional medicine. Tarzana, C A Third Line Press, 1999.

Vitamin D Serum levels of vitamin D, especially its activated dihydroxy form, are clinically accurate and useful.

Vitamin E Platelet vitamin E levels seem to be the most accurate measure of intake. However, a more clinically relevant measure appears to be the ratio of this important antioxidant with one of the key molecule it protects, triglycerides. Adipose and platelet levels of vitamin E are perhaps most accurate.

Vitamin K The various prothrombin and clotting time assays appear to be useful ways to assess vitamin K status.

CONCLUSION As described here, many procedures are now available for the assessment of functional vitamin status. Although research continues in this important area, the reader is advised to study carefully the discussion of urinary organic acids profiling (see Chapter 30). Utilizing metabolic products excreted in the urine now allows the clinician far greater specificity in recognizing dysfunctional enzyme systems, whether they are due to genetic deviations or nutritional deficiencies.

4. Brally J, Lord RS. Laboratory evaluations in molecular medicine. Norcross, GA: Institute for Advances in Molecular Medicine, 2001. 5. Homocysteine Lowering Trialists Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. BMJ 1998;316:894-898.

Lactose Intolerance Testing Jeffrey Glen Baker, ND CHAPTER CONTENTS Introduction 255

Diagnosis of Lactose Intolerance 258 Nutritional History 258 Empirical Testing (Trial Elimination of Milk Products from the Diet) 258 Breath Testing 259 Genomic Testing 260 Histology 260 Blood and Urine Tests 260

Prevalence of Lactose Intolerance 255 Pathophysiology 256 Lactose Intolerance versus Lactase Deficiency 256 Lactose Intolerance versus Dairy Allergy

256

Adult-Type (Primary) Lactase Deficiency 257 Acquired-Type (Secondary) Lactase Deficiency 257

Other Types of Sugar Intolerances 260 Fructose 260 Sucrose 260 Maltose 260 Summary 261

Congenital Lactase Deficiency 257

INTRODUCTION Lactose intolerance is the inability to properly digest lactose, the disaccharide found in mammalian milk. Affecting

testing for adult-type lactase defi~iency.~ In addition to diagnostic testing, the patient’s nutritional history and the relationship between lactose consumption and GI symptoms are important for accurately diagnosing lactose intolerance.6

more than 50 million Americans, this condition is one of the most common gastrointestinal (GI) disorders seen by primary care physicians. Lactose intolerance is commonly overlooked because its symptomsAiarrhea, bloating, PREVALENCE OF LACTOSE and abdominal pain-are similar to those of many other INTOLERANCE conditions.’ However, when properly diagnosed, lactose intoleranceis easily treated with patient education, lactase Lactose intolerance affects an estimated 25% of supplementation, and dietary modifications2 Americans and 75%of adults ~ o r l d w i d eAs . ~ shown in Self-diagnosis and empirical testing for lactose intolTable 25-1, the condition occurs in people of all ethnic erance often produce erroneous results. When this backgrounds, with the highest prevalence observed in happens, nutrient-rich dairy foods may be removed Asians and blacks. from the diet unnecessarily; without appropriate subThe symptoms of lactose intolerance can range from stitutions, such an elimination diet may increase the minor dyspepsia, bloating, and flatulence to severe risk of osteoporosis, heart disease, and colon ~ a n c e r . ~ diarrhea and abdominal cramps (Box 25-1). Studies This common clinical mistake can be avoided if the suggest that lactose intolerance may contribute to, or proper diagnostic procedure is followed. Measuring cause, many other conditions with similar symptoms. For example, lactose intolerance and irritable bowel synbreath levels of hydrogen and methane is the method of choice for diagnosing lactose maldigestion.4 The disdrome (IBS) have nearly identical clinical presentations, covery of the gene responsible for ”lactase nonpersisand it is thought that the two conditions may overlap or tence” also has led to the development of genomic coexist. For this reason, lactose intolerance should 255

Supplementary Diagnostic Procedures

Prevalence of lactose intolerance by ethnic group GrouD

For susceptible children with lactose maldigestion, only 12 g of lactose (-1 cup of milk) daily has been shown to be associated with increased abdominal pain.19

Prevalence (%)

African blacks

97-100

PATHOPHYSIOLOGY

Asians

90-100

North American blacks

70-75

Mexicans

70-80

Persons of Mediterraneandescent

60-90

Persons of Jewish descent

60-80

Lactose is a disaccharide normally hydrolyzed by the lactase enzyme lactase-phlorizin hydrolase (LPH) into glucose and galactose, which are actively absorbed in the small intestine (Figure 25-1). Lactase deficiency, also known as lactase nonpersistence or hypolactasia, is a physiologic decline in activity of LPH. It occurs when LPH activity is decreased in the brush-border membrane of the distal duodenum and proximal jejunum, leading to lactose maldigestion.20 When amounts of lactose ingested exceed digestion capacity, lactose persists in the lumen, ultimately reaching the colon, where it may lead to osmotic retention of fluid and bacterial fermentation and thus cause the symptoms characteristic of lactose intolerance (see Figure 25-1).12 The development of lactose intolerance depends on a number of factors: (a) lactase deficiency, (b) relatively high lactose load, (c) rapid rate of gastric emptying, (d) rapid small bowel transit, and (e) inadequate beneficial bowel flora.*O

~~~~

North American whites

7-15

Northern Europeans

1-5

Indigestion Bloating Flatulence Nausea Diarrhea Failure to thrive Abdominal cramps

always be investigated in cases of IBS, a condition that affects up to 20%of Americans? LACTOSE INTOLERANCE VERSUS In fact, many cases of IBS may be caused by lactose LACTASE DEFICIENCY intolerance? In a study of 146 children with a diagnosis of IBS, 24.3%had evidence of lactose malabsorption on Lactose intolerance and lactase deficiency are not synonyhydrogen breath testing. Symptoms improved signifimous. Several studies document the absence of lactose cantly after these patients were started on a lactose-free intolerance in verified cases of lactase deficiency.21-23 diet. Five years later, 87.5%of the patients still reported In these cases, beneficial bacteria may hydrolyze lactose benefit from the diet. They also reported 75% fewer even in the absence of sufficient lactase activity." visits to outpatient clinics compared with the same time One should connect the patient's symptoms with the preceding the lactose-free diet (reduction from 192 to consumption of lactose before reaching a final diagnosis, 45 visit^).^ In another study, lactose malabsorption was because several tests (e.g., genomic testing) idenbfy lactase diagnosed in 68% of patients with IBS who denied a deficiency only. One benefit of breath testing is that history of lactose intolerance. Symptoms improved after it measures hydrogen production, which is associated a lactose-free diet was introduced.10 with both lactase deficiency and the symptoms of lactose Lactose intolerance may occur more frequently in intolerance. certain types of IBS. Rana et all1found that patients with Some researchers have proposed that lactose maldigesdiarrhea-predominant IBS have a higher incidence of tion resulting from lactase deficiency may be beneficial lactose intolerance (82%)than patients who have either in the absence of lactose intolerance; this theory is based spastic-type IBS or features of both IBS types. on the idea that lactose acts as a prebiotic in the colon.25,26 Other conditions causing intestinal mucosal damage and villus atrophy may reduce the activity of the LACTOSE INTOLERANCE VERSUS enzyme lactase, which is needed to digest lactose. For DAIRY ALLERGY this reason, lactose intolerance has been observed as a secondary feature in celiac disease, tropical sprue, acute Lactose intolerance and dairy allergy are quite different. intestinal infections, neomycin toxicity, cystic fibrosis,12 Lactose intolerance results from the maldigestion of alc~holism,'~ pelvic radiation the rap^,'^ and Crohn's dairy carbohydrate (lactose), whereas dairy allergy is an disease.15Treating the underlying condition has resulted immune response to dairy proteins (e.g., casein, lactalbuin restored lactase activity.16 min, whey). Dairy allergy may involve reactions that A number of studies suggest that transient lactose affect the GI tract, skin, respiratory tract, or multiple intolerance also is associated with infantile ~ o l i c . ' ~ , ' ~systems, as in systemic anaphylaxis. These immediate

Lactose IntoleranceTesting

Figure 25-1

reactions often are mediated by immunoglobulin E (IgE) and can cause severe morbidity and even death; however, in such cases, dietary elimination of dairy products is associated with good prognosis.27The prevalence of IgE-mediated allergic reaction to dairy protein in the general population is estimated at a 1%to 3%,being highest in infants and lowest in adults. However, the prevalence of IgG-mediated allergic reactions may be higher.

ADULT-TYPE (PRIMARY) LACTASE DEFICIENCY It is theorized that the ability to digest lactose in adulthood (lactase persistence) is the result of a relatively new evolutionary genetic mutation that occurred after the domesticationof farm animals5This theory could explain why increased lactase persistence is found primarily in northern Europeans, where dairy farming began. In other populations, adult-type lactase deficiency is a common autosomal-recessive condition resulting from the physiologic decline in the activity of LPH that occurs after weaning. The single nucleotide polymorphisms C/T-13910 and G/A-22018 contribute to the lactase non-persistence phenotype. C/T-13910 occurs in distantly

Lactose digestion.

related populations, indicating that it is the original form of the gene.

ACQUIRED-TYPE (SECONDARY) LACTASE DEFICIENCY Because LPH is located in the brush border of gut mucosal cells, its deficiency may be secondary to diseases that damage the jejunal mucosa. If mucosal integrity is restored, lactase activity should normalize. One study showed that 48% (21/44) of patients with celiac disease tested positive for lactose maldigestion. All patients tested negative for lactose maldigestion after 8 weeks of a gluten-free diet, indicating that mucosal integrity and lactase activity had been re~t0red.l~

CONGENITAL LACTASE DEFICIENCY Congenital lactase deficiency (alactasia) is a very rare inborn error of metabolism characterized by the absence of lactase. At birth, lactase is not detectable in affected infants. Clinical symptoms, which include severe diarrhea, dehydration, and malnutrition, appear during the first week with the consumption of lactose. Because

Supplementary Diagnostic Procedures

congenital lactase deficiency persists throughout life, persons with this condition must always avoid lactosecontaining foods?

DIAGNOSIS OF LACTOSE INTOLERANCE Controversy surrounds the subject of lactose intolerance, stemming from the dramatic decrease in dairy consumption that can result from its diagnosis. Numerous studies show a correlationbetween decreased dairy consumption and a rise in calcium-dependent conditions, such as osteoporosis, heart disease, and colon cancer.2835Studies also indicate that food-based calcium is a better source of this nutrient than supplements. In a metaanalysis of 42 randomized, controlled calcium-intervention trials, Griffith et a131 concluded that dietary sources of calcium more effectively lowered blood pressure. Because dairy foods are the richest and best-absorbed dietary sources of calcium, careful diagnosis should be made before these foods are eliminated from the patient’s diet. This diagnosis should be based on nutritional history, the relationship between diet and GI symptoms, and diagnostic testing: Dairy consumption may have health consequences unrelated to lactose intolerance (e.g., dairy allergy) that may require further investigation.

Obvious Sources Milk (whole, skim, dry powdered, evaporated) Cheeses Butter, many margarines Goat‘s milk Half-and-half cream Ice cream and many sherbets Yogurt Hidden Sources Artificial sweeteners containing lactose Breads, biscuits and crackers, doughnuts made with milk Breading on fried foods Breakfast and baby cereals containing milk solids Buttered or creamed foods (soups and vegetables) Cake and pudding mixes, many frostings Candies with milk chocolate Cookies made with milk Hot dogs, luncheon meats, sausage, hash, processed and canned meats Mayonnaise and salad dressings made with milk Nondairy creamers (except for Coffee Rich)

Nutritional History A detailed history of the patient’s average consumption of ladose-containing food should be obtained. Often, patients do not consider yogurt, ice cream, chocolate milk, and milk ingested with cereal as important sources of lactose. They also may not be aware that lactose is added to many nondairy products to provide texture, flavor, and browning and to absorb flavors, aromas, and food colors (Box 25-2). In addition, because of its excellent binding ability, lactose is contained in many drugs and overthecounter products (Box 25-3).Idenhfymg all sources of lactose is necessary to (a) identrfy the potential relationship between GI symptoms and lactose consumption and (b)develop an effective lactose-free diet, if necessary.

EmpiricalTesting (Trial Elimination of Milk Products from the Diet) If the patient experiences symptoms after consuming food products containing lactose, lactose intolerance should be considered. A temporary exclusion of all lactose-containing products from the diet as a preliminary diagnostic procedure may be helpful. However, diagnosis of lactose intolerance should not be based solely on this empirical testing for the following reasons: All sources of lactose may not be eliminated. Many sources of lactose are hidden (see Box 25-3) and may produce symptoms during the testing period, resulting in falsenegative results.

Prescription Drugs Ativan Burnex Calan Coumadin tablets ERYC Glucotrol Lasix Lotronex Mevacor Premarin Prilosec Propecia Reglan Synthroid Vasotec Xanax Over-thecounter Drugs Actifed tablets Allbee C-800 Plus iron tablets Benadryl tablets Chlor-Trimeton Allergy tablets Ferro-Sequels lrnodium A-D caplets Marezine tablets Pepcid AC chewable Slow FE iron tablets Sudafed Plus tablets Unifed Chewable tablets

Lactose IntoleranceTesting

Unrelated symptoms may abate during testing period. Unrelated conditions with intermittent symptoms may lead to a false-positive results if the symptoms abate during the testing period.36

carbohydrate reaching the colon produce a detectable increase in breath hydrogen.51

Hydrogen and Methane Responses

The normal breath hydrogen level in a healthy, fasting patient is less than 10 ~ p m . ~ * Patients with lactose malabsorption show an increase Breath testing is the method of choice for diagnosing in breath hydrogen concentration of 20 pprn or more lactose maldigestion? It is sensitive and specific,J7simple to perform, noninvasive, and inexpensive.36Breath testing during the test peri0d.25~5~ Those who can absorb lactose may show a small variation in breath hydrogen (2 to is based on the ability of intestinal microbes to ferment 3 ppm) during the test period. carbohydrates, in this case lactose, producing hydrogen The normal breath methane level in a fasting or methane in the process. A fraction of these gases patient is 0 to 7 ppm. An increase of at least 12 ppm naturally diffuses from the bowel to the circulation and is of methane alone during the test is considered positive eliminated via the lungs. Because there is no other metafor lactose malabsorption, regardless of the hydrogen bolic production of hydrogen and methane, pulmonary r e s pon~e.4~,~5~ excretion of these gases may be used as an indirect measure of lactose maldigestion, indicating lactase defi~iency.~~ If both breath hydrogen and methane rise after a lactose challenge, the two responses are added to The benefits of breath testing are as follows: estimate the degree of malabsorption. The rises in Its results correlate strongly with the symptoms of breath hydrogen and methane levels together must be lactose i n t ~ l e r a n c e . ~ ~ 20 pprn or more to suggest lactose rnalab~orption.~~ It can be done at home by the patient or in the physiThe extent of elevation relates to the degree of cian’s o f f i ~ e . ~ ~ , ~ malabsorption: The lower challenge dose of lactose causes signifiRise of 20 to 40 ppm: mild absorption cantly fewer side effects than the large doses used in Rise of 40 to 80 ppm: moderate absorption blood- and urine-galactose tests.4I Rise of 280 ppm: severe malabsorption Breath testing is completely noninvasive. The breath hydrogen/methane test is the standard in pediatric cases in which other tests would be difficult False-Positive Results to perform.4245 False-positive results occur rarely and are usually a consequence of the following interfering factors: Historically, breath testing has measured hydrogen only. However, Tormo et a14 showed that methane is Fiber intake. Fiber should be avoided 24 hours produced instead of hydrogen in some patients with before the test. Ingesting fiber in food or in lactose malabsorption. They concluded that measuring supplements increases fermentation and hydrogen both gases is necessary for accurate diagnosis of lactose production.56-58 maldigestion. Other researchers suggest that although Exposure to tobacco smoke. Tobacco smoke increases methane is produced predominantly in some cases, hydrogen levels and should be avoided immediately hydrogen production correlates more strongly with before and during testing.59 symptoms; therefore hydrogen testing alone may be Sleeping. Sleeping between breath sample collections sufficient for the diagnosis of lactose i n t ~ l e r a n c e . ~ , ~ ~ may increase both hydrogen and methane levels.60 Breath testing using a radiolabeled lactose (C-13-lactose) challenge dose that produces 1302shows poor correlaFalse-Negative Results tion with lactose i n t ~ l e r a n c e . ~ ~ Breath hydrogedmethane testing has a false-negative Procedure rate of approximately 5%;the false-negative rate is 10% if only hydrogen is measured. False-negative results can After an overnight fast, a baseline breath sample is occur because of the following factors: collected 30 minutes after rising. The patient then ingests a challenge dose of lactose (up to a maximum of 25 g), Use of lactase supplements.61 and breath samples are collected 1,2, and 3 hours after Use of antibiotics prior to the test. Antibiotics decrease ingestion of the challenge dose.4g50 the bacteria that ferment Interpretation Use of laxatives or enemas prior to the test. These decrease hydrogen and methane responses in patients If lactose maldigestion is present, breath levels of with lactose malabsorption and reduce fermentation in hydrogen or methane will rise within 1 to 2 hours the colon.63 after ingesting the lactose challenge. As little as 2 g of

Breath Testing

Supplementary Diagnostic Procedures

Severe diarrhea or hyperacidic colon contents. Hyperacidity inhibits the production of hydrogen and promotes the production of methane by colonic bacteria.@*& One can reduce false-negative results as follows: Wait at least 1 week after antibiotic treatment and reestablish colonic flora. Avoid testing during severe diarrhea. Have the patient avoid lactase enzyme supplements 24 hours prior to the test.

of hydrogen and methane gases, which are thought to cause the symptoms of lactose intolerance. Bacteria may adequately metabolize lactose in the patient with hypolactasia; therefore a patient with the CC-recessive DNA code may not be lactose intolerant.

Histology An endoscopic biopsy of the small intestine can be tested

in vitro for its ability to metabolize lactose into glucose and galactose. This test is rarely used for disaccharide intolerance because of the expense and discomfort for patients.

High Baseline Levels

Blood and Urine Tests

An elevated baseline level of breath hydrogen indicates

Plasma testing for 13-glucose, using a challenge dose of 13C-lactose,has been shown to have increased ability to differentiate between those who can digest lactose digesters and those with maldige~tion.~~ However, this method has not been evaluated for its ability to identify symptoms directly related to lactose intolerance. Serum and urine testing for galactose change require large amounts of lactose (-2 g/kg of body weight), which commonly produce adverse reactions in lactasedeficient patients. Also these tests require oral ingestion of alcohol to suppress rapid hepatic metabolism of galactose. These added risks appear unnecessary because there is no evidence that these methodologies are superior to breath testing?]

that one or more interfering factors are present. Testing must be repeated to obtain reliable results. The degree of elevation can help to idenhfy interfering factors. A baseline breath hydrogen level >10 ppm can be due to: Improper fasting. Consumption of high-fiber foods the day before testing. Performance of test immediately after awakening.45 A baseline breath hydrogen level >20 ppm can be due to:

Possible small intestine bacterial overgrowth.66 Elevated fasting levels of hydrogen occur in up to one third of patients with small intestinal bacterial overgrowth6’ and may be caused by the fermentation of endogenous brush-border glycoproteins.bs Small intestine bacterial overgrowth may elevate baseline methane readings as we11.45,69,70

Genomic Testing Adult-type lactase deficiency is a common autosomalrecessive condition. No DNA variations have been found in the gene that encodes for LPH. However, haplotype analysis, disequilibrium mapping, and association analyses have linked adult-type lactase deficiency with an adjacent DNA variant, C/T-13910. In a study showing the distribution of genotypes in individuals with verified lactase persistence or nonpersistence, C/T-l3910 markers identified lactase nonpersistence in 100% of patients (n = 144) with homozygous recessive traits (CC) and lactase persistence in 100% of patients (11 = 187) with heterozygous- and homozygous-dominant traits (CT and TT,re~pectively).~ Genomic testing requires a single blood sample and avoids the diet restrictions, lengthy collection regimen, and potential for abdominal symptoms that are associated with breath testing. However, genomic testing identifies hypolactasia only. It does not identify the presence

OTHER TYPES OF SUGAR INTOLERANCES Inability to properly digest other types of saccharides can produce symptoms similar to those caused by lactose intolerance. For this reason, it may be necessary to investigate other types of sugar intolerances, especially in patients whose clinical test results do not support a diagnosis of lactose intolerance.

Fructose Fructose is a monosaccharide used as a sweetener in many soft drinks and is present in a number of fruits. Individuals with fructose malabsorption may suffer symptoms similar to lactose intolerance.

Sucrose Sucrose is common table sugar. Sucrase is needed to hydrolyze sucrose into glucose and fructose. If carbohydrate malabsorption symptoms exist but lactose testing results are negative, sucrose intolerance should be considered.

Maltose Maltose is contained in some foods, particularly grains. Maltase is necessary to hydrolyze maltose into two

Lactose Intolerance Testing

Although lactose intolerance is one of the most common GI disorders seen by primary care physicians, it remains underdiagnosed, especially when it overlaps or coexists with other conditions that have a similar clinical presentation. On the other hand, lactose intolerance may be erroneously diagnosed because of

improper diagnostic procedure. In this case, calciumrich dairy foods may be unnecessarily eliminated from the diet, raising the risk of osteoporosis, heart disease, and colon cancer. The majority of the world’s population is lactase deficient. However, lactose intolerance may not develop in all of these individuals. A comprehensive evaluation that incorporates diagnostic testing, the patient’s nutritional history, and the relationship between diet and GI symptoms is necessary for an accurate diagnosis. Breath testing for a change in hydrogen/methane production after a lactose challenge is the diagnostic method of choice.

1. Vemia P, Di Camillo M, Marinaro V. Lactose malabsorption, irritable bowel syndrome and self-reported milk intolerance. Dig Liver Dis 2001;33234-239. 2. Rusynyk RA, Still CD. Lactose intolerance. J Am Osteopath Assoc 2001;101:s10-12. 3.Moore BJ. Dairy foods: are they politically correct? Nutr Today 2003;3882-90. 4. Vemia P, Camillo MD, Marinaro V, Caprilli R. Effect of predominant methanogenic flora on the outcome of lactose breath test in irritable bowel syndrome patients. Eur J Clin Nutr 2003;57: 1116-1119. 5. Enattah NS, Sahi T, Savilahti E, et al. Identification of a variant associated with adult-type hypolactasia. Nat Genet 2002;30: 233-237. 6. Aurisicchio LN, Pitchumoni CS. Lactose intolerance: recognizing the link between diet and discomfort. Postgrad Med 1994;95:113116, 119-120. 7.Srinivasan R, Minocha A. When to suspect lactose intolerance: symptomatic, ethnic, and laboratory clues. Postgrad Med 1998;104 109-111,115-116,122-123. 8.Zaman A. Imtable bowel syndrome. Clin Cornerstone 2002;4 22-33. 9. Gremse DA, Nguyenduc GH et al. Irritable bowel syndrome and lactose maldigestion in recurrent abdominal pain in childhood. South Med J 1999;92:778-781. 10. Vemia P, Ricciardi MR, Frandina C, et al. Lactose malabsorption and irritable bowel syndrome: effect of a long-term lactose-free diet. Ital J Gastroenterol 1995;27117-121. 11. Rana SV, Mandal AK, Kochhar R, et al. Lactose intolerance in different types of irritable bowel syndrome in north Indians. Trop Gastroenterol2001;22:202-204. 12. Berkow R, Fletcher AJ, eds. The Merck manual, ed 16. Rahway, J: Merck, 19922322-830. 13. Keshavarzian A, Iber FL, Dangleis MD, Comish R. Intestinal-transit and lactose intolerance in chronic alcoholics. Am J Clin Nutr 1986;44:70-76. 14. Henriksson R, Franzen L, Sandstrom K, et al. Effects of active addition of bacterial cultures in fermented milk to patients with chronic bowel discomfort following irradiation. Support Care Cancer 1995;3:81-83. 15. von Tirpitz C, Kohn C, Steinkamp M, et al. Lactose intolerance in active Crohn’s disease: clinical value of duodenal lactase analysis. J Clin Gastroenterol2002;34:49-53. 16. Kanabar D, Randhawa M, Clayton P. Improvement of symptoms in infant colic following reduction of lactose load with lactase. J Hum Nutr Diet 2001;14359-363.

17. Moore DJ, Robb TA, Davidson GP. Breath hydrogen response to milk containing lactose in colicky and noncolicky infants. J Pediatr 1988;113:979-984. 18. Gremse DA, Greer AS, Vacik J, DiPalma JA. Abdominal pain associated with lactose ingestion in children with lactose intolerance. Clin Pediatr 2003;42:341-345. 19. Murphy MS, Sood M, Johnson T. Use of the lactose H2breath test to monitor mucosal healing in coeliac disease. Acta Paediatr 2002;91:141-144. 20. Saavedra JM, Perman JA. Lactose malabsorption and intolerance. In Dulbecco R, ed. Encyclopedia of human biology. New York Academic Press, 1991. 21. Peuhkuri K, Vapaatalo H, Korpela R, Teuri U. Lactose intolerance: a confusing clinical diagnosis. Am J Clin Nutr 2000;71:600-602. 22. Suarez FL, Adshead J, Fume JK, Levitt MD. Lactose maldigestion is not an impediment to the intake of 1500 mg calcium daily as dairy products. Am J Clin Nutr 1998;68:1118-1122. 23. Yang Y, He M, Cui H, et al. The prevalence of lactase deficiency and lactose intolerance in Chinese children of different ages. Chin Med J (Engl) 2OOO;1131129-1132. 24.Rizkalla SW, Luo J, Kabir M, et al. Chronic consumption of fresh but not heated yogurt improves breath-hydrogen status and short-chain fatty acid profiles: a controlled study in healthy men with or without lactose maldigestion. Am J Clin Nutr 2000;7214741479. 25. Szilagyi A. Review article: lactose: a potential prebiotic. Aliment Pharmacol Ther 2000;161591-1602. 26. Segal I. Physiological small bowel malabsorption of carbohydrates protects against large bowel diseases in Africans. J Gastroenterol Hepatol2002;17249-252. 27. Bahna SL. Cow’s milk allergy versus cow milk intolerance. Ann Allergy Asthma Immunol2002;8956-60. 28.Park YK, Yetley EA, Calvo MS. Calcium intake levels in the United States: issues and considerations. Available online at http://mjao.org/ docrep/W7336T/w7336t06.htm 29.Lipkin M, Newmark H. Calcium and the prevention of colon cancer. J Cell Biochem Suppl1995;22:65-73. 30. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997;3361117-1124. 31. Griffith LE, Guyatt GH, Cook RJ, et al. The influence of dietary and nondietary calcium supplementation on blood pressure: an updated metaanalysis of randomized controlled trials. Am J Hypertens 1999;1284-92. 32. Lupton JR. Dairy products and colon cancer: mechanisms of the protective effect. Am J Clin Nutr 1997;66:1065-1066.

molecules of glucose. If carbohydrate malabsorption symptoms exist but lactose testing results are negative, maltose intolerance should be considered.

SUMMARY

Supplementary Diagnostic Procedures 33. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med 1999;340:101-107. 34. Holt PR, Atillasoy EO, Gilman J, et al. Modulation of abnormal colonic epithelial cell proliferation and differentiation by low-fat dairy foods: a randomized controlled trial. JAMA 1998;280: 10741079. 35. Lipkin M, Newmark H. Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N Engl J Med 1985;313:1381-1384. 36. Montes RG, Perman JA. Lactose intolerance. Pinpointing the source of nonspecific gastrointestinal symptoms. Postgrad Med 1991;89 175-178,181-184. 37. Newcomer AD, McGill DB, Thomas PJ, Hofman AF. Prospective comparison of indirect methods for detecting lactase deficiency. N Engl J Med 1975;2931232-1236. 38. Brummer RJ, Armbrecht U, Bosaeus I, et al. The hydrogen (HJ breath test. Sampling methods and the influence of dietary fibre on fasting level. Scand J Gastroenterol 1985;201007-1013. 39. Zhong Y, Yin W, Huang C, Vonk RJ. [Study on the expired gas of subjects with lactose intolerance by using H,/13C02 breath test]. Wei Sheng Yan Jiu 200231:180-183. 40.Metz G, Jenkins DJ, Peters TJ,et al. Breath hydrogen as a diagnostic method for hypolactasia. Lancet 1975;1(7917):155-157. 41.Lerch MM, Rieband HC, Feldberg W, Matem S. Concordance of indirect methods for the detection of lactose malabsorption in diabetic and nondiabetic subjects. Digestion 1991;48:81-88. 42. Barillas-Mury C, Solomons NW. Test-retest reproducibility of hydrogen breath test for lactose maldigestion in preschool children. J Pediatr Gastroenterol Nutr 1987;6281-285. 43. Barillas-Mury C, Solomons NW. Variance in fasting breath hydrogen concentrations in Guatemalan preschool children. J Pediatr Gastroenterol Nutr 1987;6:109-113. 44. Solomons NW, Barillas C. The cut-off criterion for a positive hydrogen breath test in children: a reappraisal. J Pediatr Gastroenterol Nutr 1986;5:920-925. 45. Hamilton LH. Breath tests and gastroenterology. Milwaukee: QuinTron Instruments Company, 1998. 46.Tormo R, Bertaccini A, Conde M, et al. Methane and hydrogen exhalation in normal children and in lactose malabsorption. Early Hum Dev 2001;65(Suppl):S165-172. 47. Montes RG, Saavedra JM, Perman JA. Relationship between methane production and breath hydrogen excretion in lactose-malabsorbing individuals. Dig Dis Sci 1993;38445-448. 48. Bond JH, Levitt MD. Quantitative measurement of lactose absorption. Gastroenterology 1976;70:1058-1062. 49. Kolars JC, Levitt MD, Aouji M, Savaiano DA. Yogurt: an autodigesting source of lactose. N Engl J Med 1984;3101-3. 50. Robb TA, Davidson GP. Two-hour lactose breath hydrogen test. J Pediatr Gastroenterol Nutr 1987;6481-482. 51.Levitt MD. Production and excretion of hydrogen gas in man. N Engl J Med 1969;281:122-127. 52. Newcomer AD. Screening tests for carbohydrate malabsorption. J Pediatr Gastroenterol Nutr 19843:6-8.

53. Jain NK, Patel VP, Pitchumoni CS. Efficacy of activated charcoal (AC) in reducing intestinal gas: a double blind clinical trial. Am J Gastroenterol 1986;81:532-535. 54. Cloarec D, Bomet F, Gouilloud S, et al. Breath hydrogen response to lactulose in healthy subjects: relationship to methane producing status. Gut 1990;31:300-304. 55. Fritz M, Siebert G, Kasper H. Dose dependence of breath hydrogen and methane in healthy volunteers after ingestion of a commercial disaccharide mixture, Palatini. Br J Nutr 1985;54389-400 56. Behall KM, Scholfield DJ, van der Sluijs AM, Hallfrisch J. Breath hydrogen and methane expiration in men and women after oat extract consumption. J Nutr 1998;128:79-84. 57. Behall KM, Howe JC. Breath-hydrogen production and amylose content of the diet. Am J Clin Nutr 1997;65:1783-1789. 58.Kondo T, Nakae Y. Breath hydrogen and methane excretion produced by commercial beverages containing dietary fiber. J Gastroenterol 1996;31:654658. 59. Rosenthal A, Solomons NW. Time-course of cigarette smoke contamination of clinical hydrogen breath-analysis tests. Clin Chem 1983;29:1980-1981. 60.Solomons N. Evaluation of carbohydrate absorption: The hydrogen breath test in clinical practice. Clin Nutr J 1984;371-78. 61.Lerch MM, Rieband HC, Feldberg W, Matem S. Concordance of indirect methods for the detection of lactose malabsorption in diabetic and nondiabetic subjects. Digestion 1991;48:81-88. 62. Gilat T, Ben Hur H, Gelman-Malachi E, et al. Alterations of the colonic flora and their effect on the hydrogen breath test. Gut 1978;19602-605. 63. Solomons NW, Garcia R, Schneider R, et al. H2 breath tests during diarrhea. Acta Paediatr Scand 1979;68:171-172. 64. Vogelsang H, Ferenci P,Frotz S, et al. Acidic colonic microclimate possible reason for false negative hydrogen breath tests. Gut 1988;29:21-26. 65.Perman JA, Modler S, Olson AC. Role of pH in production of hydrogen from carbohydrates by colonic bacterial flora: studies in vivo and in vitro. J Clin Invest 1981;67643-650. 66. Kerlin P, Wong L. Breath hydrogen testing in bacterial overgrowth of the small intestine. Gastroenterology 1988;95982-988. 67. Romagnuolo J, Schiller D, Bailey RJ. Using breath tests wisely in a gastroenterology practice: an evidence-based review of indications and pitfalls in interpretation. Am J Gastroenterol 2002;97 1113-1126. 68. Perman JA, Modler S. Glycoproteins as substrates for production of hydrogen and methane by colonic bacterial flora. Gastroenterology 1982;83:388-393. 69. Perman ]A, Modler S, B a n RG, Rosenthal P. Fasting breath hydrogen concentration: normal values and clinical application. Gastroenterology 1984;87:1358-1363. 70. Kerlin P, Wong L, Harris B. Lactose tolerance despite hypolactasia in adult celiac disease. Gastroenterology 1986;901491. 71. Vonk RJ, Lin Y, Koetse HA, et al. Lactose (ma1)digestionevaluated by the '.T-lactose digestion test. Eur J Clin Invest 2000;30140-146.

Metal Toxicity: Assessment of Exposure and Retention David W. Quig, PhD CHAPTER C O N T E N T S Introduction 263 Assessment of Toxic Metal Exposure 264 Hair Elemental Analysis 264 Blood Analysis: Toxic Metal Exposure 265 Blood Analysis: Biomarkers of Toxic Effects 266 Urinalysis of Toxic Metals: Unprovoked 266 Urinalysis: Biomarkers of Renal Toxicity 267

DMPS 267 DMSA 269 Nonpharmaceutical Agents

270

Fecal Metals Analysis 270 Conclusion 271

Assessment of Retention: Urinalysis, Provocation Tests 267 EDTA 267

INTRODUCTION The incidence of high-level exposure to toxic metals and resultant acute "poisoning" is relatively rare, most commonly associated with occupational exposure, and the associated symptoms are well defined and accepted in the conventional medical and toxicology arenas. A plethora of published research has clearly defined many of the precise biochemical mechanisms by which specific metals elicit a vast array of adverse physiologic effects that can culminate in neurotoxicity, nephrotoxicity, cardiovascular and pulmonary disease, cancer, teratogenicity, and dysregulation of immune function. Despite knowledge of the effects of metals on the most basic biochemical processes that affect human health, the concept that "subthreshold" levels of metals in the body can negatively affect health and daily functioning is not generally accepted by the dominant medical community. However, with respect to lead, mercury, and cadmium, a consultant to the National Institute of Environmental Health Sciences stated that the margin between the levels of exposure for people in industrialized nations and the levels of exposure that are currently recognized as producing the lowest adverse effect levels is The methods for assessing metal toxicity established as standards for medical practice are best suited for

detection of acute metal poisoning or recent or ongoing exposure but do not provide an accurate determination of the actual levels of metals that have accumulated in the body over extended periods. The purpose of this chapter is to provide an overview of the various traditionally accepted and other laboratory tests for the assessment of (a) exposure to toxic metals and (b) the net retention and physiologic impact of toxic metals. It is beyond the scope of this chapter to discuss the sources and symptoms associated with long-term exposure to the most commonly encountered metals. Thorough reviews of these topics have been published el~ewhere.~~ The most commonly encountered toxic metals (mercury, lead, cadmium, and arsenic) are natural constituents of the earth's crust, but their increasing abundance in air, water, and surface soil results primarily from industrial demand and energy production (pollution).Consequently the environment today has become contaminated to the point that we are all, regardless of occupation, at higher risk for at least long-term, low-level exposure to toxic metals. However, consistent with the basic principles of toxicology, confirmation of exposure is by no means valid documentation of clinically significant retention and toxicity. For a given individual, toxicity is exhibited only when the level of retention exceeds physiologic 263

Supplementary Diagnostic Procedures tolerance, and net retention (body burden) is determined by the relative rates of toxic metal assimilation and excretion. Two important concepts that have been largely overlooked with respect to metal toxicity may explain the discrepancies of opinion expressed by practitioners of traditional medicine and preventive medicine. The first is the potential for the combined effects of multiple toxic metals, which can have not only additive but also synergistic adverse physiologic effects! This concept should be further extended to include consideration of the potential combined effects of toxic chemicals and toxic metals, the total toxic load. The broad heading of toxic chemical entities includes not only naturally occurring and synthetic exogenous compounds but also noxious endogenous compounds derived from a severely dysbiotic or poorly functioning gastrointestinal (GI) system. The second is the remarkable individual variability in susceptibility or tolerance to toxic metals. Established precedence for the phenomena has been provided by such observations as the rapid contact allergic response that is elicited by mercury in a small percentage of a population? Individual variability in susceptibility is likely determined in part by genetic polymorphisms, nutritional status, and the total toxic l ~ a d . ~The , ' ~factors of multiple toxins and individual variability impede simple interpretation of any test result for an individual patient. No single perfect test is available for the diagnosis of chronic metal toxicity; any test result must be interpreted in conjunction with a thorough review of a patient's physical findings, exposure history, and symptoms. However, the symptoms associated with a chronic, low rate of toxic metal retention appear to be diverse and rather nondescript, and they may not be fully expressed until later in life. Clear examples of such latency of symptom expression have been provided for lead and hypertension" and cardiovascular mortality.I2 Therefore, to address the needs of clinicians who focus on preventive medicine as opposed to crisis management, the following review of laboratory tests emphasizes testing that has greater sensitivity with respect to detection of chronic "low-level" accumulation of the most commonly encountered toxic metals. In addition, an attempt has been made to distinguish between testing that is most appropriate for assessment of exposure and that for net retention and physiologic impact.

ASSESSMENT OF TOXIC METAL EXPOSURE Hair Elemental Analysis When performed properly, hair elemental analysis can serve as a qualitative screening test for exposure to toxic metals, but because of limitations, it cannot alone be considered a reliable method for the diagnosis of metal

toxicity. Hair is an excretory tissue that can provide a chronologic record of bioavailable trace elements in the body, and the hair content of mercury, arsenic, lead, and thallium has been used as evidence for the cause of death.I3Once metals are incorporated into growing hair there is no back-exchange into the body; therefore the concentration of metals in hair is usually far greater than that in blood or urine. The length of the hair specimen analyzed dictates the duration of time during which exposure occurred, and segmental analysis of hair can be used forensically to estimate the chronologic course of exposure. In situations in which exposure to toxic metals is more or less constant, the relationship between the concentrations in blood and tissues also should remain steady. A study of the lead and mercury content of hair from a long-deceased president of the United States was performed at the Armed Forces Institute of Pathology in Washington, DC,exemphfymg the potential utility of hair analysis for exposure to toxic rnetals.I4Detection of toxic metals in hair actually predates that in blood and urine.15 A growing number of peer-reviewed publications support the value of elemental analysis of hair specimens for the detection of exposure to toxic metals. For example, elevations of arsenic in both hair and urine confirmed arsenic exposure from a pesticide in an individual with peripheral neuropathy and macrocytosis.16Hair levels of lead, manganese, cadmium, and other toxic metals have been correlated with psychological conditions and deviant or violent beha~i0rs.I~ Lead, cadmium, and mercury levels in children's hair has been correlated with childhood intelligence. Hair analysis has been used to identify historical as opposed to current exposure to lead.'* School children with relatively high levels of lead in their hair had slower reaction times and less flexibility in changing their focus of attention than children with relatively low concentrations of lead in hair.19 The Agency for Toxic Substances and Disease Registry (ATSDR), the United States Environmental Protection Agency, and the National Academy of Sciences recognize the scientific validity of hair mercury levels as an indicator of maternal and fetal exposure to methylmercury. In a cognitive performance study of children in the Faroe Islands, there were detectable effects on brain function in the children whose mothers had elevated levels of hair mercury.20History of fish consumption and mercury in hair samples are considered the best indicators of human exposure to methylmercury?] Fish consumption among Scandinavianz and Tyrrhenian men,= Amazonian children," and people from the h4inamata Bay areaz4was positively correlated with hair and blood mercury levels. Note that hair elemental analysis definitely provides useful information about exposure to methylmercury (fish consumption); however, it is not nearly as useful for disclosing information about exposure to inorganic mercury as

Metal Toxicity: Assessment of Exposure and Retention

derived from dental amalgams.” The concentration of methylmercury in hair is about 300 times higher than that in In sharp contrast, about 75%of total hair arsenic is present in the inorganic form.26 Although an increasing number of peer-reviewed reports support the clinical utility of elemental analysis of hair for the assessment of exposure to specific toxic metals, some considerations prevent its acceptance by governmental agencies in the United States. In June 2001, the ATSDR convened a panel of scientists with some expertise in hair analysis or risk assessment to explore ”the state of the science of hair analysis.”27 Overall the discussion was objective and focused on the existing scientific data. A summary statement from the meeting concluded, ”In general, hair analysis results can provide limited qualitative insights into environmental exposures and rarely can answer questions about potential health effects.”28Primary concerns raised by the group pertained to uncertainties about the quantitative relationship among the actual ”internal dose,” the rate of incorporation into hair, and the current lack of wellestablished data to enable one to predict potential health effects for a given concentration of a specific metal in hair. Overinterpretation of the results of elemental analysis of hair is a serious concern shared by science-based laboratories and astute clinicians as well as the ATSDR. It should be kept in mind that the ATSDR has been interested in the use of hair analysis as an initial screening tool for inexpensive exposure biomonitoring of groups of people who are exposed to toxins at suspected sites of contamination. The goal of the ATSDR to be able to use hair elemental analysis as confirmation of toxicity is quite different from the use of the procedure in preventive or comprehensive medicine simply to provide an initial indication of exposure. The consensus report by the ATSDR is consistent with the aforementioned statement that hair analysis can provide some qualitative information about exposure to toxic metals but does not provide a basis for diagnosis of metal toxicity. As such, hair analysis may be helpful to clinicians as a first step toward idenhfying potential health problems that may be associated with toxic metal exposures before significant symptoms are expressed. Further testing should be performed before treatment options are considered. The clinician should be wary of laboratories that perform hair analysis as a vehicle to sell nutritional supplements and should be aware of interlaboratory variation.29Clinicians are recommended to use only laboratories that can validate their certification or accreditation and incorporate state-of-the-art methodologies for washing, digesting, and analyzing hair specAppropriate quality control characteristics and the validation of the establishment of reference ranges, accuracy, precision, and reliability of state of the art hair analysis have been d e s ~ r i b e d . ~ l - ~ ~

Blood Analysis: Toxic Metal Exposure For the most commonly encountered toxic metals, the current standard for diagnosis of metal toxicity is abnormally high concentrations in whole blood or urine. However, blood analysis for toxic metals is a better indicator of exposure than toxiaty in most cases. Distribution of metals such as lead in the body has been long recognized as initially dependent of the rate of delivery via the blood to various tissues and organs.34Subsequent redistribution then depends on the relative affinities of tissues for the metals and toxicodynamics, which can vary markedly among individuals. Tissue affinities for metals is determined in large part by the high relative intracellular concentrations of reduced glutathione and metall~thionein.~~ Further, blood levels can fluctuate considerably with intermittent exposure and assimilation. Thus determination of a single blood metal level does not accurately reflect total body retention, being more useful for assessment of recent or ongoing exposure.36 Examining kinetic models of metal metabolism shows that the blood metal compartment has the shortest biologic half-life. Metals leave the blood by means of excretion (urine, bile, and sweat) and transfer to tissues. The retention by tissues such as bone, kidneys, and brain accounts for the much longer biologic half-lives of most toxic metals in the body. This simple concept has been obviated in studies presented in the Physician’s Desk Reference.37 Adult and pediatric patients who had been diagnosed with lead toxicity on the basis of elevated blood lead values exhibited marked reductions in blood lead levels after chelation therapy with succimer. However, 2 weeks after cessation of chelation, blood lead levels rebounded to 60% to 85% of pretreatment levels (the rebound effect is associated to some degree with all pharmacologic chelators). The relationship between blood lead levels and the quantity of lead excreted after EDTA chelation is nonlinear, in that arithmetic increases in blood lead are associated with exponential increases in lead excretion. The correlation between blood lead and chelatable lead is poor in adults with past exposure.’ Under extreme conditions of massive accumulation of metals (long-term occupational exposure), the equilibrium between the tissue stores and blood can result in blood metal levels that are at or above the established threshold values for the diagnosis of metal toxicity but still do not indicate the extent of total body retention. The current gold standard of blood lead measurement for assessment of lead toxicity in children is disturbing: No minimum response levels have been established for lead because a threshold has yet to be defined for the most sensitive effect of lead, neurot~xicity.~~ Interestingly, fractionization of blood into the plasma versus red blood cell compartments can provide valuable information to the clinician about the primary sources of

exposure to mercury. Approximately 95% of methylmercury, most commonly derived from contaminated fish, is associated with red blood ce11~13~,~ whereas about 90% of inorganic mercury (amalgams, occupational exposure) is found in the plasma compartment bound to albumin, cysteine and nonspecific proteins.40Because the first step in successful detoxification is to remove the source of exposure, documentation of the primary source of exposure to mercury can be instrumental for efficient detoxification. Blood arsenic levels, albeit with a very short half-life (approximately 6 hours), reflect exposure to inorganic arsenic and methylated metabolites of arsenic, but not dietary arsenic (shellfish) that is rapidly excreted in the urine.41,* The analysis of whole blood, plasma, and red blood cells can provide valuable information about exposure to specific forms of some metals without the need for expensive determination of subspeciation.

Blood Analysis: Biomarkers of Toxic Effects Given the dynamic nature of blood lead levels that fluctuate with intermittent exposure, standard medical practice is to further analyze blood for abnormal levels of metabolites of heme biosynthesis to accurately diagnosis lead toxicity. Currently accepted markers of exposure and physiologic impact of lead are elevated blood levels of erythrocyte zinc protoporphyrin (ZPP) and deltaamino-levulinic acid, which is the product of the enzyme aminolevulinic acid dehydrogenase (ALAD). As with any biomarker, signhcant limitations are associated with ZPP and ALAD. For example, as is well known, heme biosynthesis also can be affected by iron deficiency3and by chronic diseases such as alcoholism, cirrhosis, and porphyria.44Further, ZPP has been shown to be insensitive for detection of increased blood lead at the critical threshold (5 to 12 pg/dl) in children and adult women.45 ZPP also may be affected by zinc deficiency. T i i g of sampling also can confound interpretation of ZPP levels. With chronic lead exposure, blood lead appears to peak at 3 to 6 months, whereas peak ZPP levels lag sigruficantlybehind (6 to 9 m0nths).4~Findings of concomitant elevations of blood lead and ZPP are very likely to be good indicators of significant lead exposure associated with adverse effects on heme biosynthesis. However, confounding variables may cause discordance between the levels of the two parameters, and markers for aberrant heme biosynthesis may not be sensitive enough to permit early detection of lead exposure or retention that significantly affects the highly vulnerable central nervous system in children.

Urinalysis of Toxic Metals: Unprovoked In general, and despite the current standards for medical care, urinalysis for toxic metals does not provide a

scientifically valid basis for diagnosis of metal toxicity. However, in some cases it provides an indication of recent or ongoing exposure to certain metals. A 1993 study concluded: Urinary lead is generally not a useful biomarker to estimate low-level exposure to lead. However, elevated urinary lead-chelate complexes resulting from the EDTA mobilization test provide a good means to assess increased lead body burden.46

A different scenario exists for organic arsenic as well as inorganic and organic mercury. The most commonly accepted biomarker for exposure to inorganic mercury is the urinary level of inorganic mercury." However, the World Health Organization (WHO) standard for occupational exposure is very high (50 pg/g creatinine).48 This high standard has been challenged because neurologic impairment has been reported for occupationally exposed s u b j e ~ t swhose ~ ~ s urinary mercury levels were well below the WHO standard. Evidence that urinary mercury levels are indicative of exposure to implanted mercury amalgams has also been p u b l i ~ h e dIn . ~a~study of 1127 Vietnam-era veterans reported by the National Institute of Dental Research, a highly statistically significant correlation was detected between the level of amalgam exposure and urinary mercury levels, albeit mean urinary mercury levels were only about 2 pg/g creatinine. Several other studies have reported an association between amalgam exposure and urinary mercury level^.^^-^^ Elevations of urinary arsenic have been detected in workers during periods of occupational exposure, including copper smelting, spraying of insecticides or herbicides, and application of wood treatments .56 Arsenic can be markedly and transiently elevated in individuals within 48 hours after consumption of shellfish that contain high levels of relatively nontoxic species of organic ar~enic.~' Urinary mercury is frequently elevated in people who consume high levels of fish.2z,58 Therefore, analysis of an unprovoked urine specimen is highly recommended to avoid alarmism and confounding the interpretation of the results of a urinary metals provocation test, and patients should be instructed to abstain from the consumption of fish and shellfish for about a week before a chelation challenge is performed. The elevated urinary values of arsenic and mercury associated with the specific dietary and occupational conditions reflect recent or ongoing high-level exposure but are not necessarily reflective of the body burden of the specific metals. Although blood metal levels reflect transient transport in the body, urinary levels qualitatively reflect excretion of an unknown fraction of the total body pools of assimilated metals.

Metal Toxicity: Assessment of Exposure and Retention

Urinalysis: Biomarkers of Renal Toxicity Toxic metals such as cadmium, mercury, and lead are known to be nephrotoxic at high levels of assimilation. Cadmium is of particular concern because of its exceedingly long residence time in the kidneys.59Therefore, in addition to urine levels of cadmium, urinary biomarkers of renal damage should be assessed for documentation of cadmium toxicity. Early markers of cadmiuminduced renal damage include proteinuria, glucosuria, aminoaciduria, hypercakiuria, and polyuria.60Sensitive urinary biomarkers for more advanced cadmiuminduced tubular damage include elevated levels of the low-molecular-weight protein beta2-microglobulin,retinalbinding protein, and N-acetyl-beta-D-glucosaminidasee (NAG).61Abnormal urinary levels of NAG have also been reported in association with markedly high urinary mercury levels (35 pg/g creatinine) in chlor-alkali workers with long-term exposure to inorganic mercury?* It is noteworthy that the urinary NAG levels were correlated with urinary mercury and integrated dose of exposure but not with concurrently measured blood mercury levels?1 Thus it appears that assessment of urinary biomarkers of renal damage may be useful in the diagnosis of toxicity in cases of very high exposure to cadmium and perhaps mercury. However, negative findings for the renal biomarkers do not exclude the possibility of chronic low-level metal toxicity that is most commonly encountered in general clinical practice.

ASSESSMENT OF RETENTION: URINALYSIS, PROVOCATIONTESTS The best currently available method to estimate the level of retention of toxic metals in the body is urinalysis for toxic metals lifter the administration of a chelating agent. In the 1970s the value of a standardized Ca-Na,-EDTA (Ca-disodiumethylenediaminetetraaceticacid) provocative test was recognized as sensitive to determine the mobile and potentially toxic body lead stores, and to assess response to chelation therapy in pediatric patients with high blood lead levels.- Subsequently, Markowitz and Rosen& described the results of a comparable, yet more convenient test that would permit use in a greater number of qualifymg patients (single versus two intramuscular injections and 8-hour versus 24-hour urine collection). The concept and value of using metal complexing agents to estimate the body burden of readily available tissue depots of other toxic metals have gained increasing acceptance in the United States, and currently, several other chelators are widely used for this purpose. The most commonly used pharmaceutical agents are Ca-Na2-EDTA, DMPS (Dimaval, -(R,S)-2,3-dimercapto-propropane-l sulfonate), and DMSA (meso-2,3-dimercaptosuccinic acid). Nonpharmaceutical compounds that have also

been utilized as potentially useful provocation agents include N-acetyl-cysteine (WAC), potassium citrate, and reduced glutathione. The latter compounds are not chelators by definition and have not been studied extensively?'

EDTA Ca-Na2-EDTA (EDTA) has been approved by the U.S. Food and Drug Administration (FDA) and used intravenously for many years as the provocation agent and therapeutic agent of choice for patients exposed to lead. The compound is also well known to be effective for increasing the urinary excretion of iron, copper, nickel, cadmium, and manganese.68EDTA also has a high affinity for free zinc and, if not used properly, can cause zinc deficiency. The maximum recommended EDTA (50 mg/ kg, 13 g) infusion rate is 1g per hour, and clinicians are strongly encouraged to assess glomerular function before use (EDTA-mobilized metals are excreted in the urine). Before attempting to embark on the safe and effective use of EDTA, clinicians should attend specific training courses offered by the American Board of Clinical Metal Toxicology (formerly the American Board of Chelation Therapy). Although the "fast-push" Ca-Na2-EDTAprotocol that has been recently introduced in the United States appears to be effective for increasing the urinary excretion of it has not been thoroughly evaluated for safety. EDTA is not nearly as effective a chelator of mercury as are the dithiol chelators. Therefore this chapter focuses on the metal complexing agents that are newer to the United States, the dithiol agents DMPS and DMSA. A thorough review of the history and appropriate use of EDTA has been published.68

DMPS DMPS appears to be the most productive agent for the mobilization of mercury, as determined in vitro70and in a comparative study during the Iraqi mercury crisis, in which people were acutely poisoned after consumption of grains contaminated with a methylmercury-containing fungicide.'* More relevant to the typically encountered clinical situation, a DMPS provocation study was conducted with volunteer college students.72Subjects with and without amalgam fillings were given 300 mg DMPS (orally), and all urine was collected over the subsequent 9 hours. DMPS raised mean urinary mercury for the nonamalgam group from 0.27 to 5.1 pg and that of the amalgam group from 0.7 to 17.2 pg over the 9-hour period. A highly significant positive correlation was detected between the amount of mercury excreted after the DMPS challenge and amalgam surface area. An additional study supports the value of provocation testing for people occupationally exposed to mercury vapors. A comparison of urinary mercury levels was

Supplementary Diagnostic Procedures

only from compounding pharmacies for oral and made before and after oral administration of a 300-mg intravenous (IV) or intramuscular injection. Slow infudose of DMPS to dental technicians, dentists, and nonoccupationally exposed controls.53 Unprovoked urine sion (5 to 10 minutes) is recommended when giving mercury levels were comparable for dental technicians DMPS IV (3 to 5 mg/kg, not to exceed 250 mg) to avoid and dentists and were about five times higher than in hypotension. Because DMPS is not an FDA-approved drug but is permitted to be compounded for use by controls. Compared with prechallenge values, DMPS physicians, the clinician is advised to obtain a signed induced urinary mercury (c(g/6 h) increased by a factor of 87,49, and 34 for the technicians, dentists, and controls, informed consent form from each patient before administering DMPS. DMPS is associated with a very low incirespectively. Post-DMPS urinary mercury levels were 16 dence of serious side and its safety in general is and 6 times higher than in controls for the technicians evident from the observations made during the course of and dentists, respectively. The group mean urinary merextensive IV administration (250 mg every 4 hours for cury for the technicians after DMPS was 424 k 85 pg/6 h (to put thisvalue in perspective see Figure 26-1). Baseline 12 consecutive days) in a young woman who had severe arsenic The most commonly reported side urinary coproporphyrin levels, which are biomarkers of effects associated with DMPS are nausea, weakness, veraberrant heme biosynthesis, were significantly correlated tigo, chills, fever, cutaneous reactions/itching, erythema with urinary mercury levels after DMPS but were not multiforme, and elevations of tran~aminases.~~,~~," An correlated with baseline urinary mercury levels. The researchers concluded that post-DMPS urinary mercury extensive review of the German literature about the pharmacokinetics, affinities for various metals, and side levels are better indicators of exposure and retention than effects of DMPS is available.= unprovoked urinary mercury levels. A detailed description of an extensively used oral The pharmacokinetics of DMPS have been well DMPS provocation protocol has been presented," as d e f i ~ ~ e d , 'and ~ , ~the ~ efficacy of DMPS for detoxification well as an intravenous DMPS provocation protocol? of rnerc~ry,'~arsenic,'6 and lead (pediatric)= have been To establish the basal urinary rate of metal excretion, documented. Although DMPS is not approved by the the patient is instructed to fast overnight and to collect a Food and Drug Administration (FDA),it is registered in urine specimen. In the morning, with an empty stomach Germany with the German Drug Regulatory Authorities and is available in the oral form without pre~cription.~~and after the bladder is emptied, the patient is given 300 mg (or 10 mg/kg) DMPS PO, and all urine is collected In the United States, DMPS is available by prescription

H g in 2 Hour Urine (5 m g DMPSlkg BW)

68th Percentile

95th Percentile

70 60

c

0

20 10

0 220

p g Hg per g creatinine

Figure 26-1 Post-DMPS urinary mercury levels. Urinary mercury levels (pug creatine) were determined for patients ( n = 259) who had received 250 mg DMPS (Dirnaval) intravenously.All urine was collected for 2 hours. (From Bass DA. Urek K. Quig D. Clin Chem 1999:45:A164. Poster presented at American Association of Clinical Chemistry Conference, New Orleans, July 1999.)

Metal Toxicity: Assessment of Exposure and Retention

for the subsequent 6 hours.73A light meal (no seafood or fish) may be consumed after about 4 hours, and fluid consumption is encouraged. The specific laboratory instructions should be followed for preserving and shipping the specimen. Equilibrium and stability constants (in vitro) for various DMPSmetal complexes have been presentedn and can be used for guidance. In the clinical setting, DMPS is effective for the mobilization and excretion of bismuth, mercury (organic and inorganic), copper, lead, arsenic, antimony, cadmium, nickel, tin,tungsten, thallium, and gold but does not affect aluminum or uranium excretion. In the vast majority of adult patients, mercury is the predominant metal excreted after DMPS, and elevation of copper is normal. As mercury levels decline during detoxification therapy, it is common to see increased urinary levels of other metals, such as lead, cadmium, and tin,with subsequent challenges. The shifting pattern of metal species excreted is based on a combination of affinities of DMPS for the different metals as well as on mass competition for metal binding sites. There are no well-established guidelines for the interpretation of the results of the DMPS challenge test. Figure 26-1 presents a summary of the distribution of the post-DMPS (5 mg/kg, IV) urinary mercury concentrations (pg/g creatinine) for 259 patients who were tested at a clinic in Nevada that specializes in nutritional therapy, homeopathy, and antiaging medicine. Some of the patients presented with fatigue, whereas others were asymptomatic and merely interested in antiaging medicine.78 Most of the patients had dental amalgams. Statistical analysis revealed that in 68% of the patients, urinary mercury concentrations were less than 66 pg/g creatinine, whereas in 5% of this population, values exceeded 145 pg/g creatinine. These data are presented simply to give an indication of the range of values that one might expect to see in clinical practice. Urinary mercury values expressed per gram creatinine are higher in specimens collected from 90 minutes to 2 hours after DMPS infusion than with longer collection times, because the peak rate of mercury excretion occurs about 90 minutes after infusion of DMPS." Conclusions about toxicity cannot be made from the DMPS test results alone. Consideration has to be given to the overall medical examination, medical and exposure history, and presenting symptoms. If a decision is made to proceed with some form of detoxification therapy, the initial challenge result can serve as a reference point against which subsequent challenge results can be compared to evaluate the efficacy of treatment. Some individuals may be significantly affected at a much lower level of retention than others, and some individuals may be completely asymptomatic at relatively high levels of retention. The levels of other toxic metals also should be considered, and one should note that DMPS does not provide direct information

as to the level of mercury present in the central nervous system. It is beyond the scope of this chapter to discuss protocols for metal detoxification; but it is emphasized that if a pharmaceutical metal complexing agent is to be used, glomerular filtration must be assessed before initiation of chelation therapy. Metals mobilized by DMPS are excreted primarily by the kidney and to a much lesser extent by the liver (biliary/fe~al).~~ A thorough discussion of mercury detoxification protocols based on clinical experience has been pre~ented.~

DMSA Another dithiol metal complexing agent, DMSA, is also widely used for provocation testing, as well as detoxification therapy for lead, mercury species, and other sulfhydryl reactive metals (e.g., arsenic, antimony). Several studies demonstrate the effectiveness of DMSA to increase the urinary excretion of lead and mercury and decrease the blood levels of these metals.79-81 DMSA was approved by the FDA for lead detoxification and is the method of choice for lead detoxification in children and adults. DMSA is available only for oral administration, and only about 20% of orally administered DMSA is systemically available after a single DMSA, when used in conjunction with Ca-Na,-EDTA, increases cumulative urinary lead excretion and ameliorates redistribution of lead and mercury to soft DMSA is restricted to the extracellular ~ o m p a r t m e n tand ~~ does not appear to cross the blood-brain barrier. In rodent models, however, DMSA has been demonstrated to be effective in decreasing the levels of lead and mercury in the brainw Animal studies also indicate greater efficacy of DMSA for lead detoxification when the compound is concomitantly administered with antioxidant^.^^,^ This is probably the case for all metal complexing agents. However, the antioxidants lipoic acid and N-acetylcysteine alone had no effect on lead excretion. To date, no reliable studies have been published to indicate that lipoic acid is an effective metal-binding agent that has a net effect on metal excretion in humans, and the potential for lipoic acid-induced mercury redistribution, particularly to the brain, is a sigruficant con~ideration.~~ DMSA is generally well tolerated with common but mild side effects, including GI bloating/gas, occasional loose stools, and skin rash. Periodic assessment of liver enzyme levels is recommended during the course of extended administration. Compared with DMPS and EDTA, DMSA has minimal effect on essential elements such as copper and zinc, but DMSA is excreted primarily as a mixed disulfide with two molecules of c y ~ t e i n e . ~ ~ Thorough reviews of the pharmacokinetics and clinical use of DMSA have been p r e ~ e n t e d . ~It, ~should ~ , ~ ~be ,~~ noted that there is a tremendous difference between the DMSA protocol described for acute lead poisoning82and that commonly used for chronic low-level lead retention.

Supplementary Diagnostic Procedures

Various protocols for DMSA provocation testing have been suggested?,%The most commonly used protocol in recent years has entailed a daily dosage of 10 mg/kg, PO tid for 3 consecutive days, with a 24-hour urine collection on day 3 (total daily dose of 30 mg/kg). However, a much more convenient and productive provocation protocol has been described that entails giving a single dose of DMSA PO (30 mg/kg) on an empty stomach and collection of all urine for the subsequent 6 hours.67The peak rate of excretion of mercury occurred after about 3 hours. The protocol is well tolerated, enhances compliance, and significantly reduces exposure to the compound. However, the potential for a single large dose of DMSA to leave behind some metals that have been mobilized but not excreted should be considered. It may be wise to continue to give DMSA at the standard treatment dose of 10 mg/kg tid for the next day or two to "clean up" metals that may have been left behind. Patients should be advised in advance that their urine will transiently have a foul, sulfurous odor.

Nonpharmaceutical Agents Nonpharmaceutical compounds, such as N-acetyl-L-cysteine (N-AC) and potassium citrate (K-citrate)have been tested for efficacy as provocation agents for mercury in one published study.67 Urinary mercury levels, expressed as pg/l, were compared before and after a single oral dose of N-AC (30 mg/kg), K-citrate (5 g in 200 ml water), DMSA (30 mg/kg), or DMPS (Unithiol, 250 mg in 5 ml water). Basal urinary mercury levels (about 5 pg/l) were comparable for all of the treatment groups, each of which contained 16 to 65 polysymptomatic subjects. All subjects either had dental amalgams or had recently undergone removal of amalgams. Urine was collected for 3 hours after the challenge compounds were given, except that urine was collected for only 2 hours after the DMPS. The different collection time for the DMPS prohibits valid comparisons of the effects of the other agents with that of DMPS. The high bolus doses of N-AC and K-citrate significantly increased urinary mercury, by 131%and 83%,respectively, compared with basal values. Under these conditions of different collection times, DMSA and DMPS increased mercury excretion by 163% and 135%, respectively. No mention was made of the urine volumes associated with the different test groups, and clearly, the data would have been easier to interpret had the results been standardized per gram urinary creatinine. Grossly misleading values for urinary metals can be associated with expression of excreted metals because concentration per unit volume of urinary output can vary considerably. No other data are currently available to permit further evaluation of the value of the nonpharmaceutical compounds as provocation agents. These two compounds also should be tested in animal models to determine

whether they are associated with sigruficant redistribution of metals among various tissues, because neither is a true chelator and their stability constants are likely to be low. Currently, no definitive studies are available to assess the utility of either orally or parentally administered reduced glutathione as a metal complexing agent, although the compound is being used for that purpose. A final note about other routes of administration of various authentic and potential metal detoxification agents, particularly with respect to provocation testing: The author is not able to find any published research addressing the systemic bioavailability or efficacy of any agent that is given as a rectal suppository or via a transdermal delivery system. Such methods of administration are currently being used, and they may or may not be effective. Clearly, additional clinical studies should be performed before sound conclusions can be made.

FECAL METALS ANALYSIS Several toxic metals, including mercury, lead, and cadmium, are naturally excreted primarily or partially in the bile. Therefore under certain conditions analysis of fecal metals, without provocation, may provide at least qualitative information about the rate of biliary excretion of assimilated metals. However, contaminated foods present a significant source of exposure to metals, and metals that have not been assimilated by the GI tract can contribute to a significant percentage of the total amount of metals measured in a fecal specimen. In addition to dietary contamination, fecal mercury is very much influenced by the amount of mercury that is present in the mouth in the form of mercury amalga1ns.9~ Fecal mercury concentrations,expressed per gram of dry weight, are roughly an order of magnitude higher in people who have an average of six to eight mediumsized amalgams than in individuals who are amalgam free.95Day-to-day variability in fecal mercury levels in amalgam bearers who do not consume fish are remarkably reproducible. Fecal mercury levels are highly correlated with the number of amalgams (Figure 26-2). Further it has been demonstrated that fecal mercury levels decline significantly after extraction of amalgams.96 Therefore levels of fecal metals generally are more a representation of exposure to metals than an indication of total body retention or toxicity. Current research efforts are focusing on the identification of metal complexing agents that increase the biliary or fecal excretion of metals. To date no such agent or phytonutrient has been identified. Preliminary evidence suggests that high-dose vitamin C (50 g) given intravenously may markedly enhance the biliary excretion of lead and mercury97; however, additional studies are needed. Fecal metals have been analyzed for autistic children ( 1 1 = 54), and on average they are higher compared

Metal Toxicity: Assessment of Exposure and Retention

Conc. (PPW

Number of amalgams Figure 26-2 Fecal mercury levels versus the number of dental amalgams. Fecal mercury (pglkg dry weight) was plotted against number of amalgams for 200 subjects. (From Bass DA. Urek K. Quig D. Clin Chem 1999;45:A164. Poster presented at American Association of Clinical Chemistry Conference, New Orleans, July 1999.)

Summary of the potential value of hair analysis Urine (retention) Metallmetalloid

Hair (exposure)

No provocation

DMSA

DMPS

Ca-Na,-EDTA

Aluminum

Fair

Poor

Poor

Poor

Fair, best with deferoxamine

Antimony Arsenic

Good Good

Poor Poor

Good Good

Good Excellent

Good Poor

Cadmium

Fair

Poor

Fair

Fair

Good

Lead

Good

Poor

Good

Good

Excellent

Inorganic mercury

Poor to fair

Poor

Excellent

Excellent

Poor

Organic mercury

Excellent

Poor

Excellent

Excellent

Poor Good

Nickel

Poor

Poor

Fair

Fair

Tin

Poor

Good

Good

Good

Iron

Poor

Poor Poor

Poor

Poor

Good, best with deferoxamine

Tungsten

?

Poor

Fair

Fair

Poor

Uranium

Excellent

Poor

Poor

Poor

?, Poor

~~~~~~~~~

Summary of the potential value of hair analysis (exposure), and the most commonly used provocation agents used in conjunction with urinalysis for the detection of retention of specific metals. It is emphasized that retention is not necessarily associated with overt toxicity. The qualitative guidelines are based on the authors' perception of affinities, in vivo, derived from examination of thousands of test results, and stability constants as determined under highly defined conditions in vitro. The information provided does not include the potential use of adjunctive agents/protocols and does not cover all known metal complexing agents.

with age-matched, nonautistic controls (n = 83).98The reason for the higher levels in association with autism is not known, and pica is a possible issue that may contribute to higher levels of exposure in autistic patients.

CONCLUSION Chronic, low-level exposure to environmental toxins is a growing global problem, and evidence is accumulating to link the bioaccumulation of toxic metals in humans to subtle and overt health effects. Increasing numbers of patients dissatisfied with the care provided by clinicians who rely only on methods for the assessment of acute

metal poisoning are seeking out progressive clinicians who are more aware of the value of tools that are yet to be accepted for the assessment of subacute metal toxicity. Analyses of metals in hair, blood, and urine all have advantages and disadvantages, and no single test is likely to enable unequivocal diagnosis of low-level metal toxicity. However, consideration of the results of the various tests discussed in this chapter as well as a complete medical examination and exposure history can be used to design a comprehensive therapeutic detoxification program that is likely to provide signtficant relief for the patient. Table 26-1 provides an overview of value of the various tests for assessing a patient's problem with metals.

Supplementary Diagnostic Procedures

1. Goyer R. Chelation of toxic metals: current interests. Env Health Persp 1995;103:98&989. 2. Goyer RA, Cherian MG, Jones MM, et al. Role of chelating agents for prevention, intervention, and treatment of exposures to toxic metals. Env Health Persp 1995;11:1048-1341. 3. Patrick L. Mercury toxicity and antioxidants. Part I. Role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity. Altern Med Rev 2002;7456-471. 4. Patrick L. Toxic metals and antioxidants. Part II. Arsenic and cadmium toxicity. Altern Med Rev 2003;8:106-128. 5. Crinnion WJ. Environmental medicine. Part III. Long-term effects of chronic mercury exposure. Altern Med Rev 2000;5:209-223. 6. Q u g D. Cysteine metabolism and metal toxicity. Altern Med Rev 1998;3262-270. 7. Grandjean P. International perspectives of lead exposure and lead toxicity. Neurol Toxicol 1993;14:9-14. 8. Schubert J, Riley EJ, Tyler SA. Combined toxic effects in toxicology, rapid systematic testing procedure: cadmium, mercury and lead. J Toxicol Environ Med 1978;4763-776. 9. Finne K, Goransson K, Winkler L. Oral lichen planus and contact allergy to mercury. Int J Oral Surg 1982;11:236-239. 10. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1993:134. 11. Nash D, Magder L, Lustberg M, et al. Blood lead, blood pressure, and hypertension in perimenopausal women. JAMA 2003;289:1523-1532. 12. Lustberg M, Silbergeld E. Blood lead levels and mortality. Arch Intern Med 2002;1622443-2449. 13. Bencze K. Determination of metals in human hair. In Seiler HG, Sigel A, Sigel H, eds. Handbook on metals in clinical and analytical chemistry. New York Dekker, 1994:214. 14. Deppisch LM, Centeno JA, Gemmel DJ, et al. Andrew Jackson’s exposure to mercury and lead: poisoned president? JAMA 1999;282:569-571. 15. Bencze K. Determination of metals in human hair. In Seiler HG, Sigel A, Sigel H, eds. Handbook on metals in clinical and analytical chemistry. New York Dekker, 1994:202. 16. Heaven R, Duncan M, Vukelja S. Arsenic intoxication presenting with macrocytosis and peripheral neuropathy, without anemia. Acta Haematol1994;92:142-143. 17.Rose J, ed. Environmental toxicology. New York Gordon and Breach, 1997. 18. Marlow M, Vukelja S. Correlations of metal-metal interactions as measured in hair on childhood intelligence. J Advancement Med 1988;1:195-203. 19. Minder B, Das-Smaal EA, Brand EF, et al. Exposure to lead and specific attentional problems in school children. J Learn Disabil 1994;27393-399. 20. Grandjean P, Weihe P, White RF, et al. Cognitive performance of children prenatally exposed to “safe” levels of methylmercury. Environ Res 1998;77:165-172. 21. Malm 0, Branches FJ, Akagi H, et al. Mercury and methylmercury in fish and human hair from the Tapajos river basin, Brazil. Sci Total Environ 1995;175141-150. 22. Salonen JT, Seppanen K, Nyssonen K, et al. Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in eastern Finnish men. Circulation 1995;91:646-655. 23. HoLsbeek L, Das HK, JoirisCR Mercury in human hair and relation to fish consumption in Bangladesh. Sci Total Environ 1996;186: 181-188. 24. Harada M, Nakanishi J, Kunuma S. The present mercury contents of scalp hair and clinical symptoms in inhabitants of the Minamata area. Environ Res 1998;77:160-164.

25. Phelps RW, Clarkson TW, Kershaw TG, et al. Interrelationships of blood and hair mercury concentrations in a North American population exposed to methylmercury. Arch Environ health 1980;35:161-168. 26. Yamato N. Concentration and chemical species of arsenic in human urine and hair. Bull Environ Contam Toxicol 1988;40: 633-640. 27. Eastern Research Group. Hair Analysis Panel discussion: exploring the state of the science. Lexington, MA: Agency for Toxic Substances and Disease Registry, 2001. 28. Agency for Toxic Substances and Disease Registry (ATSDR). Document 03-0330: Hair Sampling Testing-Scientific. PM65. Available online at: http://www.atsdr.cdc.gov/hir-analysis. 29. Seidel S, Kreutzer R, Smith D, et al. Assessment of commercial laboratories performing hair mineral analysis. JAMA 2001;285: 67-72. 30.Steindel SJ, Howanitz PJ. The uncertainty of hair analysis for trace metals. JAMA 2001;28583-85. 31. F’uchyr RF, Bass DA, Gajewski R. Preparation of hair for measurement of elements by inductively coupled mass spectrometry (ICP-MS).Biol Trace Elem Res 1998;62167-182. 32. Bass DA, Hickok D, Quig D, et al. Trace element analysis in hair factors determining accuracy, precision, and reliability. Altem Med Rev 2001;6:472481. 33. Druyan ME, Bass DA, Puchyr R, et al. Determination of reference ranges for elements in human scalp hair. Biol Trace Elem Res 1998;62183-197. 34. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1993100. 35. Sanders BM, Goering PL, Jenkins KJ. The role of general and metal-specific cellular responses in protection and repair of metal-induced damage: stress proteins and metallothioneins. In Chang LW, ed. Toxicology of metals. New York CRC Press, 1996165-187. 36. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1993:ll. 37. Physicians desk reference, ed 54. Montvale, NJ:Medical Economics, 2000. 38. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: U.S. Department of Health and Human Services, Public Health Service, 1993:108. 39. Gehardsson L, Skerfving F. Concepts on biological markers and biomonitoring for metal toxicity. In Chang L, ed. Toxicology of metals. New York CRC Press, 199681-110. 40.Ishihari N. Inorganic and organic mercury in blood, urine and hair in low level mercury vapor exposure. Int Arch Occup Environ Health 1978;40249-253. 41. Foa V, Colombi A, Maroni M, et al. The speciation and chemical forms of arsenic in the biological monitoring of exposure to inorganic arsenic. Sci Total Environ 1984;34:241-259. 42. Iffland R. Arsenic. In Seiler HG, Sigel A, Sigel H, eds. Handbook on metals in clinical and analytical chemistry. New York Dekker, 1994243. 43. Hastka J, Lasserre JJ, Schwarzbeck A. Zinc protoporphyrin in anemia of chronic disorders. Blood 1993;81:1200-1204. 44. Somashekaraiah BV, Venkaiaha B, Prasad AR. Biochemical diagnosis of occupational exposure to lead toxicity. Bull Environ Contam Toxic01 1990;44:268-275. 45. Lueng FY, Bradley C, Pellar TG. Reference intervals for blood lead and evaluation of zinc protoporphyrin as a screening test for lead toxicity. Clin Biochem 1993;26491496.

Metal Toxicity: Assessment of Exposure and Retention 46. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for lead. Atlanta: US.Department of Health and Human Services, Public Health Service, 1993131. 47. Clarkson TW. Principles of risk assessment. Adv Dent Res 1992;6:22-27. 48. World Health Organization (WHO). Inorganic mercury. Environmental Health Criteria 118. Geneva: World Health Organization, International Program on Chemical Safety, 1991. 49. Echeverria D, Heyer NJ, Martin MD, et al. Behavioral effects of lowlevel exposure to HgO among dentists. Neurotoxicol Teratol 1995;17161-168. 50. Langworth S, Almkvist 0, Soderman E, et al. Effects of occupational exposure to mercury vapour on the central nervous system. Br J Indust Med 1992;49:545-555. 51. Kingman A, Albertini T, Brown LJ. Mercury concentrations in urine and whole blood associated with amalgam exposure in a US military population. J Dent Res 1998;77:461-471. 52. Skare J, Engqvist A. Human exposure to mercury and silver released from dental amalgam restorations. Arch Environ Health 1994;49:384-394. 53. Gonzalez-Ramirez D, Maiorino RM, Zuniga-Charles M. Sodium 2,3-dimercaptopropane-l-sulfonatechallenge test for mercury in humans. 11. Urinary mercury, porphryns and neurobehavioral changes of dental workers in Monterey, Mexico. J Pharmacol Exper Ther 1995;272264-274. 54. Schweinsberg F. Risk estimation of mercury intake from different sources. Toxicol Lett 1994;72:345-351. 55. Begerow J, Zander D, Freier I, et al. Long-term mercury excretion in urine after removal of amalgam fillings. Int Arch Occup Environ Health 1994:66209-212. 56. Apostoli P, Bartoli D, Alessio L, et al. Biologicalmonitoring of occupational exposure to inorganic arsenic. Occup Environ Med 1999;56:825-832. 57. Buchet JP, Pauwels J, Lauwerys R. Assessment of exposure to inorganic arsenic following ingestion of marine organisms. Environ Res 1994;66:44-51. 58. National Research Council. Toxicologicaleffects of methylmercury. Washington, DC:National Academy Press, 2000:31-70. 59. Lauwerys R, Bernard A, Roels HA, et al. Cadmium exposure markers as predictors of nephrotoxic effects. Clin Chem 1994;40: 1391-1394. 60. Herber RFM. Cadmium. In Seiler HG, Sigel A, Sigel H, eds. Handbook on metals in clinical and analytical chemistry. New York Dekker, 1994202,289-290. 61. Verschoor M, Herber R, Van Hemmen J, et al. Renal function of workers with low-level cadmium exposure. Scand J Work Environ Health 1987;13:232-238. 62. Barregard L, Hultberg B, Schutz A, et al. Enzymuria in workers exposed to inorganic mercury. Int Occup Environ Health 1988;61:65-69. 63. Centers for Disease Control. Preventing lead poisoning in young children. J Pediatr 1978;93:709-714. 64. Chisolm JJ Jr. Chelation therapy in children with subclinical plumbism. J Pediatr 1974;53:441-449. 65. Chisolm JJ Jr. The use of chelating agents in the treatment of acute and chronic lead intoxication in childhood. J Pediatr 1968; 73~1-15. 66. Markowitz ME, Rosen JF. Assessment of lead stores in children: validation of an 8-hour CaNa2EDTA provocative test. J Pediatr 1984;1O4:337-341. 67. Hibberd AR, Howard MA, Hunnisett AG. Mercury from dental amalgam fillings: studies on oral chelating agents for assessing and reducing mercury burdens in humans. J Nutr Environ Med 1998;8:219-231. 68. Rozema TC. Protocols for chelation therapy. J Adv Med 1997;lO 3-100.

69. Quig DW. Systematic and functional assessment of nutritional status and exposure to toxins. Paper presented at Orthomolecular Health and Medicine Conference, San Francisco, March 2003. 70. Keith RL, Setiarahardojo I, Fernando Q, et al. Utilization of renal slices to evaluate the efficiency of chelating agents for removing mercury from the kidney. Toxicology 1997;11667-75. 71. Clarkson TW, Magos L, Cox C, et al. Tests of efficacy of antidotes for removal of methylmercury in human poisoning during the Iraq outbreak. J Pharmacol Exp Therap 1981;218:74-83. 72. Aposhian HV,Bruce DC,Alter W, et al. Urinary mercury after administration of 2,3-dimercaptopropane-l-sulfonicacid: correlation with dental amalgams. FASEB J 1992;62472-2476. 73. Aposhian HV, Maiorino RM, Gonzalez-Ramirez D, et al. Mobilization of heavy metals by newer, therapeutically useful chelating agents. Toxicology 1995;9723-38. 74. Aposhian HV.DMSA and DMPS: water soluble antidotes for heavy metal poisoning. Ann Rev Toxicol 1983;23:193-215. 75. Campbell JR, Clarkson TW, Omar MD. The therapeutic use of 2,3-dimercaptopropane-l-sulfonate in two cases of inorganic mercury poisoning. JAMA 1986;256:3127-3130. 76. Wax PM, Thorton CA. Recovery from severe arsenic-induced peripheral neuropathy with 2,3-dimercapto-l-propanesulfonic acid. Clin Toxicol 2000;38:777-780. 77. Dimival (DMPS): summary of scientific literature. Houston: Heyltex Corp, 1991:6237-6793. 78. Quig DW, Gerber M. Effects of toxic metals on nutritional status and immune function. Paper presented at American College for Advancement in Medicine Conference, Salt Lake City, UT, October 2000. 79. Graziano JH, Siris ES, LoIacono NJ, et al. 2,3-dimercaptosuccinic acid as an antidote for lead intoxication. Clin Pharmacol Ther 1985;37431-438. 80. Grandjean P, Jacobsen LA, Jorgensen PJ. Chronic lead poisoning treated with dimercaptosuccinic acid. Pharmacol Toxicol 1991;68:266-269. 81. Roels HA, Boeckx M, Ceulemans E. Urinary excretion of mercury after occupational exposure to mercury vapour and influence of the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA). Br J Ind Med 1991;48:247-253. 82. Physicians desk reference, ed 54. Montvale, NJ: Medical Economics, 2000. 83. Lee B, Schwartz BS, Stewart W, et al. Provocation chelation with DMSA and EDTA evidence for differential access to lead storage sites. Occup Environ Med 1995;5213-19. 84. Besunder JB, Super DM, Anderson RL. Comparison of dimercaptosuccinic acid and calcium disodium ethylenediaminetetraacetic acid versus dimercaptopropanol and ethylenediaminetetraacetic acid in children with lead poisoning. J Pediatr 1997;130966-971. 85. Aaseth J. Treatment of mercury and lead poisonings with dimercaptosuccinic acid and sodium dimercaptopropane sulfate. Analyst 1995;120853-854. 86. Jones MM, Singh PK, Kostial K, et al. Comparative in vivo lead mobilization with meso- and rac-2,3-dimercapto-succinicacids in Albino Wistar rats. Pharmacol Toxicol 1997;186:182-186. 87. Gong Z, Evans HL. Effects of chelation with meso-dimercaptosuccinic acid (DMSA) before and after the appearance of lead-induced neurotoxicity in the rat. Toxicol Appl Pharmacol1997;144.205-214. 88. Smith D, Bayer L, Strupp 8. Efficiency of succimer chelation for reducing brain lead levels in a rodent model. Environ Res 1998;78:168-176. 89. Pande M, Mehta A, Pant BP, et al. Combined administration of a chelating agent and an antioxidant in the prevention and treatment of acute lead intoxication.Environ Toxicol Pharmacol2001;9:173-184. 90. Pande M, Flora SJS. Lead induced oxidative damage and its response to combined administration of a-lipoic acid and succimer in rats. Toxicology 2002;177:187-196.

Supplementary Diagnostic Procedures 91. Gregus Z, Stein AF, Varga F, et al. Effect of lipoic acid on biliary exmtion of glutathione and metals. Toxicol Appl Pharmacol 1992;11486-96. 92. Maiorino RM, Aposhian MM, Xu ZF, et al. Determination and metabolism of thiol &elating agents. XV. The meso-2,3-dimercaptosuccinic acid-cysteine (1:2) mixed disulfide, a major urinary metabolite of DMSA in the human, increases the urinary excretion of lead in the rat. J Pharmacol Exp Therap 1993;2671221-1226. 93. Miller A. Dimercaptosuccinic acid (DMSA), a non-toxic, watersoluble treatment for heavy metal toxicity. Altem Med Rev 19983:199-207. 94. Frumkin H, Manning CC, Williams PL, et al. Diagnostic chelation challenge with DMSA: a biomarker of long-term mercury exposure? Environ Health Persp 2001;109:167-171.

95. Bass DA, Urek K, Q u g D. Measurement of mercury in feces. Clin Chem 1999;45:A164.Poster presented at American Association of Clinical Chemistry Conference, New Orleans, July 1999. 96. Bjorkman L, Sandborg-Englund G, Ekstrand J. Mercury in saliva and feces after removal of amalgam fillings. Toxicol Appl Pharmacol1997;144:156-162. 97. Quig D. Metal detoxification: a research based update. Paper presented at the International Oxidative Medicine Association Conference, Westminster, CO, March 2000. 98. Quig D. Mineral status, toxic metal exposure and childrens’ behavior. Paper presented at American Academy of Environmental Medicine Conference, Hot Springs, VA, November 2002.

Mineral Status Evaluation Stephen P. Markus, MD Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Introduction 275 Minerals and Disease 275 Essential Minerals 276 Calcium 276 Chromium 276 Copper 277

INTRODUCTION The importance of trace mineral metabolism has become appreciated only in the past 35 years. Minerals play as important a role as vitamins in the subtle biochemistry of the body. Virtually all reactions in the body require minerals as cofactors. Infinitesimally small amounts of some trace elements may be necessary, but others, such as calcium, make up a quarter of our body weight. Assessment of body status for a particular trace element is extremely difficult (Table27-1 lists recommended methods for the different elements).l For years there has been considerable controversy about hair mineral analysis. Although hair is the most convenient tissue for analyzing minerals, only a limited number of elements in the hair accurately reflect the true body content (see Chapter 20). Others are better measured intracellularly or extracellularly, depending on their state of equilibrium, or in specific cells, such as leukocytes. Many factors, such as specific protein carriers, the ionic charge of the element, and its capacity to be in equilibrium in the blood, affect the usefulness and reproducibility of a specific assay method and the appropriateness of a chosen tissue. Over the last century, with increasing industrialization of our society, our exposure to toxic metals has grown enormously. Hair serves as an excellent source for measurement of continuous cumulative exposure more typical of environmental sources. Hair is biologically stable and can be stored for analysis over a long period without degradation. Hair also concentrates toxic minerals several hundred times higher than blood, allowing for analytical determinationsof ultra-trace quantities. The fact that toxic

Iron 277 Magnesium 277 Manganese 278 Potassium 278 Selenium 278 Zinc 278

Conclusion 279

minerals can have deleterious effects on multiple enzyme systems, neuronal structures, and organs, including the brain, heart, thyroid, liver, kidneys, and skin, at extraordinarily low levels suggests that hair mineral analysis should be an important screening test for many patient^."^

MINERALS AND DISEASE Serum levels of selenium, as well as zinc, copper, magnesium, calcium, and manganese, have been investigated as possible clinical markers and prognostic indicators of various disease states. Patients with cirrhosis have demonstrated low serum selenium, calcium, magnesium, and zinc levels. Those with emphysema and cancer have shown elevated serum copper concentration, and copper and manganese levels are often elevated in congestive heart failure, infection, and pschoses.6Other associations have been observed between trace minerals and cases of breast cancer: gastrointestinalmalignancy,8and malignant ascites? although in other studies, selenium, copper, zinc, and magnesium seem to have no diagnostic value for distinguishing malignant from nonmalignant effusions'O or cervical cancer." Differences in arterial and serum concentrations of calcium, magnesium, zinc, and copper among different types of arterial pathologies have also been documented. Heart tissue levels of selenium, iron, copper, zinc and phosphorus are associated with ejection fraction and cardiac index.12 In men infected with human immunodeficiency virus (HIV), helper T type 4 cells seem closely correlated with serum magnesium c~ncentration.'~ Zinc, magnesium, and 275

Supplementary Diagnostic Procedures Recommended methods for assessing essential mineral status Mineral

Method

Normal range

Calcium

Hair analysis

340-850 pg/g

Chromium

Hair analysis

0.5-1.5 ppm

Copper

Serum copper

0.8-1.5 ppm

Hair analysis

8-22 ppm

Serum iron

0.65-1.75 ppm

Serum ferritin

Male, 27-329 ng/rnl Female, 12-120 ng/ml

Magnesium

Mg retention test Leukocyte Mg

~ The most extreme example of a chronic viral infection is AIDS. Although thymus extracts have not been shown to reverse this difficult disease, studies have shown an ability to improve several immune parameters, including an ability to raise the T-helper cells, a critical goal in AIDS treatment.%

Cancer The primary application of thymus extracts in cancer has been to counteract the immune-suppressing effects of radiation and chemotherapy. The net effect of thymus extract administration is to prevent the tremendous depression of white blood cell levels and activity that result from chemotherapy or

Allergies In patients with allergies, levels of the allergic IgE antibody and eosinophils are typically elevated, while levels of suppressor T-cells are typically depressed. These abnormalities are clear indications of altered immune function. The oral administration of thymus extracts has been shown in double-blind clinical studies to improve the symptoms and course of hay fever, allergic rhinitis, Presumably this asthma, eczema, and food allergies.54*6062 clinical improvement is the result of restoration of proper immune function, as levels of IgE and eosinophils have been shown to be reduced while the ratio of helper to suppressor T-cells has improved. Interestingly, in several clinical studies, children receiving thymus extracts during food allergy elimination diets are often able to tolerate foods that had previously been allergenic and symptom producing.61,62

Autoimmune Disorders Autoimmune disorders, such as rheumatoid arthritis, are characterized by autoimmunity. Central to this immune dysfunction is a high T-helper-to-suppressor cell ratio. A high T-helper-to-suppressor cell ratio results in increased antibody formation. The higher the ratio, the higher the number of antibodies being produced to damage body structures. In one clinical study, rheumatoid arthritis patients with a T-helper-to-suppressor cell ratio of 3.3 achieved normal ratios (1.02 to 2.46) after 3 months of therapy with a thymus extract.54 Although use of a thymus extract may not result in substantial clinical improvement, it appears to be useful in restoring proper immune function in autoimmunediseases including rheumatoid arthritis, lupus, and scleroderma.

Dosage From a practical view, products concentrated and standardized for polypeptide content are preferable to crude preparations. The daily dose should be equivalent to 120mg pure polypeptides with molecular weights less than lO,OOO, or roughly 750 mg of the crude polypeptide fraction. No side effects or adverse effects have been reported with the use of thymus preparations.

Thyroid Extracts

it is nearly impossible to remove all the hormone from the gland. These nutritional thyroid preparations can be considered milder forms of desiccated natural thyroid. The primary use of thyroid preparations is in the medical treatment of hypothyroidism. In all but its mildest forms, treatment involves the use of desiccated thyroid or synthetic thyroid hormone. For more discussion, see Chapter 179.

Dosage Dosage is determined by basal body temperature (see Chapter 179 for directions).

Desiccated natural thyroid is available by prescription according to USP guidelines. Preparations are derived from porcine thyroid glands. Many naturopathic physicians prefer natural thyroid to isolated synthetic T4, as it contains both thyroxine (T4) and tri-iodothyronine (T3). Typical levels of thyroid hormone contained per grain in USP thyroid are 38 pg of T4and 9 pg of T3. The thyroid extracts sold as "nutritional supplements" are required by the FDA to be thyroxine free. However,

From the scientific data that currently exists, there is enough evidence to support the use of orally administered glandular extracts. For best results, physicians should choose glandular products made by reputable companies that employ established methods of manufacture to produce extracts of known concentration.

1.Gardner ML. Gastrointestinal absorption of intact proteins. Annu Rev Nutr 1988;8.329-350. 2. Gardner ML. Intestid assimilation of intact peptides and proteins from the dkt-a neglected field? Biol Rev 198459289-331. 3. Udall JN, Walker WA. The physiologic and pathologic basis for the transport of macromolecules across the intestinal tract. J Pediatr Gastroenterol Nuk 1982;1:295-301. 4. Kleine MW,Stauder GM, Beese EW. The intestinal absorption of orally administered hydrolytic enzymes and their effects in the treatment of acute herpes zoster as compared with those of oral acyclovir therapy. Phytomedicine 1995;27-15. 5. Hemmings WA, Williams EW. Transport of large breakdown products of dietary protein through the gut wall. Gut 1978;19715-723. 6. Ambrus JL, Lassman HB, De Marchi JJ.Absorption of exogenous and endogenous proteolytic enzymes. Clin Pharmacol Ther 1967;8362-368. 7. Kabacoff BB. Absorption of chymotrypsin from the intestinal tract. Nature 1963;199:815. 8.Ormiston BJ. Clinical effects of TRH and TSH after IV and oral administration in normal volunteers and patients with thyroid disease. In Hal R, Werner I, Holgate H, eds. Frontiers of hormone mearch, vol 1.Basel, Switzerland Karger, 1972:45-52. 9. Amos MS, Rivier J, Guillemin R. Release of gonadotrophins by oral administration of synthetic LRF or tripeptide fragment of LRF. J Clin Endocrinol Metab 19729375-177. 1 O . S e i f e r t J. Mucosal permeation of macromolecules and particles. An@ology1966;17505-513. 11. Laskowski M Jr, Haessler HA, Miech RP, et al. Effect of trypsin inhibitor on pasage of insulin across the intestinal barrier. Science 1958;1271115-1116. 12.Britton SW, Silvette H. Further experiments on cortico-adrenal extract. Its efficacy by mouth. Science 1931;74:440-441. 13. Abate G, Berenga A, Caione F, et al. Controlled multicenter study on the therapeutic effectiveness of mesoglycan in patients with cerebrovascular disease. Minerva Med 1991;82101-105.

14. Mansi D, Sinsi L, De Michele G, et al. Open trial of mesoglycan in the treatment of cerebrovascular ischemic disease. Acta N e w 1 (Napoli) 1988;10:10&112. 15. Laurora G, Cesarone SR, De Sanctis MT, et al. Delayed arteriosclerosis progression in high risk subjects treated with mesoglycan. Evaluation of intima-media thickness. J Cardiovasc Surg 19939: 313-318. 16. Vecchio F, Zanchin G, Maggioni F, et al. Mesoglycan in treatment of patients with cerebral ischemia. Effects on hemorheologic and hematochemical parameters. Acta Neurol (Napoli) 1993;15:449-456. 17. De Donato G, Sangiuolo P. [Instrumental evaluation of the effects of mesoglycan in venous disease patients. Prospective randomized double-blind study]. Minerva Med 1986;77:1927-1931. 18. Oddone G, Fiscella GF, De Franceschi T. Assessment of the effects of oral mesoglycan sulphate in patients with chronic venous pathology of the lower extremities. Gazz Med Ital1987;146:111-114. 19. Prandoni P, Cattelan AM, Carta M. [Long-term sequelae of deep venous thrombosis of the legs. Experience with mesoglycan]. Ann Ital Med Int 1989;4:378-385. 20. Sangrigoli V, Carra G, Lazzara N, et al. [Mesoglycan in acute and chronic venous insufficiency of the legs]. Clin Ter 1989;129207-209. 21. Petruzzellis V, Velon A. [Therapeuticaction of oral mesoglycan in the pharmacologic treatment of the varicose syndrome and its complications]. Mherva Med 1985;76543-548. 22. Saggioro A, ChiozziniG, Pallini P, et al. [Treatment of hemorrhoidal crisis with mesoglycan sulfate]. Minerva Dietol Gastroenterol 1985;31:311-315. 23. Stevens RL, Colombo M, GonzalesJJ, et al. The glycosaminoglycans of the human artery and their changes in atherosclerosis. J Clin Invest 1976;58:470-481. 24.Tammi M, Seppala PO, Lehtonen A, et al. Connective tissue components in normal and atherosclerotic human coronary arteries. Atherosclerosis 1978;29:191-194. 25. Day CE, Powell JR, Levy RS.Sulfated polysaccharide inhibition of aortic uptake of low density lipoproteins. Artery 1975;1:126-137.

SUMMARY

Glandular Therapy 26. Postiglione A, De Simone B, Rubba P, et al. Effect of oral mesoglycansulphate on plasma lipoprotein concentration and on lipoprotein concentrationin primary hyperlipidemia.Pharmacol Res Commun 1984;16:1-8. 27. Saba P, Galeone F, Giuntoli F, et al. Hypolipidemic effect of mesoglycan in hyperlipidemic patients. Curr Ther Res 1986;40:761-768. 28. Nakazawa K, Murata K. The therapeutic effect of chondroitinpolysulphate in elderly atherosclerotic patients. J Int Med Res 1978;6 217-225. 29. Nagai K. A study of the excretory mechanism of the liver-effect of liver hydrolysate on BSP excretion. Jpn J Gastroenterol 1970;67 633-638. 30.Ohbayashi A, Akioka T, Tasaki H. A study of effects of liver hydrolysate on hepatic circulation. J Therapy 1972;54:1582-1585. 31. Sanbe K, Murata T, Fujisawa K, et al. Treatment of liver d i s e a s e with particular reference to liver hydrolysates. Jpn J Clin Exp Med 1973;502665-2676. 32. Fujisawa K, Suzuki H, Yamamoto S, et al. Therapeutic effects of liver hydrolysate preparation on chronic hepatitis-a double blind, controlled study. Asian Med J 1984;26497-526. 33. Minter MM. Agranulocytic angina: treatment of a case with fetal calf spleen. Texas State J Med 1933;2338-343. 34.Gray GA. The treatment of apanulocytic angina with fetal calf spleen. Texas State J Med 1933;29366-369. 35. Greer AE. Use of fetal spleen in agranulocytosis.Preliminaryreport. Texas State J Med 1932;28:338-343. 36. Fridkin M, Najjar VA. Tuftsin: its chemistry, biology, and clinical potential. Crit Rev Biochem Mol Biol1989;241-40. 37.Diezel W, Weber HA, Maciejewski J, Volk HD. The effect of splenopentin (DA SP-5) on in vitro myelopoiesis and on AZTinduced bone marrow toxicity. Int J Immunopharmacol 1993;15: 269-273. 38. Rastogi A, Singh VK,Biswas S, et al. Augmentation of human natural killer cells by splenopentin analogs. FEBS Lett 1993;31793-95. 39.Volk HD, Eckert R, Diamantstein T, et al. [Immunorestitutive action of hydrolysates and ultrafiltrates of bovine spleen]. Armeimittelforschung1991;41:1281-1285. 40. He SW. [Effect of splenectomy on phagocyhc function of leukocytes]. Zhonghua Wai Ke Za Zhi 1989;27354-356,381. 41. Spirer Z, Zakuth V, Diamant S, et al. Decreased tuftsin concentrations in patients who have undergone splenectomy.Br Med J 1977; 215741576. 42. Berressem P, Frech S, Hartleb M. Additional therapy with Polyerga improve immune reactivity and quality of life in breast cancer patients during rehabilitation. Tumor Diagnos Ther 1995;16:45-48. 43. Borghardt J, Rosien B, Gortelmeyer R, et al. Effects of a spleen peptide preparation as supportive therapy in inoperable head and neck cancer patients. Armeimittelforschung2000;50:178-184. 44.Maar K. Improvement of the general condition of tumor patients. Erfahrungsheilkunde1998;4760-64. 45. Klose G, Mertens J. Long term results of post-operative treatment of carcinoma of the stomach with Polyerga. Therapiewoche 1977;27 5359-5361. 46.Baier JE,Neumann HA, Taufighi-Chirazi T, et al. Thymopentin, Factor AF2, and Polyerga improve impaired mitogen induced

interferon-g release of peripheral blood mononuclear cells derived from tumor patients. Tumor Diagnos Ther 1994;15:21-26. 47. Zarkovic N, Hartleb M, Zarkovic K, et al. Spleen peptides (Polyerga) inhibit development of artificial lung metastases of murine mammary carcinoma and increase efficiency of chemotherapy in mice. Cancer Biother Radiopharm 1998;13:25-32. 48. Jurin M, Zarkovic N, ILic Z, et al. Porcine splenic peptides (Polyerga) decrease the number of experimentallung metastases in mice. Clin Exp Metastasis 1996;1455-60. R, Portoles P, et al. Polyerga, a biological 49. de Ojeda G, Diez-jas response modifier enhancing T-lymphocyte-dependent responses. Res Exp Med (Berl) 1994;194:261-267. 50. Klingmuller M. Spleen peptides activate natural killer cells. Erfahrungsheilkunde 1999;12:756-759. 51.Vassilev M, Antonov K, Theocharov P, Krastev Z. Effects of low molecular weight glycoproteins in chronic hepatitis B. Hepatogastroenterology1996;43882-886. 52. Hartleb M, Leuschner J. Toxicological profile of a low molecular weight spleen peptide formulation used in supportive cancer therapy. Arzneimittelforschung 1997;471047-1051. 53. Cazzola P, Mazzanti P, Bossi G. In vivo modulating effect of a calf thymus acid lysate on human T lymphocyte subsets and CD4+/ CD8+ ratio in the course of different diseases. Curr Ther Res 1987; 421011-1017. 54. Kouttab NM, Prada M, Cazzola P. Thymomodulin:biological properties and clinical applications. Med Oncol Tumor Pharmacother 1989;65-9. 55. Fiocchi A, Borella E, Riva E, et al. A double-blind clinical trial for the evaluationof the therapeutic effectivenessof a calf thymus derivative (Thymomodulin) in children with recurrent respiratory infections. Thymus 1986;8:331-339. 56. Galli M, Crocchiolo P,Negri C, et al. Attempt to treat acute type B hepatitis with an orally administered thymic extract (Thymomodulin).Preliminary results. Drugs Exp Clin Res 1985;ll: 665-669. 57.Bortolotti F, Cadrobbi P, Criverllaro C, et al. Effect of an orally administered thymic derivative, Thymodulin, in chronic type B hepatitis in children. Curr Ther Res 1988;43:67-72. 58. Valesini G, Bamaba V, Benvenuto R, et al. A calf thymus lysate improves clinical symptoms and T-cell defects in the early stages of HIV infection. Second report. Eur J Cancer Clin Oncol 198723: 1915-1919. 59.Kang SD, Lee BH, Yang JH, Lee CY. The effects of calf-thymus extract on recovery of bone marrow function in anticancer chemotherapy.N Med J (Korea) 1985;2811-15. 60.Marzari R, Mazzanti P, Cazzola P, Piodda E. [Perennial allergic rhinitis. Prophylaxis of acute episodes using thymomodulin]. Minerva Med 1987;78:1675-1681. 61.Genova R, Guerra A. Thymomodulin in management of food allergy in children. Int J Tisue React 1986;8:239-242. 62. Cavagni G, Piscopo C, Rigoli E, et al. Food allergy in children: an attempt to improve the effects of the elimination diet with an immunomodulating agent (thymomodulin).A double-blind clinical trial. Immunopharmacol Immunotoxicol1989;11:131-142.

Homeopathy Andrew Lange, BSc, ND CHAPTER CONTENTS Introduction 387 History 387 Philosophy 388 Provings 388 Like Treating Like 388 The Organon of Medicine 389 Vitalism 389 The Clinical Application of Homeopathic Principles 390 The Homeopathic Interview 390 Follow-up and Case Evaluation 391

INTRODUCTION Homeopathy is a highly systematized method of medical therapeutics and clinical evaluation. The term homeopathy is derived from the Greek words homeos, meaning “similar,“ and pathos, meaning “suffering.” The medicines used in this system of therapeutics are chosen according to the Law of Similars (the concept of like curing like), a fundamental homeopathic principle based on the observed relationship between a medicine’s ability to produce a specific constellation of signs and symptoms in a healthy individual and the same medicine’s ability to c m a sick patient with similar signs and symptoms. This principle was first recognized by Hippocrates, who noticed that herbs given in low doses tended to cure the same symptoms they produced when given in toxic doses. Homeopathic medicines are derived from a wide variety of plant, mineral, and chemical substances. They are prepared according to standards of the US. Homeopathic Pharmacopoeia, a revised version of which has been approved by the U.S.Food and Drug Administration and US.Congress.

HISTORY The homeopathic school of medicine was founded by a German physician, Samuel Hahnemann. He had already

Prescription 391 Homeopathic Pharmacy and Potency Selection 392 Mechanism of Action 392 Determination of Potency 393 The Study of the Materia Medica 393

Research in Homeopathy 394 Meta-analyses 394 Human Trials 394 Animal Studies 395 Basic Research 395 Conclusion 396

gained a reputation in chemistry and medicine, having formulated a soluble form of mercury and developed a safer method for its use, and having written a number of works on pharmacology, hygiene and public health, industrial toxicology, and psychiatry. His treatise on arsenic poisoning (1786) is still considered authoritative. A prolific writer, Hahnemann collected, compiled, revised, and edited the existing pharmacologic knowledge. The work was well received by the medical profession of the time. In fact, Hahnemann was one of the most learned men of his generation in medicine, chemistry, and pharmacology, making his later criticisms of medicine all the more sigruficant.l Disillusioned with the theories and practice of eighteenth century medicine, Hahnemann retired from practice in 1782 and spent the next 14years earning a meager living doing chemical research; writing; and translating English, French, Italian, and Latin works. He wrote of his time of practice: It was painful for me to grope in the dark, guided only by books in the treatment of the sick. To prescribe according to this or that (fanciful)view of the nature of diseases, substances that only owed to mere opinion their place in the materia rnedica; I had conscientious scruples about treating unknown morbid states in my suffering fellow creatures with these unknown medicines which, being powerful substances, may, 387

if they were not exactly suitable (and how could the physician know whether they were suitable or not, seeing that their peculiar special actions were not yet elucidated) easily change life into death, or produce new affections and chronic ailments, which are often more difficult to remove than the on@ disease.

In his struggle to determine a reliable basis for therapeutics, he was distressed by his inability to provide medical care for the acute illnesses of even his own growing family. In 1790, during his translation of William Cullen’s (a Scottish physician) Muteriu Medicu, he added a footnote disagreeing with Cullen’s conclusions that the basis of cinchona bark‘s effectiveness was its bitter and astringent qualities. Cinchona officinalis (Peruvianbark), from which the drug quinine is derived, was known to be clinically effective in malaria and intermittent fevers (then called ague). He argued that there were several drugs in common usage that, in smaller doses, had greater bitter and astringent qualities yet had no specific action on fevers. As an experiment, Hahnemann took four drachms of cinchona twice daily and soon developed the paroxysmal symptoms characteristic of intermittent fevers. This duplication of symptoms was a revelation to him and ultimately resulted in his formulation of the concept of determining the properties of a medicine by studying its effects on healthy humans. Although homeopathy offers a profoundly deep and unified evaluation in the treatment of chronic diseases (see the section on evaluating the case later), it had gained most of its early reputation in the treatment of acute and epidemic diseases. An uproar was caused in Cincinnati in 1849 when two immigrant German homeopaths, treating cholera with camphor and other homeopathically prescribed remedies, published in the newspapers statistics indicating that only 35 of their 1116 treated cases had died. During the nineteenth century, 33% to 50% of patients with cholera who were given standard medical care died. In the 1879 epidemic of yellow fever, New Orleans homeopaths treated 1945 cases with a mortality rate of 5.6%, while the standard medical doctors were losing 16%. These and similar statistics had a profound effect on Congress and public opinion? Over time, homeopathsestablished their own network of treatment facilities. By 1892 in the United States, they controlled 110 hospitals, 145 dispensaries, 62 orphan asylums and retirement homes, more than 30 nursing homes and sanatoria, and 16 insane asylums. Constantine Hering established the first homeopathic medical school in the United States in 1835.It later moved from its original site in Allentown, PA, to Philadelphia, where it remains today as an orthodox medical school: the Hahnemann Medical College and Hospital. Hering’s promotion of homeopathy and development of the

mferiu rnedica was equaled only by Hahnemann himself. His 10-volumework, The Guiding Symptoms ofour Muteria Medica, remains a definitive work on the clinical verifications of the homeopathic approach. Unfortunately, of the many medicines introduced by Hering, only nitroglycerin orthodox medical practice as a tribute to his ine re& medical genius. Throughout the world, homeopathy has maintained a consistent tradition. Frederick Harvey Foster Quinn introduced it to England in the 1840s. It has since become a postgraduate medical specialty, recognized by the Department of Health by virtue of an Act of Parliament. Homeopathic hospitals and outpatient clinics are part of England’s national health system. Homeopaths have been engaged as personal physicians to the Royal family for the past four generations. Homeopathy is widely practiced in Europe, India, Argentina, and Mexico, and is experiencing a renaissance in the United States.

PHILOSOPHY Provings Hahnemann defined his method of testing medicines on healthy people as ”provings.” He expanded his investigations to include a wide range of substances, using his family, friends, and associates as experimental subjects. Historically, Hahnemann was not the first to use this methodology. In 1760 Anton Stoerck reported testing strumonium (datura) by rubbing it on the skin, inhaling the vapors of the freshly crushed leaves, and, finally, ingesting the fresh extract. He theorized that if strurnoniurn disturbs the senses and produces mental derangements in healthy people, it might be administered to maniacs for the purpose of restoring the senses by effecting a change of ideas. Recent medical literature has contained examples of inadvertent provings: In 1983a study in the New England Journal of Medicine reported that pyridoxine (vitamin B6), which is used in the treatment of some types of peripheral neuropathy, was also capable of producing neuropathies when given in large doses.3In 1796 Hahnemann published, in Hufelund‘s Journal, the fruit of his investigations in an article, “Essay on a New Principle for Ascertaining the Curative Power of Drugs, with a Few Glances at Those Hitherto Employed.”

LikeTreating Like Hahnemann also recognized the tendency of a natural disease to have a ”homeopathic effect” (i.e., a preventive or therapeutic effect) on other diseases with similar symptomatology. Although he ascribed this to the stimulation of the organism to eradicate the disease, he felt the deliberate induction of a disease to be difficult, uncertain, and dangerous? This concept has many parallels in modern

medical science. Descriptions of viral interference under natural conditions were described in 1937 by G. Findlely and F. MacCallum, who found that monkeys infected with the Raft Valley fever virus were protected from the more fatal yellow fever virus. They adopted the term “virus interference” and believed that when one virus infects a group of cells, a second virus is somehow excl~ded.~ This eventually led to the discovery of interferon in 1957 by Alick Isaacs and Jean Lindenmann. These methods of inducing self-regulation are critical in enhancing the ability for the body to recognize and resolve illness. In 1799 Hahnemann gained increased professional acceptance of his ideas by the successful application of atropa belladonna (deadly nightshade) in the prevention and treatment of scarlet fever (which had at that time reached epidemic proportions). In 1860 it was recommended as the treatment of choice in the National Dispensatory, which stated: “As long as persons are under the influence of belladonna . . . the liability to contract scarlatina is very much diminished.”6

The Organon of Medicine In 1810 Hahnemann published his Organon ofMedicine, a book that, through six editions, formed the foundation and definition of the homeopathic practice of medicine. It contains the philosophy, observations, and clinical applications of homeopathy, as well as citations from the historical and current literature of the time. Hahnemann challenged the reductionistic and mechanistic practices of his time, stating that the nature of disease is dynamic and could not be defined by isolating processes, grasping for an explanation. He further asserted that the cause of disease could not be known and that the categorization of disease states and attempts to manipulate physiology were insufficient, since they did not address the integrity and complexity of organization of the organism as a whole. He described this organization as dynamic, meaning in accordance with the animating principle of life, which is the underlying energetic pattern to which matter conforms. Disease is therefore addressed descriptively in the context of the whole patient, with the patient’s unique symptoms being indicative of that individual’s vital response to the condition. For any given disease there may be a long list of remedies that have been clinically effective, but it is the individualization and differentiation among medicines, based on the patient’s unique indications, that leads to a successful homeopathic prescription.

Vitalism Disease, in the homeopathic model, is thought to arise from inherent or developed weaknesses in the patient’s

defense mechanisms, creating a susceptibility to ”morbific influences” (e.g., toxic factors in the environment, bacteria, psychologic stresses). This viewpoint is considered ”vitalistic” (see Chapter 6 for a more detailed discussion) and, while not denying a corporeal reality, considers pathology to be but a singular focus in a complex net of interactions. William Boyd, in A Textbook of Pathology, discusses the limitations of the causal approach to disease, currently in vogue in medicine, when he states’: We must admit, however unwillingly, that we seldom or never really know the cause of anyhng. Many a beautiful idea has been slain by ugly fact. We merely note a constant association with one thing always following another. We say that the tubercle bacillus is the cause of tuberculosis. That is merely another way of saying that the bacillus is associated with a constant type of lesion; it is no explanation of how the lesions are produced by the bacillus. Nor does it explain why some persons and animals are susceptible to the infection while others are immune.

Vitalism can be better understood in the context of Hahnemann’s time, when theories of the causation of disease and its treatment abounded, such as: Galen’s doctrine that the secondary quality of a medicine (i.e., its action on the disease) can be determined from its primary qualities, such as its taste or smell; the evaluation of medicines by the study of their interactions when mixed with human blood in a jar; iatrochemistry, which had been reduced from the Paracelsian application of spagyric tinctures or oils of metals to dangerous toxic doses; the classification of drugs according to the Dioscoridian approach, which was based on the physiologic action (e.g., diuresis, diaphoresis) and chemical composition; and the “doctrine of signatures,” which held that the outer form and color of a plant revealed its inner archetypal a c t i ~ n . ~ , ~ Although some studies of the effects of medicinal agents were done with animals, Hahnemann observed that they had different effects on humans: Pigs could safely eat nux vornica in quantities that would immediately kill humans. Dogs could eat aconitum napellus, a deadly poison to humans, without injury. He also rejected the method of testing drugs by studying their effects on the sick as haphazard and unreliable, particularly since the results being sought were often only symptomaticrelief rather than eradication of the disease state. Hahnemann defined the application of medicines whose purpose was to alter physiology or act as an antagonist to disease as the practice of “allopathy” ( d o meaning ”contrary” in Greek). The current dominant medical system is heavily influenced by the causalistic and allopathic paradigms. This results in the diagnosis being the focal point of practice, without which appropriate therapy cannot be instituted. The pharmacologic

approach is limited to the end results of disease rather than the origins of pathogenesis. Subsequent problems are classified as unwanted side effects, since only the primary action of the pharmaceutic agent is used for treating a specific disease state. By focusing on only the primary effects of a drug, a diverse remaining range of physiologic, as well as psychologic effects, are ignored. In the homeopathic model, the side effects are an important part of the agent’s action and the body’s response to them, and by ignoring them, a drug’s range of usefulness is greatly limited, while its toxicity is increased. Hahnemann’s empirical investigations not only led to new applications of medicines but provided a method for integrating the physical, mental, and emotional effects of a drug. This allowed the treatment of the totality of a patient’s symptoms as a dynamic pattern of interaction. Vitalists stress the teleologic behavior of organisms (i.e., the goal directedness and design in biologic phenomena). Disease is therefore regarded as a positive expression of the organism’s self-regulatory process in response to environmental or other stresses. Disease is not accidental but is rather the effort of the organism to ward off deeper or more internal disorganization. It is the natural wisdom of the body, the vis rnedicutrix nuturue, or, using current scientific terminology, the tendency of the body to maintain homeostasis. Medical intervention often acts in conflict with these vital intracellular and extracellular regulatory functions. Karl Menninger, in 1948, commented on this medical dilemmalo: I believe that clinicians have come to think more and more in terms of a disturbance in the total economics of the personality, a temporary overwhelming of the efforts of the organism to maintain a continuous internal and external adaptation to continuously changing relationships, threats, pressures, instinctive needs and reality demands . . . It is the imbalance, the organismic disequilibrium, which is the real pathology, and when that imbalance reaches a degree or duration that threatens the comfort or survival of the individual, it may correctly be denoted disease.

Homeopathy is a method of specific induction of nonspecific resistance, which stimulates the body’s lnherent defense and self-regulatory mechanisms, rather than by taking over a function of the body, initiating dependency on the medicine itself.

THE CLINICAL APPLICATION OF HOMEOPATHIC PRINCIPLES The homeopathic clinical and therapeutic process consists of three interrelated processes: case taking, evaluation, and prescribing. The process is comprehensive and engages the observations of the patient, as well as those

of the doctor. Hahnemann describes the process in paragraphs 84 to 103 of the Orgunon and stresses the importance of distinguishing between chronic and acute, or self-limiting, disease.

The Homeopathic Interview The initial history of complaints is elicited from the patient with as little interruption as possible (as long as the patient does not digress unduly) so that the patient’s train of thought is not disrupted or directed along lines imposed by the physician’s biases. According to Hahnemann: The physician elicits further particulars about each of the patient’s statements without ever putting words in his mouth, or asking a question that can be answered only by yes or no, which induces the patient to affirm something untrue or half true or else deny something really there to avoid discomfort or out of desire to please, thereby giving a wrong picture of the disease, which would lead to the wrong treatment.

An entire review of symptoms is recorded in descriptive detail, taking into consideration all modalities that affect a symptom. Hahnemann emphasized the general symptoms (i.e., those affecting the entire organism, as the leading indications for the remedy). These key symptoms include mental and emotional affects, the metabolism and its reactions to environmental stimuli, sleep positions, food cravings and aversions, thirst, body type, and all manifestations of unconscious and autonomic regulation. Unique characteristic symptoms, particularly those regarded as ”strange, rare, and peculiar,” are important considerations in the selection of the remedy. These might be the expression of a paradoxical or unusual relationship, such as pain ameliorated by pressure or the sensation of the legs being made of wood or glass. The association of the start of a disease or symptom complex with an environmental or emotional event can be important and emphasizes the importance of an accurate and extensive interview. Hahnemann emphasizes the importance of taking a comprehensive case, particularly in chronic disease”: In chronic diseases in women one should pay particular attention to such things as pregnancy, infertility, sexual desire, confinement, miscarriages, nursing, vaginal discharges, and the condition of the monthly flow, especially noting whether it recurs at intervals that are too short or too long, how many days it lasts, whether or not it is interrupted, the quantity, how dark with color, any leukorrhea before or after the flow. If there is leukorrhea, what it is like, what symptoms accompany it, what is its quantity, under what conditions does it appear, what brings it on?

Since the patient’s symptoms are the expressions of the body’s attempts to heal itself, symptomatictreatment (i.e.,many allopathic therapies) can impair the physician’s

Homeopathy ability to obtain vital information and complicate the taking of the case. This problem has also been recognized by some medical authors, such as Boyd, who stated: “We recognize that the pattern of disease has changed out of recognition during the last 30 to 40 years owing to modern drugs, particularly the antibiotic^."^

Follow-up and Case Evaluation Considering the vitalistic and holistic perspective of the homeopathic approach, a clear definition of cure is necessary in order to establish the treatment goal. Mere palliation or suppression of symptoms at the cost of the overall vitality and function of the individual is considered negligent by the homeopathic practitioner. For example, if a patient’s skin disease is treated and appears to resolve but is followed by asthma, fatigue, and confusion, the treatment is evaluated as having been suppressive. If, upon proper treatment, the more serious lung and systemic disruptions are alleviated and the prior skin lesions return, the patient is considered as progressing toward a cure. When further appropriate therapy results in final alleviation of the skin disease, without any undue stress to the patient, it is then considered a true cure. This evaluative procedure is part of Hering’s Law of Cure, an observation of the principles of curative responses that can be applied to any healing process, regardless of the school of thought. In true healing, according to this set of observations, symptoms follow these patterns: From above, down the body to the extremities From within to without (often in the form of discharges and other eliminative processes) From the most important organs (e.g., the CNS) to the least important organs (typically the skin) In reverse order of their appearance (i.e., the chronologically most recent being replaced by those of the earlier stages of the disease, and, in some instances, earlier in the patient’s life) Homeopathy holds that the disease first affects the vital force and is manifested first by a change in the patient’s well-being, long before any objective changes can be observed. Illness is usually first recognized when the patient becomes aware of the early manifestations of the disease. Disease and cure must also be considered in the context of the belief system and culture of the patient. Much of what we call disease arises from the individual’s inability to find meaning and purpose. Many forms of healing are capable of enabling the person to integrate into the fabric of daily life and of providing ways to help the person address personal needs for fulfillment. In his study of disease, Hahnemann noted that there were inherited predispositionsto disease,which he related

to the improper treatment, and therefore suppression, of skin eruptions and venereal disease. He called these predispositions miasmas and, in 1828, published his findings in Chronic Diseases: Their Nature and Homeopathic Cure. He observed that many people, despite apparently healthy lifestyles, develop degenerative diseases. These often become established in childhood and continue to plague the person throughout life, despite medical treatment. He described three miasmas: psora, which represents a fundamental flaw in human ability to eradicate disease related to the suppression of skin disease; syphilis and sycosis, which is caused by the suppression of the figwort, or what is now known as human papilloma virus. Hahnemann describes the chronic effects of bacterial and viral diseases in his explanation of miasmas. In his discussion of viral diseases such as smallpox and other epidemic diseases, Hahnemann’s descriptions of the nature of viruses and their treatment predate their discovery by 50 years. He was a contemporary of Edward Tenner and supported his use of smallpox vaccination. More recently, George Vithoulkas, a contemporary homeopathic author and teacher, has defined health on three levels: mental, emotional, and physical. The mind should be capable of functioning with clarity, rationality, coherence, and logical sequence. It should be capable of engaging in creative service for the good of others, as well as for the good of oneself, demonstrating a freedom from selfishness and possessiveness. On the emotional level, there should be a state of serenity free from excessive passion, a state that should not be confused with lack of emotional response generated as a protection against emotional vulnerability. Finally, on the physical level, there should be freedom from pain. The healing person should experience a subjective sense of wellbeing and a progressive increase in vitality.I2

Prescription Since homeopathy is oriented toward the administration of a single medicine at a time, careful prescribing is important. It is through the application of single medicines that physicians have been able to record clinical verification of the provings and amass an impressive body of literature. Combination homeopathic medicines have been introduced as specific remedies for diseases and therefore have not represented homeopathic methods, though many studies support their efficacy. The process of selecting the correct remedy involves both careful study of the patient’s symptomatology and medical history and matching these with the appropriate remedy. This requires a sound understanding of the homeopathic materia medica (see later). The symptoms of the homeopathic materia medica are indexed in repertories that have evolved both in reference books and computer analysis programs.

Homeopathic Pharmacy and Potency Selection This leads to a discussion of what has remained the greatest mystery of homeopathic medicine (and the source of considerable ridicule and misunderstanding): the use of "potentized" substances. As Hahnemann began his research, he found that when treating patients according to the Law of Similars there was an initial aggravation of the symptoms, the "healing crisis," when using the high dosages typical of that era. He empirically tried using progressive dilutions of the medicines, beginning with tinctures from plants and titurations with milk sugar for metals and salts. He made the dilutions serially by mixing 1 drop of the tincture to 100 drops of alcohol, which were then "succussed" (shaken by pounding against a resilient surface) vigorously. He found that, with increasing dilution, the severity of the aggravation lessened while the patient continued to improve, often with deeper and more enduring results. He called these diluted remedies "potentized." As an analytic chemist, he was aware of Avogadro's theories (they were contemporaries), but he persisted in evaluating dilutions beyond the point where chemical activity could be detected. This problem has been addressed by recent workers, who have suggested that the therapeutic properties of the remedy lie in the energetic impression they make on the diluting vehicle (typically alcohol and water or lactose). Various techniques have been used to determine if there is a physical difference between the potentized dilution and the unmodified vehicle. These studies have used ultraviolet spectroscopy, conductivity measurements, infrared spectroscopy, surface tension measurements, Ranian-Laser spectroscopy, nuclear magnetic resonance, and other methods. Much of this work has shown regular peaks and troughs in activity with progressive dilutions, and Heintz has claimed that the peaks correspond to the maximum effects found in the biologic studies he has reported (see later section on basic re~earch).'~

Mechanism of Action To date there is no conclusive understanding of the mechanism of action of the potentizing process. However, this has not inhibited the use of potencies, which have been diluted by a factor of 100 up to 100,000 times (102°0~ooo). At this time, most explanations for the mechanism of homeopathic high potencies are provisional (such as the postulate that the remedies act in resonance with the magnetic fields of the body, or that the physiochemical properties of water can be modified by a solute and remain so even in the absence of the solute).14 This has not affected the clinical practice or demonstration of efficacy in clinical trials any more than the use

of aspirin did, despite the fact that the discovery of its mechanism of action through modulation prostaglandins did not occur until the 1980s. There are many forces whose nature can only be recognize by their results (e.g., gravity). These observations of relationships, confirmations of experience, are the basis of an empirical system. Medicine remains an art in the field of science. Oddly, a group operating in the Hematology Department of the School of Pharmacy in Bordeaux, France tested both the effect of common aspirin and homeopathic preparations on the vascular walls of rats. Aspirin at high concentrations (100 mg/kg) induced a decrease in platelet aggregation (amplitude and speed), as well as a decrease in the area of the thrombi (arterial and venous) and the number of emboli (arterials and venous). Aspirin at ultra-low doses (9, 15, 30 CH) induced an increase in platelet aggregation (amplitude and speed), as well as an increase in the area of thrombi (arterial and venous) and the number of emboli (arterial and venous). The anti-aggregation and antithrombotic action of aspirin at high concentrations (100 mg/kg) was inhibited by the concomitant injection of aspirin 15 CH.15 This confirmed Hahnemann's observations of the primary and secondary effects of medicines mentioned in the Organon.Ib Bellavite describes these effects as "biologically active compounds (which) may cause inverse or paradoxical effects on a complex homeostatic system when either the doses of the compound, or the methods of preparation and of administering, or the sensitivity of the target system are changed."l7Js Research into both the pharmacologic effects of homeopathic preparations and the paradoxical effects of orthodox drugs that confirm the Law of Similars underlying homeopathic prescribing are a growing body of literature. Certain pharmacologic substances when tested in high dilutions act on the same biologic ~ y s t e m s . ' ~ - ~ The reaction to the high dilutions can also be the opposite to a drug at low dilutions (e.g., proinflammatory agents can be antiinflammatory at high dil~tions).2~*~ Paradoxical effects of medicines are the basis of the Amdt-Schulz Law in pharmacology and hormesis. The Amdt-Schulz law states that weak stimuli slightly accelerate vital activity, medium strong stimuli raise it, strong ones suppress it, and strong ones arrest it?O Southam and Erlich3' reported the stimulatory effect of an antifungal agent when used at low doses and proposed the term homesis. Hormesis is defined as "the stimulatory effect of subinhibitory concentrations of any toxic substance on any organism."32Hormesis is considered a nonspecific phenomenon increasing the resistance and growth of the treated organism. It exists in all living organisms. This "action-reaction" model shows the efficacy of the "vital activity" in fighting the poison in a nonspecific way,

regular arguments between low- and high-potency even though specific defense molecules are also synprescribers as to the most effective method. t h e t i ~ e dA. ~modem ~ ~ and important pathologic model has shown that a single dose of an antitumoral immunoThe Study of the Materia Medica suppressive substance (cisplatin) induced increased lymphokine-activated killer a~tivity.3~ Wagner and colConstantine Hering once stated the following: leagues demonstrated that low doses of cytostatic agents stimulate human granulocyte and lymphocyte g r o ~ t h . ~ A mere acquaintance with the principal symptoms cannot be called studying the materia medica, although we make it the The goals and methods of homeopathic pharmacy basis of our study. The study of materia niedica must be have their roots in earlier Paracelsian and spagyric regarded and dealt with in exactly the same manner as that of medical systems. The challenge remains to define homeother natural sciences. opathic empirical science in the context of a modern science. It may be that homeopathy presents a challenge To give a perspective on the way in which homeoto science itself that will bring forth new models for pathic physicians organize the proving symptoms into pharmacology. The more central challenge is for homeclinical pictures, we draw from an essay on Sepia by E.B. Nash4? opathy to discover how it can apply its own critical methods to develop a more effective health care service. This is another of our wonderful remedies of which the domThe assumption that we can find substances in nature inant school knows nothing, except what they have learned that can alter disease underlies the history of medicine from us. Its chief sphere of action seems to be in the abdomen and pharmacology, yet healing remains a mystery. and pelvis, especially in women. No remedy produces stronger Further studies are necessary to confirm and develop symptoms here. We quote from different but equally good the understanding of the mechanisms and validity of observers. Sensation of bearing down in the pelvic region, with draghomeopathic medicines. ging pains from the sacrum; or feeling of bearing down of all

Determination of Potency

In terms of clinical practice, general guidelines have evolved for the determination of potency. In the sixth edition of the Orgunon, Hahnemann recommends ascending the scale of potencies gradually. In paragraph 248, he suggests that the medicinal solution be ”succussed anew with use.” In chronic cases, the patient is directed to take one teaspoonful daily or every otherday, and in acute diseases, as frequently as needed. If the solution is used up before the problem alleviates, the next higher dilution is used (if still indicated by the symptom pattern)?* The higher potencies, whose use largely developed in the United States, are repeated much less frequently and are generally reserved for the experienced practitioner. The more potentized the remedy, the closer it must meet the Law of Similars (i.e., the accuracy of the prescription must be high for a curative effect). Lower potencies are often repeated daily depending on the condition being treated. Several ranges of potencies include the decimal scale, which uses a 1:lO dilution; the centesimal scale, which is diluted 1:lOO; and the LM potencies introduced in the sixth edition of the Organon, using daily doses of 1:50,000 dilutions. Important to note is that the sixth edition was unavailable until 1924, 76 years after Hahnemann’s death. The predominant clinical application of homeopathic potencies had developed using an ascending scale. A single dose was used until its action had ceased, when the same potency would be repeated. When that potency seemed to no longer demonstrate an enduring effect, a higher potency was used. There have been

pelvic organs. (Hahnemann) Labor-like pains accompanied with the feeling as though she must cross her legs and “sit close” to keep something from coming out through the vagina. (Guernsey) Pain in uterus, bearing down, comes from back to abdomen, causing oppression of breathing; crosses limbs to prevent protrusion of parts. (Hering) Prolapse of the uterus, of the vagina, with pressure as if everything would protrude. (Lippe) Experience has shown its value in cases of ulceration and congestion of the 0s and cervix uteri. Its use supersedes all local applications. (Dunham) No higher authority than the united testimony of these five of our best observer could be brought to show the action of Sepia upon the pelvic organs. Now when we come to examine the provings in Allen’s Encyclopedia, we find that these symptoms were mainly produced by Hahnemann and his provers, and Hahnemann advocated proving remedies in the 30th, and some of them were produced by the 200th, especially those most strongly verified by black-faced type. We confess that we cannot understand how so many question the value of potencies for proving or curing. . . Sepia, like Sulphur, affects the general circulation in a very marked manner. Flashes of heat with perspiration and faintness is almost as characteristic of this remedy as of Sulphur. But there are, with Sepia, more apt to be associated with them the pelvic symptoms already given, and they are also more apt to occur in conjunctionwith the climacteric. Indeed, these flashes often seem with Sepia to start in the pelvic organs and from thence to spread over the body. But this irregularity of circulation extends as far as that of Sulphur. The hands and feet are hot alternately, that is, if the feet are hot, the hands are cold, and vice versa. There is not so much sensation of burning with Sepia as with Sulphur, but there is

Therapeutic Modalities actual heat, and the venous congestion, which seems to be the real state of the organs where the pressive bearingdown et cetera is felt, is also accompanied with much throbbing and beating. This local congestion to the pelvic organs is not simply sensational. There are actual displacements in consequence of it, and the long continued congestion results in inflammations, ulcerations, leukorrheas and even malignanaes or cancerous organizations. Induration with a painful sense of stiffness in the uterine region is characteristic. This pelvic congestion also affects the rectum in a marked degree. The rectum prolapses, there is a sensation of fullness, or of a foreign substance as of a ball or weight, and oozing of moisture from the rectum.Indeed, the rectal and anal symptoms are almost as strong as the uterine and va@. It is impossible to enumerate all the symptoms connected with the circulatory disturbances of Sepia in such a work as this,only a general study of the Materia Medica can do it. The urinary organs come in for their share of symptoms. The same pressure and fullnessconsequent upon the portal congestion reaches here. We will now proceed to give what we have found to be particularly valuable symptoms under the various organs in this region. “Pressure on bladder and frequent miduration with tension in lower abdomen.” “Sediment in the urine likeclay; as if clay burnt on the bottom of the vessel; urine very offensive (Indium),can’t endure to have it in the room, it is reddish or may be bloody.” This is found mostly in women. With c h i l h n there is one pecuhar symptom which has often been verified. “The child always wets the bed during its first sleep.” Upon the male organs I have found it particularly useful in chronic infection. There is not much discharge, but a few drops, perhaps, which glue up the orifice of the urethra in the morning; but it is so persistent and the usual remedies will not “dry it up.” In my early practice I used to use a weak injection of Sulphte ofzinc, but it used to annoy me that I could not use it without resorting to local measures. Sepia does it in the majority of cases and Kali wdatum will do it in the rest. I have, where there was a thick discharge of long standing and the smarting and burning on urination continued, several times finished the case with Capsicum. As a rule, thislong continued slight, passive sleety discharge is a result of weakness of the male genitals, us is shown by u j u c -

cidity of the organs and frequent seminal emissions. The emissions are thin and watery. Sepia covers all of this and often sets all to rights in a short time. The mind symptoms of Sepia are like Pulsutillu, in that she is sad and cries fresuently without knowing the reason why. So if in a tearful mind with uterine disturbances Pulsutillu should fail you, the next remedy to be studied is Sepia.But there is another condition of mind not found under Pulsutillu or any other remedy in the same degree, and that is, that, notwithstanding there is no sign of dementia from actual brain lesion, the patient, contrary to her usual habit, becomes indifferent to her occupation, her house work, her family or their comfort, even to those whom she loves the best. This is a very peculiar symptom and a genuine keynote for the exhibition of Sepia . . . I once cured a very obstinate case of entero-colitis (so-called cholera infantum), after the complete failure of two eminent allopaths, with Sepia, the leading symptom being, always worse after taking milk. Oozing of moisture from the anus finds its remedy here sometimes, but oftener in Antimonium crudum. The Sepia patient is very weak. A short walk fatigues

her very much. She faints easily from extremes of cold and eat, after getting wet, from riding in a carriage, while kneeling at church, and on other trifling occasions. This fainting, or sense of sinking faintness, may be found in pregnancy, child bed, or during lactation; or, again, it may come on after hard work, such as “laundry work;” so it has come to be called the “washer woman’s” remedy.

As can be seen by this excerpt, the indications for a remedy are complex,requiring study and understanding.

RESEARCH IN HOMEOPATHY Since homeopathy arose from empiric observations and operates from empiric clinical evidence and phenomenologically descriptive fields rather than causal relationships, its evaluation by the scientificmethod, as described by Karl Popper, poses unique problems. The most promising evidence for the efficacy of homeopathy has always come from its efficacy in clinical trials. Its mechanism of action has remained a central dilemma for its detractors.

Meta-analyses The following briefly discusses some of the studies that have been done.

A critical review appeared in the British Homeopathic Journal describing the methods used in various attempts to verify this school of medicine. The study evaluated 107 controlled trials and found there was a positive trend regardless of the quality of the trial or variety of homeopathic medications used.& A meta-analysis published in the British Medical Journal of a total of 105 controlled trials showed positive results for homeopathic treatment in 81 trials, leading its authors to state, “The evidence in this review would probably be sufficient for establishing homeopathy as a regular treatment for certain indications.”44 In another meta-analysis of 119 trials that met the inclusion criteria, 89 had adequate data for meta-analysis, and 2 sets of trials were used to assess reproducibility. The combined odds ratio for the 89 studies were in favor of h0meopathy.4~ In a third meta-analysis of the effect of homeopathy versus placebo, 32 trials with a total of 1778 patients met the criteria of randomization/partial randomization comparing individual homeopathy with placebo or no treatment. Homeopathy was sigruficantly more effective than placebo in 19 trials.&

Human Trials During World War I1 isopathic preparations were given prophylactically, and homeopathic therapies were used in mustard gas burns. A recent statistical analysis shows that these treatments yielded significant results when compared with placebos. The remedies used were mustard gas, Rhus toxicodendron, and kali bi~hrornium.’~

Homeopathy

Gibson and colleagues47published a double-blind clinical trial of homeopathic treatment in rheumatoid arthritis. The 3-month study was elegantly designed in that the prescribing was individualized to the patient's symptoms and was controlled, on a double-blind basis, by giving half the patients the correct remedy and the rest a placebo. All patients continued to use conventional, nonsteroidal, antiinflammatory drugs, and the treated group showed significant improvement in subjective pain, articular index, stiffness, and grip strength. In 1980 a Scottish group published a study on rheumatoid arthritis in the British ]ournu1of Pharmacology showing improvement in 82% of patients treated, compared with only 21% in the placebo group." A 2004 triple-blind study of homeopathic treatment of chronic fatigue syndrome, published in the Journal for Psychosomatic Research, was conducted showing significant improvement clinically and as measured using the Multidimensional Fatigue Inventory scale.@ Other published studies demonstrating the efficacy of homeopathic treatment include treatment of headache, attention deficit-hyperactivity disorder in children, asthma, upper respiratory tract infections, otitis media, arthritis, allergies, male infertility, influenza, cardiac insufficiency, herpes, osteoarthritis, and acquired immunodeficiency ~ y n d r o m e . ~ ~ - ~ ~

The use of homeopathic dilutions of hormones and immunomodulators have shown potential. Immunostimulatory effects of high dilutions of thymic hormones and interferons were demonstrated in mice by Bastide's g r o ~ p . ~Other ~ , ~ studies ~ - ~ ~ have demonstrated that extremely small amounts of antigens are specific for i m m u n o m o d ~ l a t i o nThese .~~~~ have tremendous implications in pharmacy, immunology, and clinical health care that demand continued research.

Basic Research

Clinical and experimental data obtained in studies about the effect of homeopathic preparations in inflammatory conditions present a considerable degree of reprodu~ibility.~"'~~ The inability for the Benveniste group to replicate their nature study using the Human Basophil Degradation Test (HBDT) to establish the ability for high dilutions to trigger the degranulation of anti-IgE has caused considerable distraction from other more credible r e s e a r ~ h . ' ~ ~ J ~ Another group (Brown and Ennis) using different methods demonstrated the efficacy of high dilutions of histamine to inhibit the activation of basophils using HBDT.lo5Instead of measuring degranulation provoked by ultramolecular dilutions of anti-IgE, as Benveniste did, they examined the inhibition of activation of basophils by ultramolecular dilutions of histamine. Animal Studies The experiments used ultramolecular dilutions of histamine (15 to 19 c), prepared with vortexing (instead of Cuulophyllum (in the thirtieth centesimal potency) was succussion). The main experiment, performed by all the given to 10 sows to test its efficacy in the control of stilllaboratories, was based on inhibition of basophil activabirths. The results showed a statistically sigruficant drop in the number of stillbirths and led to a larger, uncontion as measured by degranulation. Flow cytometry experiments at three laboratories showed compatible trolled study in a whole herd. After 4 months of therapy, results, with inhibition of activation as high as 43%. piglet mortality dropped from 20% to 2.6%.82 Nearly all experiments showed statistically significant Cloudhury obtained dramatic results from injecting inhibition of basophil mice intraperitoneally with kali phosphoricum, calcarea Experimental study of homoeopathy in allergology1I0 phosphorica, or ferrum phosphorica (in the thirtieth dec~ - Iwell I ~ as in imal potency) 12 days after implantation of fibrosarcoma. effects have been reported in V ~ V O , ~ ~ as ,itro.ll4-1l8 Of the 77 treated mice, 52% were cured and survived The physical properties of homeopathic preparations more than 1 year, whereas all of the 77 controls died are gaining considerable understanding in research. within 10 to 15 days.83 Studies demonstrating that the physico-chemical properScofield, in his review article, discusses numerous experiments with humans, animals, and plants using ties of extremely diluted solutions (EDS)are different from those of pure untreated water, notwithstanding the identiisopathic treatment for poisoning and experimental liver cal chemicalcomposition of the two liquid^.^^^-'^^ The same damage, and various in vitro studies.13 A number of studies have been conducted to invesconclusions are inferred by LO.'^,^^ Rey'" has shown that tigate the ability for homeopathic preparations to the structure of hydrogen bonds in pure water is different from that of an extremely diluted solution obtained by an effect either the elimination or consequences of toxic iterative procedure of successive dilutions and succussubstances. sions, not identical as expected. Recent studies on the Homeopathy may be effective in assisting in the physico-chemical properties of water provide evidence elimination and treatment of heavy metals and other that the most studied liquid by far, water, still exhibits toxins. Studies of arsenic,@ b i s m ~ t h , ' ~ ~ ~ ~ , ~ ~ unexpected properties.125131Lobyshev and coworkers132 merc~ry,8~B carbon tetrachloride,21,26a-amanitine (from have shown that low concentrations and electromagnetic the mushroom Amanita phalloides)F7 and carcinogens fields can produce largescale realignmentsof its structure, such as 2-acetylaminoflourene and phen~barbitol~~ have which can be either reversible or irreversible. One can been published.

deduce from these studies that water and aqueous solutions are complex systems, capable of auto-organization as a consequence of small perturbations of various kinds. The question of whether water can maintain “memory” of solutes in EDS is best understood by understanding the physical characteristics of water and its ability to form stable clusters and crystals. This aspect of physics is not widely studied but is well documented.”9-123,1~1~,1~

CONCLUSION Homeopathy represents an integrated holistic system of natural therapeutics. Its capacity for addressing psychosomatic disease and acute pathology as a dynamic process is unique. It has remained a coherent system, with extensive clinical verification, for more than two centuries. Homeopathy is an economical and effective method that has been established as an integral part of the medical system in many countries. With the resurgence of interest in natural medicine, this discipline will undoubtedly be more widely used. Homeopathy plays an important role in the context of modern naturopathic medicine. Hahnemann emphasized the importance of lifestyle in the treatment of the

The research section of this chapter is deeply indebted to the works of Peter Fisher, editor of the British Homeopathic Journal, Madeleine Bastide, Paolo Bellavite, and Andrea Signorini. The clinical training I received from Alan Sutherland and Marion Belle Rood has continued to be the foundation of sound practice and the inspiration to sustain study in the philosophy of nature. Books

Boerke W. Pocket Manual of materia medica with repertory, 1936. Reprint, New Dehi, India: Jain, 1982. Clark 1. Dictionary of practical materia medica, vols 1-3,1900.Reprint, Essex, England Health Sciences, 1962. Kent JT. Materia medica. Philadelphia: P Blakiston, 1900. Nash EB. Leaders in homeopathic therapeutics, 1898. Reprint, New Delhi,India: lain, 1983. Hahnemann S.Organon of medicine. Los Angeles: JP Tharcher, 1982. Hahnemann S. Chronic Diseases: Their specific nature and homeopathic treatment. New York Wm Radde, 1845. Lange A. Getting at the root: treating the deepest source of disease. Berkeley: North Atlantic Books, 2002. Roberts HA. The principles and art of cure by homeopathy. Essex, England Health Sciences, 1942. Edzard E, Hahn EG. Homeopathy, a critical appraisal. Oxford, England Butterworth Heinemann, 1998. Bastide M. Signals and images. Dordrecht, Netherlands: Kluwer Academic Publishers, 1997. Bellavite P, Signorini A. Homeopathy, a frontier in medical science. Berkeley, CA: North Atlantic Books, 1995.

patient. One of his primary dictums was to first remove the obstacles to cure, as he said While taking a case of chronic disease one should examine and weigh the particular conditions of the patient’s day to day activities, living habits, diet, domestic situation,and so on. One should ascertain whether there is anything in them which may cause or sustain the disease and remove it to help the cure. Unfortunately, homeopathy is also an extremely difficult system to master, requiring both considerable understanding of case taking and materia rnedica, as well as extensive consultation time with the patient. It has therefore often been discarded, even by those aware of its efficacy. Although attempts have been made to reduce it to simpler systems (e.g., allergy desensitizations, vaccinations, Schuessler’s cell salts, and isopathic preparations from diseased tissues and heavy metals), they are not considered strictly homeopathic unless prescribed according to their effects upon healthy people or the confirmed observations of cured symptoms. Homeopathy is representative of a principle found throughout nature and its role in bringing forth concepts of resonance, constitution, and holism are shared throughout fields of science and healing.

Journals

Simillimum, journal of the Homeopathic Academy of Naturopathic Physicians The Homeopath, journal of the Society of Homeopaths (UK) Homeopathy, formerly the British Homeopathic ]ournal; the official journal of the faculty of homeopathy, London The American Homeopath, journal of the North American society of Homeopaths Homeopathic Links, international journal for classical homeopathy Web Resources

British Homeopathic Library is a library and information service dedicated to the research and practice of homeopathy. Website: http://dspace.dial.pipex.com/hom-inform/index.shtml Ad Hom, the Academic Departments of Homeopathy at Glasgow Homeopathic Hospital. Website: www.adhom.com HOMINT Documentation Information System VSM, Alkmaar (Netherlands)/DHU, Karlsruhe (Germany) containing 35,000 references, major articles, homeopathicjournals, literature-search on request. Ajo Bol, information specialistVSM/Susanne Rehm, DHU. E-mail: [email protected] Homoepathic Educational Resources Database, compiled by Dr.Russell Malcolm of the Glasgow Homoeopathic Hospital. E-mail: gh/@gn.apc.org

Homeopathy

1.Coulter HL. Divided legacy: a history of the schism in medical thought, vol2. Washington, Dc: Wehawken, 1977:310. 2. Coulter HL.Divided legacy: a history of the schism in medical thought, vol2. Washington, DC:Wehawken, 1977305. 3. Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse. N Engl J Med 1983;309:445-448. 4.Hahnemann S. Organon of medicine. Los Angeles: JP Tarcher, 1980:par 42-50(reprint). 5. Isaacs A. Interferon. Sci Am 1961;204:51-57. 6.Coulter HL. Homeopathic influences in 19th century allopathic therapeutics. Washington, DC:Am Inst Hom, 197339. 7.Boyd W. A Textbook of pathology, ed 8. Philadelphia: Lea & Febinger, 19703-12. 8. Riddle JM. Dioscorides on pharmacy and medicine. Austin, Tx: University of Texas Press, 1985. 9. Page1 W. Paracelsus: an introduction to philosophical medicine in the era of the Renaissance. New York Karger, 1982. 10.Menninger K. Changing concepts of disease. Ann Intern Med 1948;29:318-325. 11. Hahnemann S. Organon of medicine. Los Angeles: JP Tarcher, 1980:par 94 (reprint). 12. Vithoulkas G. The science of homeopathy. New York Grove Press, 1979. 13. Scofield AM. Experimental research in homeopathy-a critical review. Br Hom J 1984;73:161-180,211-226. 14. Bellavite P, SignoriniA. Homeopathy, a frontier in medical science. Berkeley, C A North Atlantic Books, 1995. 15. The Biological Action of Dilutions of Aspirin, Professor Doutremepuich (University of Bordeaux, France). Available online at h t t p : / ~ . . b o i r o n . c o m / e n / h t m / 0 4 - p o l i t ~ ~[accessed ~~le.h~ September 30,20041. 16. Hahnemann S. Organon of medicine. Los Angeles: JPTarcher, 1980, par 64 (reprint). 17. Bellavite P, Andrioli G, Lussignoli S, et al. A scientificreappraisalof the 'principle of similarity.' Med Hypotheses 1997;49203-212. 18. Teixeira M. Homeopathic use of modem medicines: utilization of the curative rebound effect. Med Hypotheses 2003;60:276-283. 19. Wurmser L, Ney J. Mobilkation de I'arsenic fix6 chez le cobaye, sous l'action de doses infinitesimales d'arseniate de sodium. Therapie 1955;10625-638. 20. Lapp C, Wunnser L, Ney J. [Infinitesimaldoses of sodium arseniate causing mobilization of fixed arsenic in guinea pigs.] Therapie 1955;10625638. 21. Bildet J, Aubin M, Baronnet S, et al. Resistance de la cellele hepatique du rat a p r b une intoxication infiniteshale au tetrachlorule de carbone. Homeopath Fr 1984;72175. 22. Aubin M. Elements de pharmacology homeopathique.Homeopath Fr 1984;72231. 23. Bastide M, Doucet-Jaboeuf M, Daurat V.Activity and chronopharmacology of very low doses of physiological immune induces. Immunol Today 1985;6234. 24. Doutremepuich C, de Seze 0, Anne MC, et al. Platelet aggregation on whole blood after administration of ultra low dosage acetylsalicylic acid in healthy volunteers. Thromb Res 1987;47 373-377. 25. Bonamin LV, Martinho Ks, Nina AL, et al. Very high dilutions of dexamethasone inhibit its pharmacological effects in vivo. Br Homeopath J 2001,90:19&203. 26. Bildet J, Guere JM, Saurel J, et al. Etude de l'action de differentes diluitions de Phosphorus sur l'hepatite toxique du rat. Ann Homeopath Fr 1975;17425. 27. Guillemain J, Douylliez C, Bastide M, et al. Pharmacologie de l'infinitesimal.Homeopathie 1987;435.

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74. Matusiewicz R. The homeopathic treatment of corticosteroiddependent asthma: a double-blind, placebo-controlled study. Biomed Ther 1997;15:117-122. 75. McCamey RW, Linde K, Lasserson TJ. Homeopathy for chronic asthma. Cochrane Database Syst Rev 2004;1:CwoO353. 76. Poitevin 8. Review of experimental studies in allergy. Br Homeopath J 1998;8789-99. 77. Reilly DT, Taylor MA, McSharry C, et al. Is homoeopathy a placebo response? Controlled trial of homoeopathicpotency, with pollen in hayfever as model. Lancet 1986,2881-886. 78. Taylor MA, Reilly D, Llewellyn-Jones RH, et al. Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. BMJ 2000;321:471-476. 79. Weiser M, Clasen BPE. Controlled double-blind study of a homeopathic sinusitis medication. Biol Ther 1995;13:4-11. 80.de Lange de Klerk ES, Blommers J, Kuik DJ, et al. Effect of homoeopathic medicines on daily burden of symptoms in children with recurrent upper respiratory tract infections. BMJ 1994;309: 1329-1332. 81. Taylor MA, Reilly D, Llewellyn-Jones RH, et al. Randomised controlled trial of homoeopathy versus placebo in perennial allergic rhinitis with overview of four trial series. BMJ 2000921:471-6. Erratum in: BMJ 2000;321:733. 82. Day CE. Control of stillbirths in pigs using homeopathy. Vet Rec 1984;114216. 83. Choudhury H. Cure of cancer in experimental mice with certain biochemic salts.Br Homeopath J 1980;69168-170. 84. Cazin JC, Cazin M, Gaborit JL, et al. A study of the effect of decimal and centesimal dilutions of arsenic on the retention and mobilization of arsenic in the rat. Hum Toxicol 1987;6:315-320. 85. Cazin JC, Cazin M, Chaoui A, et al. Influence of several physical factors on the activity of ultra low doses. In Doutremepuich C, ed. Ultra low doses. London: Taylor & Francis, 199169-80. 86. Fisher P, House I, Belon P, et al. The influence of the homoeopathic remedy plumbum metallicum on the excretion kinetics of lead in rats. Hum Toxicol 1987;6:321-324. 87. Cambar J, Desmouliere A, Cal JC, et al. Mise en 6vidence de l'effet protecteur de dilutions homkopathiques de Mercurius corrosivus vis-a-vis de la mortalitk au chlorure mercurique chez la souris. Ann Homhpath Fr 1983;5:6-12. 88.Guillemain J, Cal JC, Desmouliere A, et al. Effet protecteur de dilutionshombpathiques de metaw nkphrotoxiques vis-A-vis d'une intoxication mercurielle. Cahiers Biothkrapie 1984;8l(suppl):27-34. 89. De Gerlache J, Lans M. Modulation of experimental rat liver carcinogenesis by ultra low doses of the carcinogens. In Doutremepuich C, ed.Ultra low doses. London: Taylor & Francis, 1991:17-26. 90. Doucet-Jaboeuf M, Guillemain G, Piechaczyk M, et al. Evaluation de la dose limite d'activit6 du facteur thymique serique. CR Acad Sci Paris 1982;295:283-286. 91. Doucet-Jaboeuf M, Pelegrin A, Cot MC, et al. Seasonal variations in the humoral immune response in mice following administration of thymic hormones. In Annual Review of Chronopharmacology, vol 1.Oxford: Pergamon Press, 1984231-234. 92. Bastide M, Daurat V, Doucet-Jaboeuf M, et al. Immunomodulator activity of very low doses of thymulin in mice. Int J Lmmunother 1987;3:191-200. 93. Daurat V, Dorfman P, Bastide M. Immunomodulatory activity of low doses of interferon alpha, beta in mice. Biomed Pharmacother 1988;42197-206. 94. Weisman Z, Topper R, Oberbaum M, et al. Immunomodulation of specific immune response to KLH by high dilution of antigen. (Abstract 19). In Proceedings of the 5th G W Meeting, Paris, 1991. 95. Bentwich Z, Weisman Z, Topper R, et al. Specific immune response to high dilutions of KLH; transfer of immunological information.In Bomoroni C, ed. Omeomed 92. Bologna: Editrice Compositori, 1993:9-14.

96. Lame F, Cal JC, Guilleman J, et al. Influence du facteur dilution sur I'effet protecteur de Mercurius Corrosivus vis-a-vis de la toxicite induite par le chorure mercurique chez la souris. Homeopathie FrancEaise 1985;73:375-380. 97. Vischniac I. Influence des doses infinite s h a l e s de plomb sur l'evolution de l'intoxication au plomb chez l'animal. Homeopathie FrancEaise 1965;53:21-33. 98. Davenas E, Poitevin B, Benveniste J. Effect on mouse peritoneal macrophages of orally administered very high dilutions of Sillica. Eur J Pharmacol 1987;135:313-319. 99. Sainte-Laudy J, Belon P. Analysis of immunosuppressive activity of serial dilutions of histamine on human basophil activation by flow cytometry. Inflamm Res 1996;45(suppl l):s33-34. 100. Bildet J, Guyot M, Bonnini F, et al. [The effect of dilutions of Apis mellifica and Apium virus on ultraviolet light-induced erythema in the guinea pig.] Ann Pharmacol Fr 1989;4724-32. 101. Oberbaum M, Weisman Z, Kakinkovich A, et al. Healing chronic wounds performed on mouse ears using silica (Si02) as a homeopathic remedy. In Bastide M, ed. Signals and images. Dordrecht, Netherlands: Kluwer Academic Publishers, 1997191-199. 102. Belon P, Cumps J, Ennis M, et al. Inhibition of human basophil degranulation by successive histamine dilutions: results of a European multi-centre trial. Mlamm Res 1999;48(suppll):S17-18. 103.Ovelgonne JH, Bol AW, Hop WC, et al. Mechanical agitation of very dilute antiserum against IgE has no effect on basophil staining properties. Experientia 1992;48:504-508. 104.Hirst SJ, Hayes NA, Burridge J, et al. Human basophil degranulation is not triggered by very dilute antiserum against IgE. Nature 1993;366525-527. 105. Brown V, Ennis M. Flow-cytometric analysis of basophil activation: inhibition by histamine at conventional and homeopathic concentrations. Inflamm Res 2001;50547-48. 106. Belon,'F Cumps J, Ennis M, et al. Inhibition of human basophil degranulation by successive histamine dilutions: results of a European multi-centre trial. Inflamm Res 1999;48:S17-18. 107. Belon P, Cumps J, Ennis M, et al. Histamine dilutions modulate basophil activity. Inflamm Res 2004;53181-188. 108. Fisher P. A landmark for basic research in homeopathy. Homeopathy 2004;93:162-163. 109. Sainte-Laudy (France), Professor Mannaionni (University of Florence, Italy), Professor Ennis (Queen's University, Belfast). The effect of dilutions of antigens and various biologic factors on the activity of basophil leukocytes. Available online at http://www.boiron.com/en/htm/04-pol itiquelfondamentale-03.htm [accessed October 8,20041. 110. Poitevin B. Experimental study of homoeopathy in allergology. Br Homeopath J 1998;87154-164. 111. Linde K, Jonas WB, Melchart D, et al. Critical review and metaanalysis of serial agitated dilutions in experimental toxicology. Hum Exp Toxicol 1994;13481-492. 112. Endler PC, Pongratz W, Kastberger G, et al. The effect of highly diluted agitated thyroxine on the climbing activity of frogs. Vet Hum Toxicol 19943656-59.

113. Youbicier-Simo BJ, Boudard F, Mekaouche M, et al. Effects of embryonic bursectomy and in ovo administration of highly diluted bursin on adrenocorticotropic and immune responses of chickens. Int J Immunother 1993;9:169-180. 114. Boyd WE, Brit M. Biochemical and biological evidence of the activity of high potencies. Br Homeopath J 1954;44:7-44. 115. Davenas E, Beauvais F, Amara J, et al. Human basophil degranulation triggered by very dilute antiserum against IgE. Nature 1988;333:816-818. 116. Sainte-Laudy J, Belon P. Analysis of immunosuppressive activity of serial dilutions of histamine on human basophil activation by flow cytomehy. Inflamm Res 1996;45(suppll):S33-34. 117. Jonas W, Lin Y, Tortella F. Neuroprotection from glutamate toxicity with ultra-low dose glutamate. Neuroreport 2001;12 335-339. 118. Vickers AJ. Independent replication of pre-clinical research in homeopathy: a systematic review. Forsch Komplementarmed 1999;6311-320. 119. Elia V, Niccoli M. Thermodynamics of extremely diluted solutions. Ann N Y Acad Sci 1999;879241-248. 120. Elia V, Niccoli M. New physico-chemical properties of water induced by mechanical treatments. J Therm Anal Calorim 2000;61:527-537. 121. Elia V, Niccoli M. New physico-chemical properties of extremely diluted aqueous solutions. J Therm Anal Calorim 2004;75:815-836. 122. Lo SY.Anomalous state of ice. Mod Phys Lett B 1996;10909-919. 123. Lo SY, Lo A, Chong LW, et al. Physical properties of water with IE ~ t r u c t u r eMod ~ . Phys Lett B 1996;10:921-930. 124. Rey L. Thermoluminescence of ultra-high dilutions of lithium chloride and sodium chloride. Physica A 2003;323:67-74. Stanley HE. Decompression-induced melting of ice IV 125. h4ishima 0, and the liquid-liquid transition in water. Nature 1998;392:164-168. 126. Wourtersen S, Emmerichs U, Bakker HJ. Femtosecond mid-IR pump-probe spectroscopy of liquid water: evidence for a twocomponent structure. Science 1997;278:658-660. 127. Robinson GW, Cho CH, Gellene GI. Refractive index mysteries of water. J Phys Chem B 2000;104:7179-7182. 128. Woutersen S, Bakker HJ. Resonant intermolecular transfer of vibrational energy in liquid water. Nature 1999;402507-509. 129. Gregory JK, Clary DC,Liu K, et al. The water dipole moment in water clusters. Science 1997;275814-817. 130. Ropp J, Lawrence C, Farrar TC, et al. Rotational motion in liquid water is anisotropic: a nuclear magnetic resonance and molecular dynamics study. J Am Chem Soc 2001;1238047-8052. 131. Errington JR, Debenedetti PG. Relationship between structural order and the anomalies of liquid water. Nature 2001;409:318-321. 132. Lobyshev VI, Shikhlinskaya RE, Ryzhikov BD. Experimental evidence for intrinsic luminescence of water. J Mol Liquids 1999;8273-81. 133.Elia V, Baiano S, Duro I, et al. Permanent physico-chemical properties of extremely diluted aqueous solutions of homeopathic medicines. Homeopathy 2004;93144-150.

Hydrotherapy Robert Barry, ND Revised and Edited by Douglas C. Lewis, ND CHAPTER C O N T E N T S Introduction 401 History 402 Properties of Water 402 Physiologic Effects 403 Hydrotherapy Research 403 Local and Systemic Effects of Cold Applications 404 Local and Systemic Effects of Hot Applications 405 Local Hot Applications 405 General Hot Applications 406 Principles of Blood Movement with Hydrotherapy 406 Revulsive Effect 406 Derivative Effect 407 Spinal Reflex Effect 407

INTRODUCTlON Hydrotherapy may be defined as the use of water, in any of its forms, for the maintenance of health or the treatment of disease. In his original article, Dr.Barry wrote: ”Although one of the oldest known therapies, it [hydrotherapyJ has received little attention from the research community, particularly recently. Much of the informationpresented here is compiled from older works which, although they lack the quantification available with current technology, show a remarkable attention to clinical effects and patient response.” When the original article was published, in 1985, reviews of the available literature were at best slow and laborious. Citations were discovered while looking through large tomes that were often heavy enough to produce low back pain. Once an interesting citation was discovered, the researcher had to search through stacks of journals, only to discover that the one desired had been lost, stolen, or was in the hands of another researcher. Today, the power of the computer has been directed toward removal of some of the former limitations to

Collateral Circulation Effect Arterial Trunk Reflex 408

407

General Rules of Hydrotherapy 408 Possible Side Effects of Hydrotherapy 409 Safety Aspects of Hydrotherapy 409 Pregnancy 409 Hypertension and Cardiovascular Disease 409 Hydrotherapy Techniques 410 Compresses 410 Baths 411 Cold Friction Rubs and Ablutions 413 Constitutional Hydrotherapy 41 3 Wet Sheet Pack 414 Sauna 415 Conclusion 415

research of the available literature. Large databases with fast search engines have made it possible to perform massive literature searches that were effectively impossible only a few years ago. Now, instead of low back pain from carrying those large tomes, we have upper back and neck pain from long hours spent in front of our computers. We now have the ability to search subject headings we might never have thought of or bothered with before. The bigger problem today is sorting out the useful from the worthless. For example, while preparing this revision, sitting at an office computer with high-speed Internet access, a search of PubMed was performed. The limits for the search were established as follows: all publication types, all ages, dates ranging only from January 1,1990, to the present, human studies only, published in English. A search using the term “sauna” yielded 126 citations, 11 of which were classified as randomized controlled studies and included abstracts. A search using the term ”balneology” yielded 845 citations, 71 of which were classified as randomized controlled studies and included abstracts. 401

Therapeutic Modalities A search using the term “hyperthermia” yielded 10,531 citations, 679 of which were classified as randomized controlled studies and included abstracts. Many of these newer studies are cited here, while little of what was written previously has been changed. Additions have been made where appropriate to clarify the existing material or to add new information.

HISTORY As one of the ancient methods of treatment, hydrotherapy has been used to treat disease and injury by many different peoples, including the Egyptians, Assyrians, Persians, Greeks, Hebrews, Hindus, and Chinese. In the Rig Veda, written about 1500 BC, we read that “water cures the fever’s glow.” Hippocrates used hydrotherapy extensively around 400 BC. In his writings concerning baths are some of the earliest dictum on the therapeutic uses of water’: Much will depend on whether the patient, when in good health, was very fond of the bath, and in the custom of taking it: for such persons, especially feel the want of it, and are benefited if they are bathed, and injured if they are not. In general it suits better with cases of pneumonia than in ardent fevers; for the bath soothes the pain in the side, chest and back; cuts the sputum, promotes expectoration, improves the respiration, and allays lassitude; for it soothes the joints and outer skin, and is diuretic, removes heaviness of the head, and moistens the nose. Such are the benefits to be derived from the bath, if all the proper requisites be present; but if one or more be wanting, the bath, instead of doing good, may rather prove injurious; for every one of them may do harm if not prepared by the attendants in the proper manner.

He writes further to explain the specific contraindications to the use of the bath. As these early writings show, the uses of water had been explored extensively at very early times, with many of the principal effects having been observed and used. The modem history of hydrotherapy begins with the publication, in 1697, of The History of Cold Bathing by Sir John Floyer. Following Floyer were several works that attempted to provide a scientific foundation for the uses of water in medicine. Probably the strongest impetus for its use came from central Europe, where it was advocated by such well-known hydropaths as Priessnitz, Rausse, and Father Kneipp. They were able to popularize specific water treatments, which quickly became the vogue in Europe during the nineteenth century. By the end of the nineteenth century, many individuals in the United States and Europe were actively engaged in practicing hydrotherapy. Probably the best known American was J.H. Kellogg, a medical doctor who approached hydrotherapy scientifically, performing many and varied experiments on its

use and effects. In 1900 he published what may still be considered a definitive treatise on hydrotherapy, entitled Ratioiial Hydrotherapy? in which he considered the physiologic and therapeutic effects of water, along with an extensive discussion of hydrotherapeutic techniques. The scientific and lay literature of this period shows a wide disparity of thought as to the validity and efficacy of hydrotherapeutic treatments. In Germany the uses of hydrotherapy were openly embraced, whereas in nearby France hydrotherapy was seriously questioned, never becoming as popular or widely used. During the twentieth century, the popularity of hydrotherapy treatments declined, along with the n u n bers of practitioners and institutions providing treatments. One of the few physicians to maintain an active practice in hydrotherapy was Dr. O.G. Carroll, a naturopath practicing for many years in Spokane, WA. He developed a specific constitutional hydrotherapy treatment, which is currently receiving an increased amount of interest from the naturopathic profession. Although hydrotherapy declined in use for many years, it is rightfully being revived at the present time. It is a highly effective, noninvasive means of treating the sick, which may be used both in the office and in the home. It is also economical and involves patients directly in their care. As such, hydrotherapy is an ideal naturopathic treatment modality.

PROPERTIES OF WATER Water has several unique properties that contribute to its effectiveness as a therapeutic agent. It has an ability to store and transmit heat, which renders it most appropriate for treatment purposes. Water absorbs more heat for a given weight that any other substance-almost twice as much as alcohol or paraffin, 10 times more than copper or iron, and 30 times more than lead or gold. Water is also a good conductor of heat. The solvent properties of water account for its usefulness in the most common of all hydrotherapy procedures, baths and showers. Water is commonly considered the universal solvent. Water’s nontoxicity allows for its use both internally and externally, even in individuals who are extremely sensitive to their surroundings. Water also has the ability to change states within a narrow, easily obtainable temperature range. As ice, it is an effective cooling agent. In the liquid state, water may be applied as packs, baths, sprays, compresses, and douches at any desired pressure and temperature. As a vapor, it may be employed in vapor or steam baths or by inhalation. Because the density of water is near that of the human body, it can be used as an exercise medium for patients with paralysis, inflammations, or a t r ~ p h y . ~

Upon immersion of the body in water, hydrostatic pressure is exerted on the body surface, which has the effect of increasing venous and lymph flow from the periphery and increasing urine output. Water is also unique in that it is universally available, readily accessible, and applied with relatively simple and inexpensive equipment.

Physiologic Effects The physiologic effects of hydrotherapy may be classified as thermal, mechanical, and chemical. Thermal effects are produced by the application of water at temperatures above or below that of the body The greater the variation from body temperature, the greater the effect produced, other factors being equal. The mechanical effects are produced by the impact or force of water acting on the surface of the body in the form of sprays, douches, frictions, immersions, whirlpools, etc. The chemical effects are produced when it is taken by mouth or used to irrigate a body cavity, such as the large colon. The most commonly used effect, therapeutically, is the thermal one. It is the only one that will be dealt with in this section. Heat may be transferred from one object to another in several different ways, including conduction, convection, or conversion. In hydrotherapy the heating and cooling effects are produced by conduction of heat from the water to the body. The contact of water with the body is accomplished by means of baths, showers, sprays, packs, compresses, etc. The primary variable of concern is temperature, both of the water and of the patient. The temperature of the human body in a state of health is considered to be normal at 98.6" F orally, although it varies throughout the day from a low of near 97" F between 3 and 6 AM to a high of more than 99" F around 6 PM. These variations are important to consider when evaluating an individual before a hydrotherapy application. There is also a wide range of temperature variation within the healthy human body, as can be seen in Table 40-1.2 Body temperature is also a reflection of other factors, such as exercise, fasting, and ovulation. In an infant, the temperature may be elevated by 1" F to 3" F during a prolonged crying spell. Temperature of various tissues Tissue

Temperature (" F)

Skin

Average 93

Blood

Average 102

Brain Liver

104 106

Left ventricle of the heart

107

is immersed in water of various

Temperature (" F)

Description

Sensation

>lo4

Very hot

Can tolerate for only a short period

98-104 95-98 92-95 80-92 65-80 55-65 32-55

Hot

Skin redness if prolonged

Warm

Comfortably warm

Neutral

No sensation

Tepid

Slightly cooling

Cool

Cool

Cold

Sensation of coldness

Very cold

Pain and numbness

During a fever, the temperature is elevated due to any of several factors including the following: Infection Tissue destruction Malignancy Foreign proteins in the blood Dehydration Hormonal imbalances Muscular or chemical activity Proper evaluation of the degree and cause of a fever is necessary before hydrotherapy treatments. When we consider water temperature, the terms "hot" and "cold are related to body temperature. The range of temperatures useful in hydrotherapy applications varies from very cold to very hot. Table 40-2 provides general terminology. Deep well water is near 53" F. Cold tap water in Seattle varies in temperature throughout the year depending on the depth of the pipes and other exposures to the environment. During the winter it may be as low as 40" F, and in the summer as high as 60" F. This temperature variation may be a significant factor in hydrotherapy treatments; therefore it is advisable to be aware of the water temperature when using hydrotherapy techniques.

HYDROTHERAPYRESEARCH In a 1996 article Doering, Brix, Schneider, and Rimplefl discuss their study of the effect of hot and cold applications on cerebral hemodynamics and cerebral metabolism. Their purpose was to determine if local thermal applications would affect central nervous system reactions. Hot packs and cold packs were applied to the thighs of volunteers. Before, during, and after treatment the researchers measured cerebral blood flow velocity (CBFV),cerebral respiratory chain enzyme cytochrome aa3 (cCytaaS),and cerebral oxygen saturation (cHb02).

Therapeutic Modalities

When cold packs were applied, CBFV increased, whereas cCytaa3 and cHb02 both decreased. Upon removal of the cold packs, there was a sigruficantincrease above baseline of both cCytaa3 and cHb02. When hot packs were applied, cCytaa3 increased significantly and then decreased with removal of the hot stimulus. Likewise, with hot applications there was an increase in cHbOz during the treatment phase and a decrease following removal of the hot application. These results are in agreement with the principles of hydrotherapy as discussed elsewhere in this article: the spinal reflex response, the contrary response to hot and cold applications, and the reaction to cold.

Local and Systemic Effects of Cold Applications Cold applications may be made by means of ice, cold water, cold air, or the evaporation of water or other liquids from the surface of the body. Although the applications may vary, the principles and effects remain consistent. The primary or direct effect of cold applications is depressant in nature, leading to a decrease in function, either locally or systemically, depending on the application. The longer and colder the application, the longer and more intense the depressant effect. Local cold applications produce vasoconstriction in the local tissues that leads to a slowing of the local circulation. If the cold application is long, intense, and covering a large enough area, a slowing of the general circulation may occur. The migration of leukocytes and inflammatory agents from the vascular system into the local tissues is impeded and local metabolic activity is decreased. Nerve conduction velocities are diminished, resulting in decreased sensation and slowed motor response. Muscle tissue tends to contract, and connective tissues become less plastic. As a result of the decrease in local circulation, intense cold applications may result in a great depth of penetration. As we know from frostbite, it is possible to literally freeze tissues solid. Hence, care should be taken when applying ice packs. The greatest benefits of local cold derive from the vasoconstriction response, decrease in nerve conduction velocity, and the tendency of muscles to contract in response to cold applications. Inflammatory responses may be controlled by cold applications, leading to a better healing response to sprains and strains. Pain may be diminished through the mechanism of reduced nerve conduction velocity. Cold applications may assist in the tonification of muscle tissue, leading to benefits such as increased urinary sphincter tone. General applications of cold are hypothermic and produce a peripheral vasoconstriction with shunting of the blood to the core. There is a general decrease in the metabolism, heart rate, and respiratory rate. Muscles

become sluggish, the digestion is retarded, and eventually stupor sets in before death finally occurs. Few therapeutic applications are available for general applications of cold. Probably the best use is in lowering body temperature caused by fever due to illness or increased core temperature from exposure or exercise. As the body responds to the cold application, there is a return to normal function, which may lead to a state of increased activity. This is known as the secondary, or indirect, effect of cold, also termed the ”reaction.” If the cold application is a short one, the reaction follows quickly, its intensity reflecting the intensity (i.e., coldness) of the application. The secondary effect, or reaction, occurs only when the body has the vitality to respond to the cold, either following its removal from the body, in such applications as showers, sprays, and baths or after the body has warmed the application, in such cases as cold compresses or packs. Generally, the colder the application the greater the reaction. The reaction to a brief, vigorous cold application produces a slowing of the heart rate with a mild increase in blood pressure. Muscle tone is increased, and an increase in heat production is triggered. There is an increased sense of vigor and well-being. Many hydrotherapy techniques are directed at producing the reaction to the cold application. Cold applications are often prescribed for the relief of pain. Saeki5 found cold, but not hot, applications to be useful in the relief of prickly pain sensations experimentally induced in study subjects. Pain sensations were measured on the visual analog scale. Skin blood flow (BF) and the skin conductance level (SCL) were measured as well. Cold applications decreased pain, BF, and SCL, whereas hot applications increased pain, BF, and SCL. In 2002 a small (19 patients) study titled “To Evaluate the Effect of Local Application of Ice on Duration and Severity of Acute Gouty Arthritis” was published.6 The researchers divided the group in half. Both groups received oral prednisone 30 mg tapered to 0 mg over 6 days and colchicine 0.6 mg daily. Group A was treated daily with ice, Group B was not. At the end of a 7-day trial, Group A participants had a sigruficant reduction in pain over the control group. Schlesinger and colleagues6 concluded: “Joint circumference and synovial fluid volume tended to be more effectively reduced after 1 week of therapy in the ice group compared with controls, but these did not achieve statistical significance.” In 1993 Finan and colleagues’ tested the effects of cold applied to the abdomen of women who had undergone exploratory laparotomy. The cold was applied to 13 patients and not to 12 controls using a Hot/Ice Thermal Blanket. Self-administered morphine use was measured in both groups, with the cold group using more morphine on the first day postoperatively than the control group.

Hydrotherapy

Cold sponging has often been recommended for the reduction of fevers in children. Two articles published in 19978,9compared the use of sponging to oral antipyretics. Both studies concluded that sponging is more effective than medication in the first 30 minutes, but after that, the antipyretic medications are more effective. In 2002 Knoll, Wimmer, Gumpinger, and Haberl'O published the results of a study performed to evaluate the safety of mild hypothermia for stroke victims. Slight hypothermia has been shown to be neuroprotective in animal models. The question these researchers asked was if hypothermia would be safe for human use. The researchers concluded: "Continuous body core temperature reduction of 1"C to 2" C may safely be attained by a cooling mattress in nonventilated stroke unit patients."

Local and Systemic Effects of Hot Applications Heat may be applied to the body in various ways, including hot packs, fomentations, steam, hot air, baths, and showers.All hot applications produce definite physiologic responses, which are attempts to eliminate heat in order to prevent a rise in local and systemic temperatures. The effects produced by hot applications depend on the mode, temperature, and duration of the application and the condition of the patient. Intense moist heat applied for a long period of time (several minutes) has a depth of penetration not exceeding about 3.4 cm. A local vasodilation occurs, increasing local BF. The increased BF through the area carries away heat conducted into the tissues from a hot application and limits the depth of penetration. (This "radiator-like" effect can be overcome by intense applications of heat that are destructive to the tissues, and deep tissue destruction can occur.) Local hot applications result in increased arterial and venous capillary pressure, arterial and venous capillary oxygen carrying capacity, local metabolic activity, and migration of lymphocytes through vessel walls and into the local tissues. Local sweating is increased, and muscle relaxation occurs. General hot applications can have dramatic effects on the cardiovascular system. Peripheral dilation occurs with a marked increase in BF of as much as 400%, the pulse rate increases (6 to 10 beats per minute per 1"F rise in body temperature), cardiac stroke volume decreases, systole increases initially followed by a decrease in both systole and diastole resulting in an increased pulse pressure. The respiratory rate increases some five to six breaths per minute per 1"F rise in body temperature. Hyperventilation may occur and result in respiratory alkalosis. The blood volume increases as a result of the uptake of fluids from the tissues, leading to a decrease in the hematocrit.

A transient leucopenia occurs in the first few minutes following a hyperthermia treatment, followed thereafter by a leukocytosis. Sweating is increased, leading to a loss of water, salt, urea, uric acid, creatinine, sulfates, lactic acid, and other metabolites. Water at 98" F or above is generally perceived as hot, and water higher than 104" F is considered very hot. At 120" F, an immersion bath becomes unendurable, although small areas of the body, such as the hand, may be conditioned to endure a temperature of 10" to 15" higher for short periods. The mucous membranes, unlike the skin, may endure temperatures as high as 135" F, which accounts for our ability to drink very hot liquids, such as tea or coffee. Hot air may be tolerated by many individuals for fairly long periods, such as in a sauna, in which the temperature may reach as high as 200" F. Although exposure to the high temperatures of hot tubs and saunas has become quite popular in recent years, Kellogg believed that repeated and prolonged use may act to weaken the individual, unless counteracted by frequent cold applications, such as showers or ablutions2 In general we should consider that hot relaxes and sedates while cold stimulates, invigorates, and tonifies. However, very hot can stimulate and also be destructive while prolonged cold can be depressive and destructive. A comparison of the effects of hot and cold on several body systems is given in Table 40-3.

Local Hot Applications Inhalation of steam for the treatment of the common cold has often been prescribed. Four studies"-14 published between 1987 and 1994 demonstrated the benefit of steam inhalation regarding symptoms and nasal airflow. One of these studied3 demonstrated a decrease in inflammatory mediators in the local tissues. Another" also measured viral shed in volunteers with experimental cold. In that study, no decrease in the shedding of rhinovirus was detected. These findings were confirmed in a review performed by The Cochrane Library.15 Other local hot applications have also been used clinically. A Cochrune Reviezd6 of interventions for chronic abacterial prostatitis concluded: "The routine use of antibiotic and alpha blockers for chronic abacterial prostatitis is not supported by the existing evidence. The small studies examining thermal therapy appear to demonstrate benefit of clinical significance and merit further evaluation." Two recent studies17J8of the treatment of benign prostatic hypertrophy using thermotherapy both demonstrated a sigruficantdecrease in bladder outlet obstruction. One of these studies used heated water in a closed loop catheter system.17The other used high-energy microwave radiation to heat the tissues.18

Cold Systedorgan

Primary

Secondary

Hot

Skin Blood vessels Respiration Heat loss Blood vessels

Constriction Decreased Decreased Constriction

Dilation Increased Increased

Dilation Increased Increased

Dilation

Dilation (constriction if intense)

Heart

Rate increased

Rate decreased

First decreased, then increased

Nerves

Numbed

Excited

Muscles

Volume decreased

Volume increased

Respiration

Slowed and deepened

Rate increased

Stomach

Motility and HCI increased

Motility and HCI decreased

_ _ _ _ _ ~ ~ _ _ _

Modified from Kellogg JH Rational hydrotherapy, ed 4 Battle Creek, MI. Modern Medicine, 1923 721-722

Physicians do not normally think of hot applications in the treatment of acute sports injuries. However, one recent study19 compared the use of hyperthermia to therapeutic ultrasound. In comparing 21 randomized patients with acute muscular injuries of different sites and severity to 19 controls, researchers discovered that after 2 weeks of treatment, the hyperthermia group had signhcantly less pain and faster hematoma resolution.

General Hot Applications The presence of fever has long been associated with better survival and shorter duration of disease in cases of infection. Many studies have demonstrated the causes of that beneficial response. Four studies reviewed for this chaptePB demonstrated the activation and mobilization of blood mononuclear cells with hyperthermia treatments. One of these studies*"demonstrated signhcantly increased serum cortisol, plasma norepinephrine, and plasma epinephrine and hypothesized that these elevated stress hormones were responsible for the rise in mononuclear cells. One study" concluded that "fever-induced Hsp70 expression may protect monocytes when confronted with cytotoxic inflammatory mediators, thereby improving the course of the disease." Two recently published studies of sauna bathing24,E demonstrated improved vascular endothelial function in patients with coronary risk factors and patients with chronic heart failure. In both studies patients were treated in saunas at 60" C for 15 minutes daily for 2 weeks.

PRINCIPLES OF BLOOD MOVEMENT WITH HYDROTHERAPY In order to promote healing, either locally or systemically, it is important to maximize circulation of well-oxygenated, nutrient-rich, toxin-low blood. Hydrotherapy techniques

are one of the most effective means of accomplishing this, if used in conjunction with proper levels of activity, optimal nutritional intake, and adequate detoxification. Four basic modifications of blood movement exist within the body: Increased rate of BF through an organ or area of the body Decreased rate of BF through an organ or area of the body Increased volume of blood in an anemic area Decreased volume of blood in a congested area In order to accomplish these modifications, five relevant physiologic principles can be applied: Revulsive effect Derivative effect Spinal cord reflex Collateral circulation Arterial trunk reflex

Revulsive Effect The revulsive effect provides a means of increasing the rate of BF through an organ or other body part, such as an extremity. The most effective means of accomplishing this is by using alternating hot/cold either as compresses, baths, showers, sprays, etc. This is commonly referred to as contrast hydrotherapy. Local, alternating, hot and cold applications produce marked stimulation of local circulation. It has been shown that a 30-minute contrast bath produces a 95% increase in local BF when the lower extremities alone are immersed. When all four extremities are immersed at the same time, there is a 100% increase in BF in the upper extremities and a 70% increase in the lower extremities.26

Hydrotherapy

Contrast applications to the area of skin that is in reflex relationship to an organ increase the functional activity of that organ. Hence, liver function is increased by contrast application applied over the right upper quadrant of the abdomen. Several studies have researched the optimal treatment times for revulsive effects. Woodmansey and coll e a g u e ~found ~ ~ 6 minutes of hot application and 4 of cold to be optimal for the British subjects he studied. Krussen28found 4 minutes hot and 1 minute cold to be the best treatment protocol. Moorz9states that 3 minutes hot, followed by 30 to 60 seconds of cold, provides satisfactory clinical results. From these variations, it can be inferred that, due to the variations in procedures and locales, it is best for practitioners to determine their own ideals, based on their observations of clinical results. Basically, the cold application need only be long enough to produce vasoconstriction, and this can be shown to occur in as short a period as 20 seconds. Repetition of applications is another important variable to be considered when applying revulsive treatments. A series of three hot/cold applications seems to be practical. Most individuals show a decreasing secondary reaction to repeated applications of cold. Due to the increased BF within an area, the revulsive effect is ideal for treating situations presenting primarily as congestion. An example of this effect is the use of alternating hot/cold compresses over the face for sinus congestion. As a powerful decongestant, the revulsive effect also acts as an analgesic for pain resulting from congestion. Because of its marked stimulation of local circulation, the revulsive treatment is an exceptionally effective hydrotherapeutic procedure and one of the most generally useful considering its simplicity.

Derivative Effect The derivative effect may be considered the opposite of the revulsive effect. Its primary intent is to alter the volume of blood in an organ or area of the body. This effect is best obtained by the prolonged use of either cold or heat depending on whether one wants to draw blood into an area (hot application) or to drive blood out of an area (cold application). An example of the derivative effect would be the prolonged application of heat to the feet, as with a hot foot bath, in order to decrease congestion in the head. This form of treatment may be quite successful for certain forms of congestive headaches. In general, the greater the area of the body exposed to the application, the more extreme the temperature, and the longer the application, the greater the effect.

Spinal Reflex Effect The spinal reflex effect (see Moo$9) provides a means of affecting a distant area of the body through a local application. A sufficiently intense local application of hot or

cold not only affects the immediate skin area but also causes remote physiologic changes, mediated through spinal reflex arcs. These effects have been carefully observed over many years and have led to a mapping that correlates each surface area with its corresponding internal area or organ, or both. Most texts on hydrotherapy contain such a diagram.2,29 Some examples of studies dealing with specific reflex effects follow. Hewlett,30 Stewart?l and B r i ~ c o eall ~~ noted changes in BF in the opposite arm and hand when one arm and hand were placed in hot or cold water. R ~ h r n a n nobserved ~~ that when cold was applied to the epigastrium, there was a decrease in tone of the stomach, with a quieting of the pyloms. Heat at 50" C applied to the epigastrium produced increased tone in a relaxed stomach and decreased tone in a contracted stomach. PoultonMdemonstrated that esophageal function could be influenced by irritation of the skin over the sternum. Bing and T ~ b i a s s e nshowed ~~ reflex relationships between the skin of the abdominal wall and the colon. They also demonstrated a reflex relationship between the lungs and the skin of the chest wall. Kuntz"6stated the following: In view of the facility with which cutaneous stimulation elicits reflex visceral reactions, particularly vasomotor changes and changes in the tonic state of the visceral musculature, it must be apparent that many visceral disorders, particularly disorders of the gastrointestinal canal, may be influenced beneficially by appropriate stimulation of the corresponding cutaneous area.

Fisher and Solomon37stated: "externally applied heat not only decreased intestinal blood flow, but also diminishes intestinal motility and decreases acid secretion in the stomach, while cold has the opposite effect." This is an example of a contrary effect in which the reflex effect is not the same as that observed in the local reflex skin area (i.e., local heat decreases, rather than increases, intestinal BF as one might expect). Prolonged cold has the opposite effect. Tables 40-4 through 40-6 show some of the observed reflex effects of hydrotherapeutic p r o c e d ~ r e s . ~ ~

Collateral Circulation Effect The collateral circulation effect may be considered as a special case of the derivative effect.2In general use, the derivative effect involves blood volume changes from one area of the body to another, as previously discussed. The collateral circulation effect, on the other hand, more specifically considers the local circulatory effects on deep (rather than superficial) collateral branches of the same artery. Considering the circulatory patterns of a large body part, such as the thigh, it is clear that both superficial and deep areas are supplied by the same artery. A hot

I

Reflex effects of short cold

Reflex effects of prolonged heat

Application location

Effect

Application location

Effect

One extremity

Vasodilation in contralateral extremity

General peripheral vasoconstriction

Abdominal wall

Decreased intestinal blood flow, intestinal motility and acid secretion

Local application of intense cold as brief as30seconds

Pelvis

Relaxes pelvic muscles, dilates blood vessels, increases menstrual flow

Face, hands, and head

Increase in mental alertness and activity

Precordial area

Increase in heart rate and stroke volume

Precordium

Increases heart rate, decreases its force, and lowers blood pressure

Chest, with friction or percussion

Initial increase in respiratory rate, then slower, deeper respiration

Chest

Promotes ease of respiration and expectoration

Trunk

Relaxes ureters or bile ducts, relieves renal or gallbladder colic

Over kidney

Increases production of urine

in order to increase circulation and speed healing of the injured part.

GENERAL RULES OF HYDROTHERAPY

ADDlication location

Effect

Trunk of an artery

Contraction of the artery and its branches

Nose, back of neck and hands

Contraction of the blood vessels of the nasal mucosa

Precordium (ice bag)

Slows the heart rate and increases its stroke volume

Abdomen

Increases intestinal blood flow, intestinal motility, and acid secretion

~~

Pelvic area

Stimulates muscles of the pelvic organs

Thyroid gland

Contracts its blood vessels and decreases its function

Hands and scalp

Contraction of brain blood vessels

Acutely inflamed joints or bursae

Vasoconstriction and relief of pain

application to this area dilates the surface vessels, drawing blood to the superficial areas and concurrently decreasing the BF to the deep areas. A cold application causes the opposite effect. Local compresses and fomentations are the most commonly used techniques to affect collateral circulatory changes.

Arterial Trunk Reflex The arterial trunk reflex effect is a special case of general reflex effects2 It has been observed that prolonged cold applied over the trunk of an artery produces contraction of the artery and its branches distal to the application. Prolonged hot applications have the opposite effect of producing dilatation in the distal arterial bed. An example of this effect is the application of prolonged cold to the area of the femoral artery in the groin in order to decrease BF in a foot or ankle that had sustained an acute injury that resulted in either internal or external hemorrhage. Following the acute phase, prolonged hot applications might be used in like manner

1.The first rule of hydrotherapy is the same as for any therapy: Treat the whole person. This involves considering all aspects, including medical history, current condition, current medications, and any other relevant information. 2. Use hydrotherapy treatments in a coordinated and integrated manner with any treatments or medications the individual is receiving. 3. Always measure the person’s temperature before beginning a treatment. If the temperature is below normal, apply more heat or leave the hot applications on for a longer time. If body temperature is above normal, use less heat and more intense cold during the treatment. 4.Explain the treatment procedure before beginning, including the technique to be used, the duration, frequency, and any other relevant factors. Try to ensure that the patient feels comfortable with the procedure before beginning. 5. In order to provide as precise a treatment as possible, grade the patient in terms of age, severity of problems, vitality, emotional state, circulatory condition, etc. Be especially careful with young or elderly persons, individuals who are chilly, have cardiac problems, are weak or debilitated, are obese, or have other severe physical compromises. For individuals with insulin-dependent diabetes, the application of heat to the extremities may be contraindicated. The body dissipates heat conducted into the tissues in much the same way a radiator works. The heat is transferred to the circulating blood. Cooler blood is brought into the area and hence the heat is “moved elsewhere.’’ With poor circulation, less heat is dissipated and the local tissue temperature rises, perhaps to unsafe levels. Diabetics frequently have arterial disease, which may reduce BF to an extremity. The application of heat increases the metabolism of the tissues. Due to impaired circulation, the metabolic needs can quickly overuse

the nutrients and oxygen available from the blood and cells may die from oxygen depletion simply as the result of hot application^.^^ Therefore hot foot baths are contraindicated in diabetics. For diabetics with conditions in which a hot application to the feet would normally be the treatment of choice, a large hot compress can be used instead to the lower abdomen, groin, and thighs in order to get a reflex reaction in the lower extremities. Diabetics may also display peripheral neuropathies that decrease their ability to sense heat, thereby increasing the possibility of causing a bum with hot applications. Other individuals with neurologic injury or disease should also be treated with extreme caution during hot applications. 6. The environment in which the treatments are given should enhance and stimulate the healing forces as much as possible. This may include such considerations as color of the room, light intensity, music, and plants. 7 If a patient becomes chilled during a treatment, it may be necessary to stop the treatment and warm the person. Sometimes it may suffice to warm the person (by such means as hot drinks, friction rubs, additional blankets, or a hot water bottle to the feet) while continuing the treatment. If the person fails to warm following these attempts, then stop the treatments and warm him or her. Never allow a patient to become chilled to the point of shivering. 8. Follbwing a hydrothirapy treatment, avoid excessive heat in the form of overly warm clothing, overly warm rooms, sun exposure, or exercise. Excessive heat may slow or prevent the body reaction to the treatment and negate the benefit of the treatment. 9. It is best to do the treatment at an optimal time of day for that patient. It is best to do treatments before meals, or at least 1hour after a meal.

As with any therapy, it is important to practice hydrotherapy with a research orientation, noting unusual reactions and physiologic effects. Many physiologic parameters, such as urine chemistries and microscopic components, specific gravity, body temperature, and blood sugar levels, may be easily monitored and recorded during treatment. This information helps to optimize the treatment protocols, stimulates further research, and validates hydrotherapy as an effective and useful therapeutic modality.

cases, result simply from the individual's reaction to the treatment. They may, in the long term, be beneficial. Any time an individual experiences an undesired effect following a treatment, the therapist should review the treatment's length, intensity, and appropriateness for the individual at this time. If more treatments are considered, they may need to be modified in order to lessen the undesired effects. Some of the possible side effects of hydrotherapy treatments are as follows: Headache (resulting from too long or intense a treatment, or from the release of toxic products in the body) Vertigo Nervousness Aches and pains Insomnia Hyperventilation Nausea Palpitations Faintness Chilliness A synergistic effect has been demonstrated with hyperthermia and radiation treatments given in cancer care. Any patient receiving radiation therapy should not be indiscriminately treated concurrently with hyperthermia. Following an unpleasant reaction to a hydrotherapy treatment, discontinue the treatment and wait at least 2 to 3 hours before attempting another treatment. In cases of chilliness, always act quickly to warm the person. Coaching the person in deep, slow-breathing exercises for several minutes often relaxes the person and decreases the reaction.%If the treatment occurs in the practitioner's office, the practitioner should reassure himself or herself that the patient has fully regained balance before allowing him or her to leave. Although these effects may occur during or immediately following treatments, they may also occur as long as 24 hours later. Therefore it is important for practitioners to be available to patients during off-duty hours.

SAFETYASPECTSOFHYDROTHERAPY Pregnancy

POSSIBLE SIDE EFFECTS OF HYDROTHERAPY

What to do or take in pregnancy is always a concern. Bathing in hot water is no exception. Ridge and B ~ d d , 3 ~ in a letter to the editor of the New England Journal of Medicine, summarized these concerns and concluded "that for pregnant (or potentially pregnant) women using a spa pool at a water temperature of 40" C (104"F), any immersion longer than 10 minutes may be too long."

Although hydrotherapeutic procedures are generally mild, they may in some situations produce unexpected or undesired effects. These effects may be the result of improperly applied treatments, but they may, in some

Two studies published in 199840,41 demonstrated no adverse cardiovascular effects from bathing in water

Hypertension and Cardiovascular Disease

Therapeutic Modalities above 40" C and a response to heat stress no different form normotensive subjects. In a 1999 study of patients with coronary artery disease treated with sauna,42it was shown that "there were no arrhythmias of ECG changes," but there was evidence of "scintigraphically demonstrated myocardial ischemia."

HYDROTHERAPYTECHNIQUES The various ways in which water may be applied to the human body therapeutically is only limited by the imagination of the practitioner. J.H. Kellogg, in his seemingly exhaustive treatise on hydrotherapy, devotes 541 pages to describing the techniques of hydrotherapy. Several other books describe in detail specific procedures and t e c h n i q ~ e sThose . ~ ~ desiring to use these techniques in practice are encouraged to obtain one or more of these reference works. To successfully use hydrotherapy, one must be familiar enough with the procedure to use it in an efficient and competent manner. Although the equipment required for these techniques is quite simple, it is important that it be clean, easily available, and maintained properly. Care for the comfort and confidence of the patient greatly increases the effectiveness of the treatments.

Compresses Compresses are of three basic types: hot, cold, and alternating hot and cold. They are each applied using cloth, or other compress material, which is wrung out to the desired amount of moisture and then applied to any surface of the body. A single compress consists only of layers of the wet material, whereas a double compress is one in which the wet cloth is completely covered by dry material, usually wool, which acts to prevent cooling by evaporation or heat loss. This allows the body, in the case of a cold double compress, to warm the area, thereby producing a secondary reaction to the cold. Compresses are commonly referred to by the area of the body they are applied to, such as the throat, head, joint, trunk,or limb.

Cold Compresses and Packs A cold compress consists of a cloth wrung from cold or ice water and then applied to the body. Some practitioners may add solutes to the water such as sodium chloride, baking soda, Epsom salts, boric acid, or cider vinegar. Herbs may also be used to create a more specific effect from the compress. Some commonly used herbs are hayflower, oatstraw, and fenugreek, made as teas into which the compress cloths are dipped. Packs are also used if the goal is to cool the tissues more aggressively. Packs

may be made from crushed ice or purchased as commercially available gel packs that may be kept in the freezer. The cold puck or compress has primarily a vasoconstrictive effect, both locally and distally. Due to this effect, it may be used to prevent or relieve congestion, reduce BF to an area, prevent edema following injury, inhibit inflammation, and relieve pain due to congestion. It may also be used to reduce body temperature when applied over a large area of the body. Compresses are renewed frequently (every 1to 5 minutes) in order to maintain the primary cold effect, whereas packs remain cold longer. The temperature of a cold compress depends on the specific problem being treated, as well as the state of health of the patient. In general, the colder the application, the briefer the period of application. Cold compresses should not be used locally in a person who is chilly or who has pleurisy, sinusitis, or acute asthma, as these conditions may be seriously aggravated.

Hot Compress The hot compress is a prolonged application of moist heat, generally to a local area of the body. The fomentation is a special case of a hot compress, which provides prolonged exposure at a higher temperature. Hot compresses and fomentations have several therapeutic effects. In many situations they may create an analgesic effect, thereby decreasing pain. They are generally more effective locally for pain resulting from spasm than for pain due to congestion. They also create a derivative effect, which may be used to increase BF to the periphery, thereby decreasing internal congestion. By applying short, intensely hot compresses, a stimulation effect may be obtained. This may be used to increase BF to a part, to stimulate certain organ functions, to decrease others, and to produce tissue warming and relaxation. Mildly hot compresses may be beneficial for their sedative effects in treating insomnia, nervous tension, and mild muscular spasms. Fairly hot compresses may be applied directly to the skin surface, with care taken to not bum or startle the patient. As stated previously, hot applications are contraindicated on the extremities of diabetic individuals. When treating the elderly or those with impaired neurologic function, edema, or decreased circulation, special caution must also be taken. Fomentations are commonly applied at temperatures that are not tolerated directly on the skin, and therefore must be applied over a bath towel placed on the area.

Heating Compresses The heating compress, also known as the cold double compress, consists of a cold compress covered completely by several layers of dry material such as flannel or wool.

Hydrotherapy

It is allowed to remain on until warmed by the body. The layers of dry material prevent heat loss by evaporation, thereby permitting accumulation of heat and cresting a general heating effect. Heating compresses are used most commonly in upper respiratory infections, such as sore throats, bronchitis, influenza, pneumonia, and swollen lymph glands in the neck. They may also be applied over the trunk or abdomen, genital area, joints, limbs, or feet. A classic example of the heating compress is the wet sock treatment. This treatment is used for congestive headaches, sinusitis, and otitis media in young children. Socks are wrung from cold water and pulled on the feet. These are then covered with another pair of socks (preferably wool) and left overnight to be warmed by the patient. Frequently, the wet socks are dry by morning. The primary effect of the heating compress is to increase the local circulation, thereby providing for increased nutrition and oxygenation of the tissues, as well as increased elimination of metabolic waste from the area. In the previous example of wet socks, it is the derivative effect of the wet socks treatment that is the desired effect. As with cold compresses, the temperature of the initial application depends on the state of the patient and the condition being treated. In general, the colder the application, the stronger the secondary reaction to the cold. As weak and debilitated patients are unable to generate a strong secondary reaction, cool rather than cold application may be indicated. The same general precautions as for a cold single compress should be followed.

Baths Baths are full or partial immersions of the body into water of various temperatures: cold, hot, or contrasting. Bath waters may contain additional substances such as salts, minerals, herbs, or medications and may be in an agitated state, as with a whirlpool.

Hot Full-Immersion Baths These baths are given within a temperature range of 100" F to 106" F for 20 to 60 minutes or longer. They are indicated for rheumatoid arthritis, to aid in relief of muscular spasms, for cleansing the body, to stimulate the immune system, to induce sweating, and many other purposes. They are probably most useful in applying heat to produce a hyperthermic response in the tissues or to raise core temperatures. As stated previously, hyperthermia treatments have been found useful in the treatment of infections and malignancies. Water immersions for hyperthennia have the benefit of low cost and more consistent heating of tissues. When performing local immersions, the water temperature may be as high as is tolerable. The duration of treatment is typically 15 to 20 minutes. Treatments should be given daily.

Whole body immersion at home should be limited to a water temperature of approximately 104" F and not longer than for about 30 minutes. Treatments may be given daily for several treatments, but it may be better to limit daily use to three to four treatments. Treatments should be given every other day if many treatments are to be undertaken. Individual tolerance varies from these suggestions. Patients should have assistance when performing hyperthennia treatments at home. When hyperthermia treatments are given in the office, close supervision may allow more aggressive treatment. The water temperature may be increased to 106" F, and the duration of treatment may exceed 60 minutes. Patient tolerance is the key to performing safe and effective hyperthermia. When performing hyperthermia treatments, the following precautions should be observed regardless of whether the treatment is performed at home or in the office: Hypotension may result from hot immersions. When arising from the tub, patients may become lightheaded and lose their footing. Patients should not take hyperthermia treatments on either an empty or full stomach. Too little food may result in a hypoglycemic episode, and too much food may result in nausea and vomiting. Hyperventilation sometimes occurs. On rare occasions patients may go into early tetany from respiratory alkalosis. Being present with the patient and coaching his or her breathing can prevent this. Headaches can and often do occur. These can be prevented by the early and frequent use of cold compresses to the head, face, and ears. The sauna or steam bath can often be used interchangeably with the immersion bath. Immersion, sauna, and steam are most similar with respect to their immune stimulant and detoxification benefits. In most instances they are best followed by a brief cool bath, shower, or spray. Prolonged hot tub baths are never appropriate in the very old or very young, weak or anemic persons, individuals with severe organic disease, or in anyone with a tendency to hemorrhage. Given for brief periods, they may help to reduce fevers by creating peripheral vasodilation, thereby promoting an increased heat loss.

Neutral Bath The neutral bath is a full immersion bath given at the average temperature of the skin, 92" F to 95" F, in which the recipient has neither the sensation of being warmed nor that of being cooled. A minor variation in temperature of as little as 2" F may create a totally different therapeutic effect. As the ideal temperature depends on

Therapeutic Modalities the patient's condition and reaction to the water, it is often better to use his or her sensation, rather than a thermometer, as a guide to adjusting the temperature. The duration of a neutral bath may vary from 15 minutes to 4 hours. If the bath lasts longer than 20 minutes, it is necessary to add warm water to maintain the temperature. The primary effect of a neutral bath is to create a state of decreased excitation. This sedative effect, similar to that produced in deprivation tanks, calms the nervous system. A second effect is activation of the kidneys, creating increased urinary output due to the absorption of water into the body during periods of prolonged immersion.48 It is aided by the neutral temperature, which provides no stimulus for water loss through sweating. Nephrotic patients display increased phosphate excretion following prolonged immersion; therefore they warrant special care when given prolonged immersion Lastly, the neutral bath causes a decrease in the surface temperature of the body due to the lack of the normal heat-producing stimulus of cool air on the skin. As a result, the surface may be cooled as much as 6" F, creating a tendency to chill following the bath. This effect necessitates special care in keeping the patient warm. When prescribed for home treatment, a neutral bath is best taken just before getting into bed, in order to avoid chilling. Therapeutically, neutral baths are most commonly used for their calming effects in cases of insomnia, anxiety, nervous irritability, exhaustion, or chronic pain. By increasing kidney output, they may be appropriate in detoxification programs for substances such as alcohol, tobacco, or coffee, or as an adjunct treatment for peripheral edema. They also serve a valuable role in the control of fevers in individuals who would not be able to react to stronger measures, such as the Brand bath. These patients would include the very young, very old, feeble, or exhausted. Start the baths at about 98" F and lower the temperature slowly over a period of 5 to 10 minutes to 92" F to 93" F, until the desired body temperature is rea~hed.4~

Sitz Bath The sitz bath is a partial immersion bath of the pelvic region. It is more easily given in a specially constructed tub but may also be effectively done in a regular bath tub. Often it is taken with the feet immersed in a separate tub of hot water before or during the bath. A sitz bath may be taken hot, neutral, cold, or contrast hot and cold. The sitz bath may be undertaken at home with a bathtub and basin of cold (ice) water. The patient should sit in the hot half bath (hot water above the navel) for the prescribed time. The cold application can then be

performed with a towel wrung from cold water. The patient wrings the cold towel, stands in the bath, and pulls the cold towel into the groin, holding it like a diaper for the time prescribed for the cold application. Care should obviously be taken when standing in a tub of water, especially when standing up from a hot bath. The hot sitz bath is generally taken for 3 to 10 minutes at 105" F to 115" F. The primary effect is analgesic. It may be helpful in cramps of the uterus or ureters, pain from hemorrhoids, ovaries or testicles, sciatica, urinary retention, and after cystoscopy or hemorrhoidectomy. It is followed by cool sponging or effusion of the area. Hot sitz baths are not indicated in cases of acute inflammation but may be appropriate for chronic pelvic inflammatory disease (PID). Hot applications to the pelvis are also contraindicated during menses in most instances. The hot sitz bath is best taken with a hot foot bath at 110" F to 115" F. Neutral sitz baths are more appropriate for situations of acute inflammation, such as cystitis and acute PID. They are given at 92" F to 95" F for between 15 minutes and 2 hours. It is necessary to provide adequate coverings during this period to avoid chilling. Neutral sitz baths may also be effective for pruritus of the anus or vulva. Appropriate herbs, salts, or other medications may be added to the water to optimize the treatment. The cold sitz bath is given immediately following a warm-to-hot sitz bath of 1 to 3 minutes and lasts (at a temperature of 55" F to 75" F) from 30 seconds to 8 minutes. It is important to ensure that the water level of the hot bath on the body is at least 1 inch above the level of the cold water. This ensures adequate warming of the area, thereby preventing chilling. Friction rubs to the hips during the cold sitz bath promote an increased reaction. The cold sitz bath is used mainly for its tonifying effects. It may be used for subinvolution of the uterus, metrorrhagia, atonic constipation, enuresis, atony of the bladder, and chronic prostatic congestion. Since it increases the tone of the smooth muscles of the uterus, bladder, and colon, it lessens the tendency to bleed from the uterus, the lower bowel, and rectum. Contrast sitz baths are given in groups of three (i-e., three alterations of hot to cold). Two separate tubs are necessary to facilitate this process. The hot is at 105" F to 115" F, the cold at 55" F to 85" F, with the temperatures again dependent on the condition being treated and the strength of the patient. A standard treatment would be 3 minutes hot and 30 seconds cold. The water level in the hot tub is set 1 inch higher than in the cold. Adequate draping is necessary to prevent chilling. As with all hydrotherapy treatments, one always finishes with the cold. The contrast sitz bath increases pelvic circulation and tone of the smooth muscles of the region. It is indicated

Hydrotherapy

in chronic PID, chronic prostatitis, atonic constipation, and other atonic conditions of the pelvis. The strong revulsive effect created increases the BF in the pelvic region dramatically.

Cold Friction Rubs and Ablutions Cold friction rubs, or ablutions, consist of frictioning the body in a predetermined sequence with cold water. They differ from sponging in that they are more tonifying and are done more vigorously with rougher materials. A woolen bath mitt works well, but if this is not available, a coarse washcloth or loofa may also be used. A whole body ablution is carried out with the patient lying supine, covered completely and not chilly. Using cool to cold water, the therapist dips the mitt into the water and vigorously causes friction on a portion of the body. Depending on the cooling effect desired, the mitt may either be saturated or wrung dry before the friction occurs. The body part is treated until reddening occurs. If the patient is weak, it is best to dry the areas as one proceeds using a coarse dry towel. If the patient is strong and vigorous, one can wait and dry the areas at the end of the treatment. One sequence for an ablution treatment would be, with the patient supine, to proceed from the chest to the arms, and then the legs, then, turning the patient over, to do the back of the legs and feet, the buttocks, and finally the back. Only that part being treated is exposed at any time. The primary effect of a cold ablution is tonic. Therefore it may be used for any condition in which you desire a tonifying treatment, such as fatigue following illness or surgery or after hot applications, such as saunas, whirlpools, or hot baths. It is an excellent prophylactic hydrotherapy technique when used regularly along with saunas, hot tubs, and massage.

Constitutional Hydrotherapy The constitutional approach to hydrotherapy was, as stated earlier, developed by Carroll and was developed as an application of first hot, then cold to the trunk, front, and back. Apart from contrast hydrotherapy applications, it is the most generally useful of the various hydrotherapy treatments. It is commonly used to balance body functions, strengthen the immune system, and promote healing. It is a useful adjunct to detoxification. Constitutional hydrotherapy may be used as an adjunct to the treatment of any condition. It may be used to treat acute conditions such as upper respiratory infections, bronchitis, asthma, stomach flu, and in chronic conditions such as irritable bowel, ulcerative colitis, PMS, and arthritis. (As a general rule of thumb “when in doubt, try constitutional hydrotherapy.”)

Materials The practitioner should have the following materials available: Bed or treatment table One double sheet folded end to end (or two twin sheets) Two wool blankets (or acrylic) Three bath towels (a small bath towel is best, one that when folded in half reaches side to side across the patient and from shoulders to hips) One hand towel Source of hot and cold water Low-volt electrical muscle stimulation (EMS) unit (electrical stimulation with constitutional hydrotherapy may be optional)

Procedure The practitioner should follow these steps:

1.While preparing two hot towels, have the patient undress to the waist and lie down face up between the sheets, under one blanket. 2. Place an oral thermometer in the patient’s mouth. 3. Place EMS pads on the back at the T6 level. 4.Auscultate the patient’s heart. 5. Place two hot folded bath towels (four layers) on the patient’s trunk,shoulders to hips, side to side. 6. Cover with sheet and one blanket. 7. Check patient’s temperature, leave on for 5 minutes. 8. Return with one hot bath towel and one cold hand towel. 9. Place the new hot towel on top of two old towels and flip all three towels. Remove two old hot towels, leaving the new hot towel in place. Place the cold towel on top of the new hot towel and flip again. Remove the hot towel, leaving the cold one in place. 10. Cover the patient and add an extra layer of blanket. 11.Turn on EMS to “strong” stimulation, AT PATIENT COMFORT LEVEL. Leave on for 10 minutes or until the cold towel is well warmed. 12. Return and remove the warmed towel. Move the EMS pads transabdominally to T12 and the supraumbilical position. Turn on the device for 10 minutes with intensity at “strong” stimulation, AT PATIENT COMFORT LEVEL. 13. Return with two hot towels and have the patient roll prone. 14. Place two hot folded bath towels (four layers) on the patient’s trunk,shoulders to hips, side to side. 15. Cover with sheet and one blanket, leave on for 5 minutes. 16. Return with one hot bath towel and one cold hand towel.

Therapeutic Modalities

17. Place the new hot towel on top of two old towels and flip all three towels. Remove two old hot towels, leaving the new hot towel in place. Place the cold towel on top of the new hot towel and flip again. Remove the hot towel, leaving the cold one in place. Leave on for 10 minutes or until the cold towel is well warmed. 18. Return and remove the warmed towel. Recheck oral temperature. If the patient is warm, he or she may leave at this time. If the patient is chilled, provide hot packs or dry friction rubs to warm him or her and alter your treatment approach next visit to prevent chilling. As a variation, the contrast may be narrowed (not as hot or cold) for the very ill or weak patient or may be pushed to the hot for sedation or to cold to tonify and strengthen.

Precautions/Special Considerations If using the patient’s bed, take care not to get it wet. Hot water from the tap is usually hot enough. The hot towel should be hot enough that it’s just possible to wring it out. The cold towel should be quite cold (use ice water), but wring it out thoroughly and use only one layer. If the patient has trouble warming the cold towel, massage the back (through the blankets and towel) and feet. Patients with asthma often react negatively to cold applications on the chest. For these persons, begin with a smaller cold towel applied to the abdomen only. With later treatments, gradually increase the size of the cold towel until the entire chest and abdomen can be covered without any negative reaction.

Wet Sheet Pack The wet sheet pack is one of the most useful of all hydrotherapy procedures. It may be done either in the office or as a home treatment, if adequate direction is provided. It requires from 1 to 3 hours, depending on the patient’s condition. The technique is common to most schools of hydrotherapy. Understanding the process completely before using this treatment is important:

1. Using either a bed or treatment table, place two wool blankets lengthwise on the table with a small pillow at the head. The blankets must be large enough to cover the person being treated. If wool is not available, acrylic is the next best choice. 2. The patient must be warm before the pack is applied. If not, the patient may be warmed by a hot bath or shower, dry blanket pack, diathermy over the back, or any other appropriate technique. 3. Once the patient is ready, a clean white cotton sheet (equal in length to the height of the patient) is wrung as dry as possible after being soaked in cold water. It is much easier if two people are available to wring out the sheet. The sheet is opened and placed lengthwise

along the table with equal amounts draped over each side of the table. The sheet should be 1 to 2 inches below the height of the blankets. 4. The patient now removes all clothing and lies on the wet sheet with shoulders 4 inches below the top of the sheet. Both arms are raised while the attendants quickly wrap one side of the sheet around the body, tucking it in on the opposite side, and carefully molding it to the body. Below the hips, the sheet is wrapped around the leg on the same side. 5. The arms are now lowered, and the opposite side of the sheet is drawn over the body, covering both arms. It also wraps the opposite leg. The wet sheet is quickly smoothed over the body to ensure complete contact and is tucked in around the feet. As this is a shocking experience, it should be performed quickly and efficiently. 6 . At this point, the blankets are quickly pulled over the body and tucked in firmly, ensuring there are no drafts around the neck or the feet. Additional blankets may be laid over the patient and tucked in as appropriate. A stocking cap may be pulled over the head to increase the heating effect. While the patient is in the pack, it is necessary to have someone nearby at all times. Sudden attacks of claustrophobia in some individuals can create extreme anxiety. Allowing the patient to have one arm free during the procedure does not adversely affect the outcome of the procedure itself and often prevents the claustrophobic reaction. However, should it occur, first remove the sheet from the feet, as this may allow enough movement to allay the attack. If this is unsuccessful, it may be necessary to stop the treatment. Providing hot teas is helpful throughout the treatment. If the patient complains of chilliness, add blankets, place a hot water bottle to the feet, or provide warm drinks. The wet sheet pack proceeds through four stages: tonic or cooling, neutral, heating, and eliminative. Depending on the desired effect, the therapist may wish to prolong any one specific stage:

Tonic stage. This stage may last from 2 to 15minutes and is finished when the patient no longer perceives the sheet as being cold. This phase is intensely alterative to the body, due to the intense thermic reaction induced. The length of this stage is directly dependent on the amount of water left in the sheet. For weak or exhausted patients, the sheet should be wrung out as completely as possible. For young, strong individuals for whom a more tonifying treatment is desired, more water may be left in the sheet.

Neutral stage. Once the sheet reaches body temperature, the person no longer feels cold. At this time,

the neutral phase begins. It may last from 15 minutes to an hour or longer, depending on the vitality of the patient. During this phase, there is a sense of calm that is similar to that experienced during a neutral bath. Often the patient falls asleep during this phase. This stage is indicated in cases of insomnia, anxiety, and delirium. In order to prolong the neutral phase, provide only adequate covering to prevent the patient feeling cool. Greater amounts of blankets trap more heat, and the neutral phase finishes sooner. Heating stage. As heat accumulates beneath the blankets, the patient gradually senses the warming and eventually begins to show light perspiration on the forehead. The time between the patient feeling warm and the beginning of perspiration is known as the heating phase. This may last from 15 minutes to 1hour. Elimination stage. The final stage begins when the body begins to perspire. In a febrile patient this stage is reached sooner. This stage is especially beneficial for those patients in a detoxification process such as from alcohol, tobacco, coffee, or other toxins. It may also be used with acute infections, such as colds, flu, or bronchitis. Certain skin conditions, such as jaundice, may also benefit from this stage, as well as acute inflammatory conditions, such as arthritis. During the elimination phase, it is important to provide adequate fluid to the patient. Herbal teas, used for either their diaphoretic or therapeutic effects, are most appropriate. This phase may last up to 1 hour. The treatment should be ended quickly if the patient begins to feel chilled or becomes uncomfortable. The treatment is ended by quickly removing the patient from the pack, frictioning the skin briskly with a dry towel, and having the patient dress. As this is often an intensive treatment, it should be followed with rest or appropriate activity. Lying in a warm room for an hour is an ideal follow-up to this treatment. If done at home, it is best done in the evening just before retiring.

1. Hippocrates. Hippocratic writings. In The Great Books. Chicago: William Benton, 1952. 2. Kellogg JH. Rational hydrotherapy, ed 4. Battle Creek, MI: Modem Medicine, 1923:721-722. 3. Golland A. Basic hydrotherapy. Physiotherapy 1981;67258. 4. Doering TJ,Brix J, Schneider B, Rimpler M. Cerebral hemodynamics and cerebral metabolism during cold and warm stress. Am J Phys Med Rehabil1996;75408-415. 5. Saeki Y.Effect of local application of cold or heat for relief of pricking pain. Nurs Health Sci 2002;497-105. 6.Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy during bouts of acute gouty arthritis. J Rheumatol 2002;29: 331-334.

Sauna A recent review of the benefits and risks of sauna bathing50concluded the following: It is well tolerated by most healthy adults and children. It does not influence fertility. It is safe during uncomplicated pregnancy. It may help lower blood pressure and increase left ventricular ejection in patients with congestive heart failure. It produces transient improvement in pulmonary function, which may be helpful for patients with asthma and chronic bronchitis. It decreases pain and increases mobility in patients with rheumatic diseases. It may be contraindicated in patients with unstable angina pectoris, recent myocardial infarction, and severe aortic stenosis. It is safe for patients with stable angina pectoris and old myocardial infarction. Krop5I published a case study in 1998 demonstrating the usefulness of sauna in the detoxification of a patient with 20 years’ duration chemical sensitivity resulting from low-level exposure to solvents. Ernst, Wirz, and P e c h ~performed ~~ a long-term prospective study called “Prevention of Common Colds by Hydrotherapy.” The researchers compared 25 volunteers to 25 controls. Volunteers were asked to work up to a 5-minute hot shower followed by a 2-minute cold rinse. The study demonstrated a decrease in both the frequency and intensity of common colds as seen in the treatment group as compared with the control group.

CONCLUSION Hydrotherapy provides the naturopathic physician with an effective form of treatment for many conditions. This chapter has touched on only a few of the many techniques developed over the years. References 2, 11, 20, and 21 provide those who are interested in further study in this area with appropriate information.

7. Finan MA, Roberts WS, Hoffman MS, et al. The effects of cold therapy on postoperative pain in gynecologic patients: a prospective, randomized study. Am J Obstet Gynecol 1993;168:542-544. 8. Aksoylar S, Aksit S, Caglayan S, et al. Evaluation of sponging and antipyretic medication to reduce body temperature in febrile children.Acta Paediatr Jpn 1997;39:215-217. 9. Agbolosu NB, Cuevas LE, Milligan P,et al. Efficacy of tepid sponging versus paracetamol in reducing temperature in febrile children. Ann Trop Paediatr 1997;17283-288. 10. Knoll T, Wimmer ML, Gumpinger F, Haberl RL. The low normothermia concept-maintaining a core body temperature between 36 and 37 degrees C in acute stroke unit patients. J Neurosurg Anesthesiol2002;14304-308.

Therapeutic Modalities 11. Hendley JO, Abbott RD, Beasley PP, Gwaltney JM Jr. Effect of inhalation of hot humidified air on experimental rhinovirus infection. JAMA 1994;271:1112-1113. 12. Georgitis JW. Nasal hyperthermia and simple irrigation for perennial rhinitis. Changes in inflammatory mediators. Chest 1994; 106:1487-1492. 13. Georgitis JW. Local hyperthermia and nasal irrigation for perennial allergic rhinitis. effect on symptoms and nasal airflow. Ann Allergy 1993;71:385-389. 14.Ophir D, Elad Y. Effects of steam inhalation on nasal patency and nasal symptoms in patients with the common cold. Am J

Otolaryngol1987;8:149-153. 15. Singh M. Heated, humidified air for the common cold (Cochrane Review). In The Cochrane Library, Issue 1. Oxford, England Update Software,2003. 16. McNaughton Collins M, MacDonald R, Wilt T. Interventions for chronic abacterial prostatitis (Cochrane Review). In The Cochrane Library, Issue 1. Oxford, England: Update Software, 2003. 17. Cioanta I, Muschter R. Water-induced thermotherapy for benign prostatic hyperplasia. Tech Urol2OOO;6294299. 18. de la Rosette JJ, de Wildt MJ, Hofner K, et al. Pressure-flow study analyses in patients treated with high energy thermotherapy. J Urol 1996;156:1428-1433. 19. Giombini A, Casciello G, Di Cesare MC, et al. A controlled study on the effects of hyperthermia at 434 MHz and conventional ultrasound upon muscle injuries in sport. J Sports Med Phys Fitness 2001;41:521-527. 20. Kappel M, Stadeager C, Tvede N, et al. Effects of in vivo hyperthermia on natural killer cell activity, in vitro proliferative responses and blood mononuclear cell subpopulations. Clin Exp Immunol 1991;&1:175-180. 21. Kappel M, Barington T, Gyhrs A, Pedersen BK. Influence of elevated body temperature on circulating immunoglobulin-secreting cells. Int J Hyperthermia 1994;10653-658. 22. Oehler R, Pusch E, Zellner M, et al. Cell type-specific variations in the induction of hsp70 in human leukocytes by feverlike whole body hyperthermia. Cell Stress Chaperones 2001;6:306-315. 23. Zellner M, Hergovics N, Roth E, et al. Human monocyte stimulation by experimental whole body hyperthermia. Wien Klin Wochenschr 2002;114102-107. 24. Imamura M, Biro S, Kihara T, et al. Repeated thermal therapy improves impaired vascular endothelial function in patients with coronary risk factors. J Am Coll Cardiol2001;381083-1088. 25.Kihara T, Biro S, Imamura M, et al. Repeated sauna treatment improves vascular endothelial and cardiac function in patients with chronic heart failure. J Am Coll Cardiol2002;39:754-759. 26. Engel JP,Watkin G, Erickson DJ, Krussen FH. The effect of contrast baths on the peripheral circulation of patients with R.A. Arch Phys Med 195031:135. 27. Woodmansey A, Collins DH, Ernst MM. Vascular reactions to the contrast bath in health and in rheumatoid arthritis. Lancet 1938;ii:1350. 28. Krusen FH. Physical medicine; the employment of physical agents for diagnosis and therapy. Philadelphia: WE3 Saunders, 1941.

29. Moor FB, Peterson S, Manwell E, et al. Manual of hydrotherapy and massage. Mountain View, C A Pacific Press, 1964:9-15,964. 30.Hewlett AW. The effect of some hydrotherapeutic procedures on the blood flow in the arm. Arch Intern Med 1911;8:591. 31. Stewart GN. The effect of reflex vasomotor excitation on the blood flow in the hand. Heart 1912;3:76. 32. Briscoe G. Observations on venous and capillary pressures with special reference to the Raynaud Phenomena. Heart 1918;735. 33. Ruhmann W. Reflex irritability of abdominal organs by local application of heat and cold. Munchn Med Wochensdu 1926;73:401. 34.Poulton El? An experimental study of certain visceral sensations. Lancet 1928;ii:1223,1277. 35. Bing HJ, Tobiassen ES. Viscerocutaneous and cutovisceral abdominal reflexes. Acta Med S a n d Supp 1936;78:824. 36. Kuntz A. Autonomic nervous system. Philadelphia: Lea & Febiger, 1945. 37.Fisher E, Soloman S. Physiological responses to heat and cold. In Licht S, ed. Therapeutic heat and cold, ed 2. New Haven, C T Elizabeth Licht, 1965. 38. Thrash AM, Thrash CL. Home remedies. Seale, A L Thrash, 1981. 39. Ridge BR, Budd GM. How long is too long in a spa pool? N Engl J Med 1990;323:835-836. 40.Allison TG, Reger WE. Comparison of responses of men to immersion in circulating water at -40.0 and 41.5 degrees C. Aviat Space Environ Med 1998;69:845-850. 41. Kellogg DL Jr, Morris SR, Rodriguez SB, et al. Thermoregulatory reflexes and cutaneous active vasodilation during heat stress in hypertensive humans. J Appl Physiol 1998;85:175-180. 42. Giannetti N, Juneau M, Arsenault A, et al. Sauna-induced myocardial ischemia in patients with coronary artery disease. Am J Med 1999;107228-233. 43. Buchman D. The complete book of water therapy. New York: EP Dutton, 1979. 44.Ring J, Teichmann W. Immunologische Veranderungen bei hydrotherpeutischer Kurbehandlung. Dtsch Med Wochenschr 1977;1021625-1630. 45.Bierman W, Licht S. Physical medicine in general practice. New York: Hoeber, 1957. 46.Finnerty GB, Corbitt T. Hydrotherapy. New York Frederick Ungar, 1960. 47. Jones WB. Mineral springs and medicine in North Carolina. N C Med J 1983;44:593. 48. Epstein M, Saruta T. Effect of water immersion on renin, aldosterone, and renal sodium handling in normal man. J Appl Physiol 1971;31:368-374. 49. Brown C, Sutton JV,Adler A, et al. Renal calcium and magnesium handling in water immersion in nephrotic patients. Nephron 1983;33:17-20. 50. Hannuksela ML, Ellahham S. Benefits and risks of sauna bathing. Am J Med 2001;110:118-126. 51. Krop J. Chemical sensitivity after intoxication at work with solvents: response to sauna therapy. J Altem Complement Med 1998;477-86. 52.Ernst E, Wirz P, Pecho L. Prevention of common colds by hydrotherapy. Physiotherapy 1990;76;207-210.

Manipulation Robert M. Martinez, DC, ND CHAPTER C O N T E N T S Therapeutic Keys

Methods of Accentuating the Signs and Symptoms of Space-Occupying Lesions of the Spine 423 Cervical Spine 424

417

Historical Perspective 418 Schools of Thought in Manipulation 418 Early History (Oriental, Egyptian, Greek, Indian) 418 Bone Setters of England 418 Differential Diagnosis 420 Five Basic Categories of Spinal Disorders 420 Pretreatment Assessment 423 Lumbar Spine and Sacroiliac Joint

423

THERAPEUTIC KEYS Manipulation is a passive manual maneuver that is performed in such a way that the patient cannot prevent it and that introduces movement beyond the passive range of motion's elastic barrier but does not exceed the anatomic barrier.l Mobilizations are passive stretches with or without oscillations over which the patient can exert control? Spinal adjustments are chiropractic techniques that range in force from a near imperceptible force to high-velocity thrust with joint cavitation (popping noise). Initial evaluation to determine if manipulation of the patient is appropriate seeks for contraindications and "red flags" of fracture, infection, neoplasm, progressive neurologic deficit, cord pressure, or cauda equina syndrome as a prudent starting p~int.~A A correct differential diagnosis is key to the selection of patients, and the functional assessment is key to the selection of appropriate manual medicine techniques? If gross signs of inflammation are present in a joint (heat, swelling, redness, and pain), manipulation of that joint would most likely aggravate the condition. When bringing the joint complex to tension, if the pain peripheralizes, it is a contraindication to manipulation.

The Differential Diagnosis of Soft Tissue Injuries by Means of Active and Passive Movements 424 Active Movements 424 Passive Movements 425 Barrier Concepts 425 Treatment Concepts 425 General Guidelines for Manipulative Technique 426 Motion Palpation 427 Psychology 429

Following a progression of force, the manipulator can reduce the risk of adverse events. Relaxation techniques (heat, muscle work, calming environment) before a manipulation are helpful in achieving best results. They are especially indicated in patients complaining of aching and stiffness before manipulation.6 If pain is the chief complaint, icing the area for 5 minutes causes surface anesthesia, and 20 minutes causes sedation of the actions of the muscle spindle cells. Sedation of a muscle reflex arc before manipulation of a fixated painful joint facilitates the treatment.* If the patient reports an increase in pain or stiffness after a manipulation, ice the area of treatment for 10 to 30 minutes after manipulation to reduce spasm and ~ a i n . ~ , ~ "The goal of manipulation is to restore maximal pain-free movement of the musculoskeletal system in postural balan~e."~ Don't treat muscle spasm as a primary condition. Muscle spasm is almost always a response of the body to a noxious stimulus. Find the cause and treat it.1o Trigger points (TPs) are myofascial irritations that are frequently caused by underlying joint fixations. If one 417

Therapeutic Modalities

manipulates over a ’I”, it frequently precipitates a muscle spasm later that day or the next morning.”

HISTORICAL PERSPECTIVE The popularity of manipulation could be likened to the course of a roller coaster-diving up and down and taking many unexpected turns. The literature is replete with references to the use of manipulation. Manipulations are depicted in prehistoric cave drawings and Chinese statues, circa 2700 w.12 The early history of manipulation has been researched by Lomax and PIPsented in two papers. She credits Hippocrates with the earliest recorded written physician’s prescription of manipulative treatment methods. Worthington notes that Hippocrates in On Joints clearly states method and motive for the application of manipulative therapy.13 Hippocrates advocated many of the premises in use today: judicious use of force, direction of thrust, and proper levering of the joints. Even at this early date, mention is made of the abuse of manipulative therapy.l3 Until the sixth century, manipulative treatment saw little change. At that time, treatment with open wounds was used by Arab physicians, based on the humoral theory of disease.I3During the Dark Ages, priests provided medical treatment at their monasteries. Kessler states: “Friar Moultan, of the order of St. Augustine, wrote The Complete Bonesetter. The text, which was revised by John Turner in 1656, suggests that manipulation was practiced in medical settings throughout the Middle Ages and Renai~sance.”’~ The course of the history of manipulation in the late 1700s and afterward is colorful and flamboyant. Three main concepts developed during this time still have a major influence on our thoughts regarding manipulation. The first held that vertebral luxation was responsible for spinal deformity. The second was held by the largest group that followed the writings of Percival Pott and maintained that caries of the spine were more common than previously thought. This idea caught hold and was taken to an extreme. This faction of physicians treated spinal deformity by blood-letting and rest, while condemning extension and manipulation as both useless and dangerous. A third group held that muscles were the main cause of problems, and treatment should be complete rest or active exercise, as the case ~ a r r a n t e d . ’ ~ Central to the early issues, aside from the political and economic waves the irregulars were creating for the allopaths, were concerns about the potentially disastrous effects of manipulating tuberculous, neoplastic, rheumatic, or fractured joints. More recently, questions of vertebral disk herniation, precipitation of CVAs (cerebral vascular accidents),and the lack of a differential diagnosis by many nonallopathic manipulators has caused concern. To this add the controversial issues of cost-effectiveness

and efficacy of treatment, and one can begin to understand the apprehension with which allopathic practitioners approach manipulative therapy. It is interesting to note the following: Hippocrates railed against the abuse of manipulative therapy by physicians and others of his time. Physicians of the late 1700s assailed one another’s methods of treatment (e.g., in The Lancet, December 16, 1826, the banner on page 347 appropriately read ”THE YELLOW JOURNAL”). Surgeons held “bonesetters” in great contempt “when they condescend[ed] to speak at all of bonesetters and their works.”I2 Bonesetters held their secrets and passed them from father to son. Financial competition was noted early in the literature. “It is known to most practitioners of surgery, and has been made known to many to their great cost and loss, that a large portion of the cases of impaired mobility or usefulness of limbs after injury fall into the hands of a class of men called bone setter^'."'^ Although there is a great deal of animosity, and claims of superiority are made by the various practitioners of manipulative treatment even today, “specific conclusions cannot be derived from the scientific literature for or against either the efficacy of spinal manipulative therapy or the pathophysiologic foundations from which it is derived.”16 Nothing appears to be new in the controversies except the names of the groups and the coined terms they use. The allopathic group claims the right to control over all the healing arts, and the sole privilege of using the generic terms “physician,” “medicine,” and ”medical treatment.”” The “unorthodox” groups buck this authority. They seek a physician’s position, while not always being willing to accept the accompanying responsibilityof adequate differential diagnosis and critical assessment and validation (other than empirical and anecdotal reporting) of their therapeutic regimens. Each group maneuvers politically, judicially, and economically to gain advantage over the other.18

SCHOOLS OF THOUGHT IN MANIPULATION Early History (Oriental, Egyptian, Greek, Indian) Knowledge of exactly which techniques were used, and with what success, is limited or speculative. It is known that many cultures have used manipulativetechniques.12

Bone Setters of England Bonesetters of England generally held that a bone was out of place and had a “feel” for what was wrong. Hutton described the information gained from a bonesetter as

Manipulation

”bring[ing] some spoils out of the camp of the philistine^."'^

Chiropractic D.D. Palmer, “the founder,” and his son B.J. Palmer, ”the developer,” of chiropractic added one of the most colorful pages to the history of manipulative treatment. D.D., who “rediscovered” the principle of ”lost nerve tone” in a revelation from a deceased friend, Dr.Atkinson, reestablished this method of healing. The first chiropractic manipulation was given to a deaf janitor. D.D. learned that the janitor’s hearing had been lost when he stooped over and felt something give in his back. D.D. reasoned that if the deafness occurred from something slipping out, restoring the vertebra to its correct position should cure the condition: “With this new objective in view, a half-hour’s talk persuaded Mr. Lillard to allow me to replace it.”19 The stormy history of chiropractic was led by a son who hated his father (and was actually accused of running him down in a parade, causing injuries that led to his death), who drove chiropractic to a zenith, and who later nearly destroyed the profession. The evolution of chiropractic is well documented by Gibbons. Interestingly, many early developments in chiropractic were years ahead of their time. B.J. developed the prototype of today’s electroencephalogram, he started a radiology laboratory only 13 years after Roentgen discovered x-radiation, and he had one of the finest diagnostic centers in the Midwest at his school (completewith MDs and PhDs)?O A new focus in chiropractic is rehabilitation and incorporation of manual medicine techniques. Rehabilitation of the Spine, A Practitioner’s Manual, edited by Craig Liebenson; is considered by many in the field a landmark publication. It emphasizes the need for rehabilitation and includes manipulation as a component of the process.

Naturopathic All naturopathic techniques result from the blending of the thoughts of the other schools of medicine. This is appropriate when one realizes there is little new in manipulation, only refining and relabeling. It is also appropriate that naturopathy does not lay claim to originating a school of thought on manipulation but uses this method of treatment, when indicated, not exclusively but as part of a therapeutic regimen. Several naturopathic schools in the past were associated with chiropractic and eclectic schools of medicine. The genesis of the naturopathic profession is well documented in Chapter 4.

Osteopathic Andrew Still, three of whose children died from meningitis, in the tradition of Hanneman left the practice of medicine and started the school of osteopathy in Kirksville, MO. It is highly probable that D.D. Palmer

went to this school and learned some of the techniques, but it is not well documented. The famed ”equal but separate” movement of the osteopaths led to a 1921 resolution, submitted at the American Osteopathic Association convention, that allowed entrance of chiropractors with advanced standing into their schools. Still, before his death, saw the defection of his osteopathic profession into the ranks of medical orthodoxy.20-22 Interestingly, manipulation is now only an elective segment in some American osteopathic schools, while in England it is still the mainstay of osteopathic practice. The resurgence of interest in manual medicine has been brought to the forefront by the Osteopathic College at Michigan State University. Greenman’s’ Principles of Manual Medicine adds a useful text to the field of manual medicine. This school has been teaching manual medicine to physical therapists, Doctors of Medicine, and Doctors of Osteopathy.

Allopathic In the twenty-first century, the numbers of allopathic practitioners who promote manipulative treatment are growing daily. The individuals mainly responsible for major contributions are James Cyriax, James Mennell, and John Mennell. These brilliant physicians have written valuable texts on manipulative therapy, although they do not agree totally on the effects they achieve with manipulation. Mennell holds to the correction of lost joint play and denies effect on the intervertebral disk,= while Cyriax claims reduction of a protruding disk.1° Bourdillion, Calliet, McNabb, Maigne, Maitland, Kaltenbom, and Williams are popularizing the treatment modality. Their works are too exhaustive to mention in this brief chapter. “Controversy and contention” best describe the higher levels of the respective schools of medical thought. The impression one gets in reading through the literature is intolerance of others’ ideas expressed in ad hominem attacks. The mistake “lay” manipulators and ”nonphysicians” make is not ineffectiveness but their willingness to seek training outside the fraternal order of the “medical” brotherhood; to address the public directly rather than communicating exclusively within the order; and, worst of all, to openly compete, economically and politically, against the fraternal ~ r d e r . ~ ~ J ~ , * ~ Donald B. Tower, in the chairman’s summary at the National Institute of Neurological and Communicative Diseases and Stroke conference in 1975, noted a physician who has received little credit for his early contribution to the field: J. Evans Riadore, a London physician who wrote a treatise on the irritation of spinal nerves in 1843. He attributed many diseases to this condition, stating: “If any organ is deficiently supplied with nervous energy of blood, its functions immediately, and sooner or later its structure, become deranged.” This was a

Therapeutic Modalities viewpoint subsequently echoed by osteopaths and chiropractors.” Spinal Manipulation (edition 5) by Bourdillion and colleagues,25the first author of whom was a medical manipulator, has been largely reworked from previous editions and heavily influenced by osteopathic methods. Over the past 15 years, American awareness of contributions in manual medicine from other countries has been growing. Jirout, Lewit, Janda, Bogduk, and many others have been teaching and publishing in the United States.

Physical Therapy The field of physical therapy is diverse, and only one major group, influenced by James Cyriax, MD, is discussed. Dr.Cryiax had a major influence on physical therapy by training physical therapists (PTs) in assessment, deep tissue cross fiber massage, and manipulation. Cryiax influenced Robin McKenzie, a New Zealand I T who subsequently developed a systematic approach to mechanical diagnosis and treatment of musculoskeletal conditions. McKenzie’s approach is often prejudicially dismissed as ”extension exercises for the low back.” He proposed a new tack in the approach to back pain that has been found to be highly effective in acute and chronic back pain populations and low in cost.26 McKenzie Mechanical Diagnosis and Therapy (MDT) approach is evaluation and treatment of musculoskeletal disorders based on a mechanical history and the patient’s symptomatic and mechanical response to movement, positions, and 10ading.2~His observations that most conditions are self-resolving and the focus should be on prevention by teaching patients proper posture and self management are astute. After years of studying manipulation, he feels that only 20% of patients need manipulative therapy, and 80% can self-treat using end-range loading strategies from books or practitioners.28

DIFFERENTIAL DIAGNOSIS The methodology for performing the differential diagnosis of musculoskeletal pain can follow many diverse patterns depending on the approach taken, but the multiple branching pathway3.29 for patient selection is a good start. Five basic categories of spinal disorders are proposed to begin the sorting process: neoplasm, infection, neurologic, psychosocial, and mechanical disorder. The following presents a brief overview in differentiating among these and is organized to aid the generalist in selecting a starting point for making the final diagnosis. Refer to the texts and articles noted for detailed information.

Five Basic Categories of Spinal Disorders 1. Neoplasm When the patient history includes prior episode of cancer, a red flag goes up as the spine is a common site

for metastasis. A family history of neoplasm is less of a concern, but risk factors should be double-checked. The character of the pain is often described as deep, boring, and usually worse at night. The pain is progressivesometimes better, sometimes worse-but is usually always present to some degree. Laboratory tests may reveal an elevated sedimentation rate, C-reactive protein (CRP), or anemia. Although there may be no signs in the early stages of cancer, the American Cancer Society has identified seven major warning signs: A change in bowel or bladder habits A sore that does not heal Unusual bleeding or discharge from any place A lump in the breast or other parts of the body Chronic indigestion or difficulty in swallowing Obvious changes in a wart or mole or Persistent coughing or hoarseness Most mechanical conditions show a 50% improvement in 2 to 4 weeks with appropriate care, or the patient should be carefully reevaluated or referred for a second opinion.

2. Infection There may be signs of acute or chronic illness.30 Laboratory tests may reveal a shift to the left in the white blood cell count (WBC) and possibly an elevated sedimentation rate or CRP. There may be local joint inflammation.

3. Neurologic A routine office neurologic screening examination may reveal the presence of a lesion. A screening examination will help to determine if additional testing or referral to a specialist is indicated. The search pattern for neurologic lesions breaks the system into the following: Cerebrum. Lesions are discovered during the consultation by the patient’s affected cognition; interaction; mannerisms; or loss of orientation in time, space, or body part awareness. Nausea, vomiting, seizure, loss of consciousness, visual disturbances, and headache are warning signs. Cerebellar versus posterior column lesions. Test coordination of movements, with basic differentiation done by repeating acts with the eyes open and eyes closed. Cerebellar. Actions are jerky with the eyes open or closed; dysarthria, ataxic (drunken) gait, and dysdiadochocinesia may be present. Posterior columns. The actions are smooth with the eyes open but cannot be repeated as well with the eyes closed, due to the loss of proprioception. A broadbased, stomping gait may be present.

Manipulation Brainstem. This area is evaluated by testing the cranial nerves. Differentiation between upper and lower motor neuron lesions. Think of the abnormal reactions by focusing on the words “spastic” and “flaccid.” If the superficial reflexes are absent, continue with tests to rule out upper motor neuron lesions (UMNs) and lower motor neuron lesions (LMNs). Table 41-1 lists the key differential considerations. Muscle stretch reflexes (MSRs). These are often incorrectly called deep tendon reflexes.31Communication of results can be confusing, since various practitioners use different notations (e.g., a grade 3 may be listed 3, +3, 3+, H+, or just 3) and do not have a consistent definition. Table 41-2 lists a grading scale that is commonly used. The main objective is to compare the reflexes side to side and in comparison with Table 41-2. If the reactions are not equal, note according to the scale. Pathologic reflexes. Toe sign (Babinski),Hoffman’s, and glabellar signs are only present in UMN lesions. Newborn babies may display these signs, and this is an opportunity for one to elicit and observe these abnormal signs. Painless loss of strength. This is usually neurologic. Use numbers 0 to 5 to rate muscle strength according to the scale shown in Table 41-3. Loss of sensation. If it follows a dermatome, the problem is usually a nerve root; if it follows a named nerve pattern, a peripheral mixed nerve is involved. If it affects the entire extremity, consider circulatory, metabolic, and pathologic processes. Nerve root tension signs. Patients may be bracing themselves when they present (in an effort to decompress Comparison of neurologic signs of upper versus lower motor neuron disease Sign/symptom

Upper motor neuron (spastic)

LMN (flaccid)

Paralysis

Spastic

Flaccid

Deep tendon reflexes

Clonic

Diminished absent

Muscle tone

Hypotonia, then in 2-3 wk hypertonia

Decreased

Pathologic reflexes

Present

Absent

Superficial reflexes

Absent

Decreased-absent

Fasciculations

Absent

Present while LMN degenerates

Reaction of degeneration

Not characteristic

May occur

Modified from Haerer A, ed. DeJong’s the neurologic examination, ed 5. Philadelphia: Lippincott, 1992339, 433, 445. LMN,Lower motor neuron lesions.

Grading of reflexes Grade

Reflex

0 1 2

Absent with reinforcement Hypoactive-less than the expected response Normal-you may note brisk or sluggish

3

Hyperactive--more than the expected response

4

Hyperactive with transient clonus

5

Hyperactive with sustained clonus

Clonus

More than one muscle jerk when the tendon is tapped

the nerve root) and may complain of pain radiating into an extremity.Movement may cause pains shooting into the extremity. Loss of sensation follows the dermatome distribution, MSRs are diminished or lost, and muscle strength in muscles innervated by the affected nerve is lost or diminished.

If neurologic findings are present, other than minor changes in sensation, keep the patient under close observation. Direct nerve root pressure can cause permanent muscle weakness with resultant permanent impairment. Appropriate conservative care is Progressive neurologic deficit is an indication for referral to a neurosurgeon or physiatrist.

4. Psychosocial If the presenting complaints do not seem to follow a mechanical pattern and the pain diagram is nonanatomic, consider the possibility of psychosocial factors. Psychosocial workplace factors associated with risk of spinal injury include high job dissatisfaction, high psychologic job demands, employer practices, coping abilities, lack of recognition at work, low supervisor support, a high frequency of job problems, and negative beliefs of or attitudes toward the consequences of having “low back trouble.’f33,34A major factor in identifying the incidence of future pain is the patient’s perception of being disabled.35

1 Grading of muscle strength Grade

Muscle strength

0 (zero)

No trace of muscle contraction

1 (trace)

Evidence of slight contractility, no joint motion

2 (poor) 3 (fair)

Complete range of motion with gravity eliminated

4 (good)

Complete range of motion against gravity with some resistance

5 (normal)

Complete range of motion against full resistance

Complete range of motion against gravity

Therapeutic Modalities

5. Mechanical

The test by definition has a positive response, which correlates to a specific condition, that must be produced when the test is performed for the test to be positive (e.g., Lindner's test and Soto Hall test are performed in the same way, but the findings to report a positive test are different). The test must reproduce the pain of the primary complaint and be positive by the test's definition. The tests are centered in allopathic medicine to diagnose pathology, fracture, moderate to severe sprain/ strain and dislocation and are often negative in the ambulatory, chronic patient.

Mechanical factors include fractures, dislocations, sprain/ strain, derangement, dysfunction, and mechanical overload of normal tissue. Mechanical overload of normal tissue is a common cause of pain. To illustrate this point, bend your finger backward until you feel strain and hold it. At first you may only feel discomfort, but after an extended period of time it will become painful. Next, try bending the finger backward beyond strain until it hurts. The pain you feel is due to abnormal stresses on a normal tissue; there is nothing wrong with your finger! You do not When used without an understanding of the mechaneed drugs, modalities, or manual therapy. Simply stop nism of action of the stress and the tissues the stress overstraining the soft tissues. Robin McKenzie uses this act on, the plethora of tests and maneuvers available seemingly simple experiment to teach the consequences of sustained end-range loading as a cause of ~ a i n . ~ usually , ~ ~ serve to confuse the practitioner and aggravate the patient's condition. A detailed text that covers this This is profound when you think of the workers hanging and bouncing. area in detail, such as Magee38or is helpful and should be referred to for additional information. A fracture is usually traumatic when presenting in young and middle-aged patients. In older patients, pathoMcKenzie Concepts logic fractures are a concern. Presentation may be delayed The MDT is an invaluable system for practitioners in motor vehicle accidents or athletic injuries or nontraumatic fractures in the elderly. The cardinal signs of fracture who perform manual therapy. Rather than technique, it is a method that, once mastered, allows rapid assessare the following: ment and selection of patients for treatment and identiPinpoint pain over the site fies those not likely to respond to conservative care Deformity of the part so they can quickly receive and appropriate referral. Crepitus Two weeks of instruction by the McKenzie Institute Loss of function of the part, usually proportional to the on Mechanical Diagnosis and Therapy, McKenzie's severity of the injury textbook^,^,^^ and a chapter in Liebenson's text cover Abnormal mobility at the site of pain this material in detail. Only a few of the helpful concepts Always check for nerve lesions and soft tissue injuries from the McKenzie method are discussed as follows. Keep in mind that McKenzie asserts only 20% of patients that would complicate the injury before beginning treatment. need manipulative therapy, and prevention is key to success in his model. Also check for multiple injuries (ring fracture in two places). In particular, look above and below the site of Centralization and Peripheralization injury, as the force of trauma may be transmitted and cause a fracture some distance from the site of impact.29 A cervical spine problem can refer pain to the shoulder blade, arm, forearm, and hand. A low back problem can Note: Do not be deceived by the absence of obvious signs of fracture. refer pain to the sacroiliac joint (SIJ),buttock, thigh, leg, and foot. When the referred pain from the spine is Orthopedic Tests brought closer to the midline in response to movements, position, or load and remains reduced, it is called "cenOrthopedic tests are designed to stress the damaged tissue tralization."" When the pain moves out from the spine and reproduce the pain of the primary complaint. The in response to movements, position, or load, it is examiner is not looking merely for pain to be reported as a called "peripheralization." When a movement produces result of the maneuver, but rather pain that is specific for centralization, it is a motion to pursue for treatment. the test and reproduces the pain of the primary complaint. When a movement causes peripheralization, it is a motion Therefore the following should be remembered: to avoid, as it will likely worsen the condition. If no movement or position centralizes the pain, it is a poorer progThe examiner can make the patient worse by forcing tests or performing them incorrectly. nosis for response to the treatment method being used. Although this phenomenon is typically associated with The least stressful tests should be done first. If the first vertebral disk problems, it can be observed in many mustest causes severe pain, most of the other motions will be painful afterward and confuse the findings. culoskeletal problems.

Manipulation

End-Range Pain and Pain during Motion End-range pain (ERP) is felt only when the joint is moved to end range (ER). It is a sign of shortened soft tissues around the joint complex. The importance is that this is an indication that stretching and mobilizing techniques should be used before manipulation. If the joint is not mobilized to ER repeatedly the manipulation may cause aggravation of the complaint. When the joint is fully stretched, following a progression of forces described later, the practitioner can determine when and if manipulation is indicated. Pain during motion (PDM) is pain that is felt during joint movement, as well as at the end range. The joint range of motion may be restricted as well. PDM is a sign of soft tissue inflammation or a vertebral disk problem. Movements or positions that increase the PDM and restriction should be avoided. When a mobilization or manipulation increases PDM or restriction, it is important to find a motion or position that will reduce the PDM and restore the motion as soon as possible to reduce the irritation of the tissues. Progression of Forces This is a logical stepwise progression of the force generated first by the patient, then by the practitioner. The advantages are increased patient comfort, ability to “test the waters,” and decreased risk of harm from the procedure. The steps are as follows: 1. Patient-generated force-the patient does all the motion actively. 2. Patient generated overpressure-the patient uses a strap, fulcrum, etc. to increase the movement to ER. 3. Practitioner-generated force-the practitioner mobilizes the joint to ER repeatedly. 4. Practitioner uses manipulative thrust. Positive responses would include centralization, reduction of antalgic postures, increased range of motion, and decreased PDM. It is a relative contraindication to continuing to step 4 if there is no positive response in steps 1 to 3.

PRETREATMENT ASSESSMENT Observe the posture of the patient. If he or she becomes antalgic to the side and forward, or both, due to this episode, it indicates a large space-occupying mass, which is most often the disk but could be other soft tissue or pathology. Proceed slowly and carefully, avoiding any movements that cause peripheralization, increase PDM, or increase the obstruction of motion. Establish the baseline of the location of the complaint and its response to motion and then repeat motions to ER. In the cervical spine test flexion, extension, rotation, and lateral bending. In the lumbar spine test flexion,

extension, and lateral translation. The testing procedures are described in detail with photos in Liebenson’s text.43 Note the ranges of motion. If there are complaints at or below the shoulder blade or buttock, it is important to test reflexes, muscle strength, sensation, and nerve root tension signs to assess if the nerve root is affected. Additional tests can be added as indicated.

Lumbar Spine and Sacroiliac Joint During supine straight leg raise (SLR) the lumbar nerve roots begin to develop tension at about 35 degrees. If SLR is causing leg pain below 30 degrees, it is likely due to stretch of the lumbar nerve root in the presence of a space-occupying lesion or significant hip pathology. SLR above 30 degrees causes increasing ipsilateral nerve root tension, causes ipsilateral hamstring tightness, and may expose lumbar dysfunction or derangement as the straight leg moves toward end range (ER). Once the painful ER is found, one lowers the limb to the pain-free range and then performs internal rotation and dorsiflexion of the foot and great toe. If this maneuver causes return of the leg pain, there is likely tension on the lumbar nerve roots. Because the SLR maneuver stresses multiple tissues, the test can be misleading and somewhat difficult to determine what a positive finding is until the practitioner’s skills are developed, but the positive result should be described to help clarify the findings.

Methods of Accentuating the Signs and Symptoms of Space-Occupying Lesions of the Spine Following the principle of ”Do no harm,” one should test reflexes and sensation first, then proceed to active tests such as the Valsalva maneuver to test for increased intrathecal pressure. If radiating pain results, it is a sign of a space-occupying lesion. Next the practitioner should do light stretch/distraction tests (SLR and dorsiflexion of the foot with extension of the great toe) and finally compression tests (Milgram’s bilateral leg raising and Lindner’s test [forcefully flexing the trunk while the patient is supine]): This forces the disk posteriorly (if herniated) and causes increased intraabdominal pressure, resulting in increased intrathecal pressure (Valsalva effect). ButleP described in detail the identification of cervical root tension signs, by upper limb tension tests developed by Elvy in 1979. The tests are used primarily by physical therapists but may be useful to help guide treatment. Some additional ideas to finding the area of lesion in the lumbar spine are as follows: Support Adams (the belt test)-With the patient standing, the doctor has him or her bend forward and notes the level of pain. The doctor then secures the patient’s pelvis by hugging the anterior superior iliac spines with

the arms, pressing the patient’s sacrum into the doctor’s hip. If the patient’s pain is decreased, it indicates the lesion is in the pelvis (probably the SIJ or hip); if pain increases, it is in the lumbar spine (probably the lumbar disks). Patrick’s test-Flexion, abduction, and external rotation of the hip are blocked; this causes pain over the inguinal fossa and into the thigh when a hip lesion is present.

This is only an introduction to one common problem that may present with many variations. Careful study of the mechanism of action of the tests used can confirm, rather than confuse, a diagnostic impression.

Cervical Spine The cervical spine presents another diagnostic challenge. Although the mechanism of the tests in the lumbar spine are similar, the area is much more delicate and thus requires more careful application. There is considerable discussion of the topic of vertebrobasilar stroke (VBS) following manipulation of the cervical spine. Tests done in the office have not proved effective, but the history should alert the practitioner to the possibility of VBS insult from manipulation. The presence of the “five Ds” (dizziness, drop attacks, diplopia, dysarthria, dysphagia) and “three N’s” (nausea, numbness, nystagmus) are important to note. The most important risk factors identified by Terrett were dizziness, unsteadiness, giddiness, vertigo, and sudden severe pain in the side of the head or neck, which is different from any pain the patient has had bef0re.4~If the practitioner elects to follow the pattern of the progression of force, the occurrence of these sympt o m in the early mobilizations would contraindicate manipulation. However, VBS has occurred with testing and with a patient simply turning his or her head. The incidence is small, but clinical presentation should not be missed. If there is compression of the nerve root or cervical instability, the patient may present holding the head, lifting it cephalically to decompress the spine and root, an indication to stabilize and transport. Any such presentation is best handled by emergency department staff because even passive range-of-motion assessment may cause permanent injury. If there is irritation of the brachial plexus or a nerve root, the patient may support the arm in abduction and flexion, often resting the hand on the top of his or her head. This is a sign to proceed cautiously. Any movements that cause peripheralization must be avoided, and movements that produce centralization should be pursued. If overt signs of nerve root compression are present, mobilization and manipulation must be performed with skill and caution.

Cervical Distraction If distraction of the head from the shoulders causes aggravation of the patient’s complaints at 12 lb of traction (the average weight of the head), stabilization and relaxation techniques are indicated. If distraction of the head from the shoulders causes relief of the radiating pain at 12 lb of traction, slowly increase the traction to 25 lb. If this relieves the complaint of neck pain, it is an indication that mobilization and traction are indicated therapies. If it aggravates the complaint, it is an indication of inflammation or instability and suggests caution in using mobilization or traction. Cervical compression that causes radiating pain to the arms is a sign that indicates nerve root irritation from the disk and is treated by symptom response that centralizes the arm complaint.

Maximum Cervical Rotation, Lateral Bending, and Compression If maximum cervical rotation, lateral bending, and compression (MCRC) causes radiating arm pain, it is a sign of nerve root compression and manipulation in that direction should be avoided.

Spurling‘s Maneuver When combined cervical rotation, lateral bending, and extension with overpressure (Spurling’s maneuver) aggravates or reproduces the complaint or radiating pain to the midback or arm, it indicates nerve root irritation, and manipulation in that direction places the patient at risk for aggravation of this condition. If the pain is local, it is a sign of facet irritation that often responds well to manipulation. The practitioner can test the response with repeat mobilization to the ER and if only ERP increased force can be used. After determining that the lesion is not a “hard” orthopedic or neurologic lesion, differential tissue tension tests are used to determine the involved tissue.

THE DIFFERENTIAL DIAGNOSIS OF SOFT TISSUE INJURIES BY MEANS OF ACTIVE AND PASSIVE MOVEMENTS This is based on the work of James Cryiax,’O but recent texts give a much improved presentation of the materia1.143 This brief overview is only intended to give an introduction to the material.

Active Movements First, active ranges of motion (ROM) are performed to determine voluntary ROM and patient status. Measuring active ROMs cannot differentiate whether the loss of function is due to pain, weakness, or stiffness/lesion but is helpful to determine patient tolerance to motion and how guarded the patient is when moving.

Manipulation

Resisted Isometric Tests Next, isometric muscle tests are performed to test the contractile tissue (muscle and tendons) with the joint in neutral to avoid involving the noncontractile tissues. The following results may be noted: Normal-painless and full strength Minor tear-pain with full strength Moderate tear-pain with little strength Neurologic deficit-no pain and little strength

Passive Movements When the joint is put through passive motion, it reaches an end point, which has an “end-feel” that helps to determine the status of the soft tissue around the joint. The end-feel of a joint may be one of the following: Normal-the amount of motion and feel of the tissues are appropriate for age Abnormal-normal end-feels that are not normal for the joint and ROM that are being tested (e.g., the feeling of bone on bone is the normal end-feel at the elbow when extended but is abnormal when it occurs at the ER of knee extension) Pathologic-these end-feels are only present in joints that have undergone pathologic changes

Normal End-Feels Capsular end-feel. This is a firm, “leathery” feeling, felt, for example, when the normal shoulder is at full external rotation. When felt in conjunction with a capsular pattern of restriction, and in the absence of significant inflammation or effusion, it indicates capsular fibrosis.

Bony end-feel. This feels abrupt, as when moving the normal elbow into full extension. When accompanying a restriction of movement, it may suggest hypertrophic bony changes, such as those that occur with degenerative joint disease, or possible malunion of bony segments following healing of a fracture. Soft tissue approximation end-feel. This is a soft end-feel, as when fully flexing the normal elbow or knee. It may accompany joint restriction in the presence of significant muscular hypertrophy.

Muscular end-feel. This more rubbery feel resembles what is felt at the extremes of straight-leg raising from tension on the hamstrings. It is less abrupt than a capsular end-feel. Pathologic joint end-feels indicate disease; they are limited and are never normal: Empty-bursitis, space-occupying lesion, neoplasm Boggy-joint effusion Spasm-guarding from inflammation Internal derangement-loose body/ torn meniscus

The tissue involved is determined by the response to the passive ROMs and by moving the joint into closed pack position.

Muscle or tendon. Active and passive movements are limited or painful, or both, when the muscle is contracting and the muscle is being stretched at the same time. Ligaments. Both active and passive movements are limited or painful, or both, in the same direction. Capsular pattern. Only joints that are controlled by muscles have a capsular pattern. Pain is caused on both active and passive motions, and the limitation of motion is in a specific proportion that is listed in tables in the texts referenced.

Barrier Concepts’ Joint motion is described from neutral to an ER that is ultimately limited by the anatomic barrier of the surrounding tissues, which, if exceeded, causes tissue trauma. The extent of the active ROM can be increased by passive motion to a point at which all of the tissues around the joint have been brought to tension, called the elastic barrier. Beyond the elastic barrier is a small ROM referred to as the paraphysiologic It is within the paraphysiologic space that joint cavitation, the “popping’’ sound, occurs. When joints and soft tissues are dysfunctional, alterations of ROMs may occur both within the ROM and at the end of it. If one focuses only on working in the paraphysiologic space, one severely limits the effects that can be made on dysfunction.

TREATMENT CONCEPTS In the case of injury, treatment with passive therapies is indicated to control pain and inflammation until the tissues heal. Use of passive therapies in chronic conditions is falling into disfavor due to the issues of cost-effectiveness and managed care protocols. Determining the stage of inflammation can be accomplished by comparing the cardinal signs of inflammation (heat, swelling, pain, redness, and loss of function) with the suspected stage of the acute inflammatory process. In reality, the stages overlap and a continuum exists4’: 1. Vasoconstriction-inconsistent, lasting only 3 to 5 seconds in minor injuries 2. Active congestion-caused by vasodilation and increased vessel permeability (minutes to hours) 3. Passive congestion-the venous return is partially dammed by clotting (minutes up to 48 hours) 4.Consolidation-fibrinous coagulation at the site of the injury (3 to 5 days) 5. Fibrosis-resulting from the formation of scar tissue (5 to 20 days)

Therapeutic Modalities

6. Remodeling-21 days generally and completed at 6 to 8 weeks, but major injuries may continue up to 12 months By knowing time frame and pathophysiology of the affected tissues, one can select an appropriate therapy. Manipulation is generally contraindicated until the tissue has sufficiently healed. Often the presenting problem does not have tissue damage, just pain from mechanical causes. Treatment of the tissues should be directed according to the level of inflammation. Observe the posttreatment results to see if the signs of inflammation worsen, indicating incorrect application or inappropriate therapy. During treatment, the patient should be in a position that relieves symptoms. If the patient cannot get into such a position, it is probable that the severity of the lesion is such that it will not respond to conservative therapy alone or that the patient's condition is misdiagnosed or misunderstood. The practitioner can use the differential tissue tension tests and joint function tests to determine joint lesions and functional assessment to determine the therapeutic regimen. Before using manipulation, think about the joint endfeel (the way the joint feels at the end of its ROM) and determine which pattern is present: Edematous and boggy end-feel-indicates joint effusion and possibly inflammation. Muscle spasms should not be treated as a primary condition, as they are almost always the body's response to a noxious stimulus or pathophysiologic fault. Cryotherapy; positive galvanism; pulsed ultrasound; and gentle, frequently repeated movements within the active ROM are indicated. Springy and taut end-feel-ligamentous fixations (as felt in the normal knee in lateral bending stress tests and drawer tests). Manipulation works well on these types of fixations. Surging sinusoidal and interferential current, ultrasound, and moist hot packs facilitate the treatment. One can use follow with cryotherapy in the subacute stages. Bone on bone end-feel-usually indicative of degenerative joint disease (as felt in the normal elbow in extension). If there is fine crepitus, mild degenerative joint disease (DJD) may be present; coarse crepitus indicates moderate DJD; and joint creaking may be advanced DJD. Diathermy, contrast baths, and other naturopathic therapies indicated in osteoarthritis are helpful. The practitioner should develop the habit of examin-

ing the sedimentation rate, CRP, and WBC differential count to avoid missing a concurrent condition or a difficult diagnosis.

By always starting high on the differential list, one misses few diagnoses. Exhaustive work-ups are infrequently warranted, but if treatment is directed to mechanical relief and the patient cannot find a comfortable position that relieves the pain, it is doubtful that satisfactory results can be achieved using a mechanical approach.

General Guides for Manipulative Technique Texts on manipulative techniques by Liebenson, Lewit, Greenman, McKenzie, Bourdillion, and Maitland are good sources for learning the basics of the art (refer to the reading list later). Personal instruction is invaluable, but unless the rationales of joint mechanics, pathomechanics, and pathophysiology are the basis of the teacher's approach, it can be confusing and lead to cookbook approaches.

Functional Assessment Often the focus is on injury, pathology, and disease, but the majority of musculoskeletal pain is from pathomechanics due to postural and repetitive strain, disuse, deconditioning, fatigue, and nutritional factors that must be addressed if treatment is to be successful. Once the portion of the patient's condition that is a musculoskeletal problem has been established, the mechanical fault should be determined. Manipulative treatment without correction of the mechanical fault results in prolonged treatment and recurrence. Detecting this is sometimes easy, while at other times it is a mystery that takes careful investigation, as discussed in M c K e n ~ i e , 3Greenman,' ~,~~ Lewit? and Liebenson.4

Preparation for the Manipulation The patient should be comfortable and relaxed on a firm but well-padded table. The room should be at a comfortable ambient temperature, and the physician should wear no watches or jewelry that might catch the patient's hair or skin. The physician must be comfortable and relaxed. Manipulation is an individual art, but in general sideposture manipulation of the pelvis and lumbar spine is easiest on a table that is at knee height; prone and supine thoracic manipulation is easiest at midthigh height; and cervical manipulation is easiest when seated, kneeling, or on a table at waist height. One may either change the height of the table or simply bend at the knees. Manipulation of the joints of the extremities can be performed in any position that allows the physician control over the joint and body parts.

Notes on the Art Manipulation is an art. Assuming a proper differential diagnosis, one acquires a "feel" that allows recognition

Manipulation

of the differences among the three basic types of fixations and knowledge of when to manipulate. If a movement causes pain, it should not be performed unless the diagnosis of the patient’s condition is sure and the motion will cause no harm. Frequently, motion in the direction that is free and painless will free other ROMS.~

Joint Motion Joint motion descriptions can become elaborate, or one may simply say that there are six degrees of freedom of motion (plus long-axis extension): flexion, extension, left and right rotation, and left and right lateral bending. Not all joints have all six degrees of motion. The normal degrees and ROMs of joints are listed in anatomy and kinesiology texts. If a degree of motion is lost or blocked, the type of fixation and which form of manual medicine is indicated should be determined.

The Fixation Manipulation of a joint is performed to correct joint fixation. Therefore one must do the following: 1. Determine if mobilization or manipulation is the appropriate technique. 2. Identify the location and direction of the fixation. 3. Bring the joint to tension removing the periarticular tissue slack. Mobilization with tissue slack not taken up is safe, but manipulation when tissue slack is present invites injury. 4.Test the direction of manipulative thrust with repeat mobilization to ER to ascertain that the pain does not peripheralize, the movement does not increase PDM, and the movement does not result in increased obstruction to motion from mobilization. 5. Thrust only when the patient is relaxed and the fixation is felt. 6. After the elastic barrier has been stretched, repeated manipulation in the same direction is complicated because the end-feel tension normally felt before a manipulation is reduced or absent for at least 20 minutes. The same phenomenon occurs when one “pops” knuckles. The risk of injury is much greater, and changing to mobilization or active muscular relaxation techniques is recommended rather than repeated manipulation.

Stabilization A point of stabilization is created by one hand and the physician’s body weight, while the other hand performs the manipulation. Minor corrections of the position of the stabilized part or hand, or both, are frequently interpreted by an observer as twisting or wrenching motions. Twisting and wrenching are difficult to control and may injure the patient.

Thrust The manipulative thrust can be described according to the following: Direction of line of thrust-through the joint space, parallel to joint surfaces, or tangential to the point of fixation Velocity-slow for mobilizations. High velocity can correct joint fixations, and the speed must be faster than the patient’s reaction time or a strain injury will result if the patient’s muscular resistance occurs at the time of the manipulative thrust Amplitude--governed by the quality of the health of the tissue, the quality of the fixation, and the location of the condition on the spedrum of the inflammation response

Reassess The condition of the joint fixation should be reassessed after each treatment to determine if the therapy has been successful. A single manipulation rarely corrects a problem completely. Learning a joint-scanning technique shows one where the problems are that need further evaluation. The goal is to alleviate acute conditions or, if unsuccessful, to turn them into subacute conditions and resolve subacute and chronic conditions before they cause a chronic fatigue response, joint fixation, degeneration, or chronic myositis.

Troubleshooting Technique Common problems blocking successful manipulation can be overcome by the following: Learning joint play analysis on the peripheral joints and practicing manipulations of those joints before attempting to manipulate the spinal joints Practicing the manipulative procedure with repeated light oscillatory movements while modifying the direction to feel the changes in joint tension, thus gaining experience, confidence, and knowledge without inflicting injury Being sure of the procedure; otherwise, the patient may sense the physician’s hesitation and guard, preventing the manipulation and increasing the risk of a poor outcome Feeling the fixation of the joint as it is brought to tension; otherwise, the manipulation traumatizes the tissues unnecessarily or does not gain the desired result Learning the arthrology of the joint to be manipulated so as not to put the joint in a ”locked” or jammed position that will cause the force of the manipulation to be dispersed to the surrounding tissues and joints

Motion Palpation The following is a short lesson in motion palpation to determine the presence of SIJ fixation.

Therapeutic Modalities

Review of Anatomy and Motion Mechanism Anatomy of the sacroiliac joint. The joint is L- or ear-shaped, with the apex of the L facing anteriorly. There can be fixation of the upper fibrous or lower synovial SIJ, thus altering the normal axis of rotation of the pelvis and causing excess wear on the lumbar spine, hip, knee, and ankle joints.

SacroiZiac gait mechanism. The sacrum and both ileums must be free to move in relation to each other. The sacrum flexes, extends, and ”nutates” (nods) in a gyrating figure-of-eight motion.

Effect of position on sacroiliac angles. As one sits, there is usually a decreased sacral base angle (slight flexion of the pelvis), and as one stands, the sacral base slightly increases (the pelvis slightly extends). Mechanism of gait. Analysis of the normal right forward step is as follows:

1. The left leg is weight bearing. 2. The right leg is in swing phase just before heel strike. 3. The left gluteus medius contracts to tilt the pelvis right superior, and the right sacrospinalis contracts and is counteracted by contraction of the left psoas muscle. 4.The right knee bends, allowing for foot-drop. 5. The hip rotates internally on the weight-bearing side (left)and rotates externally on the non-weight-bearing side (right). This motion results in right ilium flexion, left ilium extension, and a relative flexion of the sacrum in relation to the ilium on the left. In normal gait, the lumbar spine does not deviate to either side. The sacrospinalis exerts a pull on the weightbearing side, and the psoas group counters the movement by contracting on the non-weight-bearing side, so the lumbar spine remains in the midline. In the past, many practitioners have used the Gillette‘s test, described later, to identify fixation of the SIJ. It is helpful to remember that the SIJ is the ”dumping ground” for pain from the lumbar spine, just as the shoulder blade is the “dumping ground” for pain from the cervical spine. The key to determining if the problem is in the SIJ is to rule out all lumbar problems first. Second, Laslete9has determined that when two or more of the following SIJ tests produce concordant pain, it is highly likely the SIJ is the pain generator. 1. Gapping test-patient is supine. The examiner crosses his or her arms, placing hands on the anterior superior iliac spine, forcefully pressing laterally and down into the table to ”gap” the SIT, attempting to stretch the anterior SIJ ligaments.

2. Compression test-The patient is side lying with the painful SI up. The pressure is directed to the opposite iliac crest, attempting to compress the anterior SI and stretch the posterior SIJ ligaments. 3. Posterior shear or “thigh thrust”-The patient is supine with a small block or sand bag under the sacrum, the hip and knee are flexed to 90 degrees, and overpressure is applied down the shaft of the femur. One should avoid adduction of the hip, as this will cause pain in normals. 4. Pelvic torsion (Gaenslen’s test)-The patient is supine at the edge of the table with one thigh extended over the edge of the table. On the other side, the hip and knee are flexed to the chest. Overpressure is applied to the extended thigh to accentuate the posterior rotation of the opposite side. This should be performed on both sides. 5. Sacral thrust-With the patient lying prone, the examiner thrusts down on the sacrum. 6 . Cranial shear-With the patient prone, cranial pressure is applied to the apex of the sacrum with the examiner‘s hands, while the painful side ankle is placed between the examiner’s knees and is tractioned caudally.

Method of Motion Palpation of the Sacroiliac Joints Practitioners should follow these steps to palpate the SIJs: Contact the posterior sacroiliac spine (PSIS) on the right with the right thumb. Contact the second sacral tubercle with your left thumb. Ask the patient to flex his or her right thigh slowly three times up and down to below 90 degrees. This causes flexion of the right innominate, while the sacral prominence remains relatively stationary. The motion of the PSIS is normally posterior, toward the floor, and slightly toward the midline. If no motion occurs between the PSIS and second sacral tubercle, there is a fixation of the right upper joint in flexion. Remember, it is the motion between the PSIS and second sacral tubercle, not the motion of the joint relative to the floor, that is important. 4. Ask the patient-to flex his or her left thigh slowly three times above 90 degrees. The right leg is now weight bearing and fixed, and this motion causes the sacrum to flex, which causes a relative extension of the right ilium. If the sacral prominence does not swing medially away from the PSIS as the left thigh flexes above 90 degrees, theh the right upper joint is fixed in extension.

Manipulation

Maigne (pp. 390-395), Bourdillion (pp. 146-173), and Maitland (pp. 314-317).

5. Shift your right thumb to the posterior inferior iliac spine (PIIS) and have the patient slowly flex their right thigh three times to below 90 degrees again. The PIIS should move laterally away from the sacral prominence, or there is a flexion fixation of the right lower SIJ. 6. Again, the left thigh is flexed slowly three times above 90 degrees and the sacral prominence should swing medially away from the PIIS, unless there is an extension fixation of the right ilium in the lower joint (after Gillette and Gittleman).

Psychology Management of chronic pain and assistance for the patient in dealing with stress are of major importance in the treatment of all conditions, especially neuromuscular spindle injuries. The psychosomaticcomponent of myofascial pain syndromes and the unique combination of therapies the naturopathic physician can offer necessitate a thorough understanding of the relaxation response, hypnosis, biofeedback, guided imagery, and personal motivation. If this area is not developed, some patients seeking help do not find their treatment results satisfactory.

Techniques for correction of these fixations are described in many manipulative texts. I recommend

~

1. Greenman P. Principles of manual medicine. Baltimore: Williams & Wilkins, 1996:39. 2. Maitland GD. Peripheral manipulation, ed 3. London: ButterworthHeinemann, 1991. 3. Bigos S, Bowyer 0,Braen G, et al. Acute low back problems in adults. Rockville, MD: US Department of Health and Human Services,Public Health Service, Agency for Health Care Policy and Research, 1994. 4. Liebenson C, ed. Rehabilitation of the spine: a practitioner’s manual. Baltimore: Williams & Wilkins, 1996:355. 5. Lewit K. Manipulative therapy in rehabilitation of the locomotor system. London; Boston: Butterworth-Heinema, 1985:5. 6. Amell P, Beattie S. Heat and cold in the treatment of hypertonicity. J Can Phys Assoc 1972;24:61-67. 7. Stamford B. Giving injuries the cold treatment. Available online at

http://www.physsportsmed.com/issues/l996/03_96/cold.htm#avoid [accessed December 29,20031. 8. Rizzo TD. Using RICE for injury relief. Available online at http://www.physsportsmed.com/issues~996/10_96/rizzo.htm [accessed December 29,20031. 9. Dvorak J, Dvorak V, Schneider W, eds. Manual medicine. Heidelberg, Germany: Springer Verlag, 1985. 10. Cryiax J. Textbook of orthopaedic medicine, vol 1, ed 8. London: Bailliere Tindall, 198210. 11. Travel1 JG, Simons DG. Myofascial pain and dysfunction: the trigger point manual. Baltimore: Williams & Wilkins, 198355. 12. Schafer R. Chiropractic health care: a conservative approach to health restoration, maintenance, and disease resistance. Des Moines: Foundation of Chiropractic Education and Research, 1976. 13.Lomax E. Manipulative therapy. In Buerger AA, Tobis JS, eds. Approaches to the validation of manipulation therapy. Springfield, I L CC Thomas, 1977. 14. Kessler RM. Management of common musculoskeletal disorders: physical therapy principles and methods. Philadelphia: Harper & Row, 1983:129. 15. Hood W. On the so-called ”bone-setting,” its nature and results. Lancet 1871:1:304-10,344-349. 16. Goldstein M. The research status of spinal manipulative therapy: a workshop held at the National Institutes of Health, February 2-4, 1975. Bethesda, MD: US Department of Health, Education, Welfare, Public Health Service, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, 19756. 17. Webster’s New Collegiate Dictionary. Springfield, MA: GC Merriam, 1975.

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18. Starr P. The social transformation of American medicine, the rise of a sovereign profession and the making of a vast industry. New York Basic Books, 1982. 19. Palmer DD. The science, art and philosophy of chiropractic. Portland, OR Portland Printing House, 1910:18. 20. Gibbons R. The evolution of chiropractic: medical and social protest in America. Notes on the survival years and after. In Haldeman S, ed. Modem developments in the principles and practice of chiropractic. New York Appleton-Century-Crofts. 19803-24. 21. Northup G. History and development of osteopathic concepts: osteopathic terminology. In Goldstein M. The research status of spinal manipulative therapy: a workshop held at the National Institutes of Health, February 2-4, 1975. Bethesda, MD: US Department of Health, Education, Welfare, Public Health Service, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, 1975, p. 43-51. 22. Wardwell WI. Discussion: the impact of spinal manipulative therapy on the health care system. In Goldstein M. The research status of spinal manipulative therapy: a workshop held at the National Institutes of Health, February 2-4, 1975. Bethesda, MD: US Department of Health, Education, Welfare, Public Health Service, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, 1975:20-21. 23. Zhon DA, Mennell JM. Musculoskeletal pain: diagnosis and physical treatment. Boston: Little, Brown and Company, 1976:147.

24.Tower DB. Chairman summary: evolution and development of the concepts of manipulative therapy. In Goldstein M, ed. The research status of spinal manipulative therapy: a workshop held at the National Institutes of Health, February 2-4, 1975. Bethesda, MD: US Department of Health, Education, Welfare, Public Health Service, National Institutes of Health, National Institute of Neurological and Communicative Disorders and Stroke, 1975:59. 25. Bourdillion JF, Day EA, Bookhout MR. Spinal manipulation, ed 5. Oxford, England; Boston: Butterworth-Heinema, 1992ix-x. 26. McKenzie R. The lumbar spine. Waikanae, New Zealand: Spinal Publications, 1981. 27. Liebenson C, ed. Rehabilitation of the spine: a practitioner’s manual. Baltimore: Williams & Wilkins, 1996251. 28. McKenzie R, Kubey C. Seven steps to a pain-free life: how to

rapidly relieve back and neck pain using the McKenzie method. New York: Plume, 2000:121.

Therapeutic Modalities 29. Waddell G. An approach to backache. Br J Hosp Med 1982;28:187, 190-1,1934. 30.Wasson J, et al. The common symptom guide: a guide to the evaluation of 100 common adult and pediakic symptoms, ed 2. New York McGraw-Hill, 1984. 31. Haerer A, ed. DeJong’s the neurologic examination, ed 5. Philadelphia: Lippincott, 1992339,433,445. 32. Beneliyahu DJ. Chiropractic management and manipulative therapy for MRI documented cervical disk herniation. J Manipulative Physiol Ther 1994;17177-185. 33. Krause N. Psychosocial job factors, physical workload, and incidence of work-related spinal injury: a 5-year prospective study of urban transit operators. Spine 1998;23:2507-2516. 34. Feuerstein M, Berkowitz SM, Huang GD. Predictors of occupational low back disability: implications for secondary prevention. J &cup Environ Med 1999;41:1024-1031. 35.Estlander AM, Takala EP, Viikari-Juntura E. Do psychological factors predict changes in musculoskeletal pain? A prospective, two-year follow-up study of a working population. J Occup Environ Med 1998;40:445-453. 36. McKenzie R, Kubey K. Seven steps to a pain-free life: how to rapidly relieve back and neck pain using the McKenzie method. New York:Plume, 2000:21. 37. McKenzie R. Treat your own back, ed 7. Waikanae, New Zealand: Spinal Publications, 19978.

38. Magee DJ. Orthopedic physical assessment, ed 2. Philadelphia: WB Saunders, 1992. 39. Evans RC. Illustrated essential in orthopedic physical assessment. St. Louis: Mosby, 1994. 40.McKenzie R. The lumbar spine. Waikanae, New Zealand Spinal Publications, 1997. 41. McKenzie R. The cervical and thoracic spine. Waikanae, New Zealand: Spinal Publications, 1990. 42. McKenzie R. The lumbar spine. Waikanae, New Zealand: Spinal Publications, 198122. 43. Liebenson C, ed. Rehabilitation of the spine: a practitioner’s manual. Baltimore: Williams & Wilkins, 1996:251. 44. Butler D. Mobilization of the nervous system. New York Churchill Livingstone, 1991:147. 45. Terrett AGJ. Vertebrobasilar stroke following manipulation. West Des Moines, Iowa: National Chiropractic Mutual Insurance Company, 1996:24. 46.Sandoz R. Some physical mechanisms and effects of spinal adjustments. Ann Swiss Chirop Assoc 1976;691. 47.Robbins SL, Cotran RS. Pathologic basis of disease, ed 2. Philadelphia: WB Saunders, 1979:55-106. 48.Maigne R. Orthopedic medicine, a new approach to vertebral manipulation. Springfield, IL: CC Thomas, 1972:137. 49. Laslett M, Williams M. The reliability of selected pain provocation tests for sacroiliac joint pathology. Spine 1994;19:1243-1249.

BourdilLion JF, Day EA, Bookhout h4R. Spinal manipulation, ed 5. Oxford, England; Boston: Butterworth-Heineman, 1992. A good text that covers the bases. It is exceeded in ninny areas by Greennian’s text. Boyling JD, Palastanga N. Grieve’s modem manual therapy, ed 2. New York Churchill Livingstone, 1994. A heavily rqferenced tome. Cox JM. Low back pain: mechanism, diagnosis and treatment, ed 5. Baltimore: Williams & W W , 1990. Addresses aspects of consmative care of low back, especially lumbar disk herniation history, research, diagnosis,and consmativc treatment with statisfics and research that supports the methods described. Cryiax J. Textbook of orthopaedic medicine, vol 1, ed 8. London: Bailliere Tidall, 1982. A dificult text to read that has been translated to a readable format by the other authors listed, but a classic. He was strongly anfi-nltmiatiiie medicine in his approach to certain aspects of physical medicine fespecially those who should and should not practice it), and his z~iewpointsare narrow arid limited compared with the more recent publications and jo~inials. Greenman P. Principles of manual medicine, ed 2. Baltimore: Williams & Wilkins, 1996. One of the best texts that covers the material in a clear, undcrstniidable, and usableformat. Haldeman S, ed. Principles and practice of chiropractic, ed 2. New York Appleton-Cenhuy-Crof, 1992. The second edition has major changes and new contributors and is an excellent source of information on history, research, diagnosis. and treatment of all phases of manipulation, with special attention to the spine. Kessler RM. Management of common musculoskeletal disorders, physical therapy prinaples and methods, ed 3. Philadelphia: Harper & Row, 1996.

A good text for the therapist’s approach to treatment, with recap of much of Cyiax’s work. Basic concepts of embryology, arthrology, pain, and assessment. Techniques of case management, use of hot and cold, manipulative, and relaxation techniques. Ends with detailed discussion of all of the joints of the body. Well worth rending. Liebenson C, ed. Rehabilitation of the spine: a practitioner’s manual. Baltimore: Williams & Wilkins, 1996. Liebenson has brought together many fine contributors who address the cutting edge methods of nianual medicine. It covers much of what is needed in clinical practice. Very useful and readable. A gold mine of information. Magee DJ. Orthopedic physical assessment, ed 2. Philadelphia: WB Saunders, 1992. One of the best texts for learning the orthopedic assessment techniques and many of thefunctional tests. Maitland GD. Vertebral manipulation, ed 4. London; Boston: Butterworth-Heineman, 1977. A physical therapist’s approach with emphasis on patienf selection, pretreatment assessment, assessment during treatment, assessment after treatment, and therapeutic approach for each area of the spine. Maitland GD. Peripheral manipulation, ed 3. London; Boston: Butterworth-Heineman, 1991. The Snme approach as previous book, but for the extremities. The author suggests learning on the extremities bt$orc attempting to learn spinal manipulation. After all, a joint is a joint. Walther DS.Applied kinesiology, vols 1 and 2. Pueblo, C O Systems DC, 1983. A chiropractic approach thnt is in a different realm froin physical medicine texts. Treatment approaches that arc dificult to find and that are empirically based+teti gives a iiscful solution that defies scient+c fact.

Nonpharmacological Control of Pain Richard Kitaeff, MA, MD, Dip1 Ac, LAC CHAPTER CONTENTS Introduction 431 The Experience of Pain 431 A Psychological Model 431 Neuropsychological Mechanisms of Pain 432 Pain in Childbirth 432

Counterstimulus Methods: Massage, Acupuncture, Transcutaneous Electrical Nerve Stimulation 434 Other Methods 438 Conclusion 438

Pain Control 433 Moderating Variables and Psychological Techniques 433

INTRODUCTION Pain in its myriad forms is one of the most common symptoms for which patients seek relief. Acute pain is an unpleasant experience primarily associated with tissue injury, and the protective response patients have to pain provides the clinician with valuable diagnostic information. The reaction to pain is highly subjective and, as a function of higher centers, is extremely variable. It is influenced by many factors, depending on the individual patient and his or her situation. When pain becomes chronic, the multifactorial influences (e.g., anxiety, depression, social, cultural, and economic factors, secondary gain) play an even larger role. When treating a patient for pain, the clinician must first determine the primary cause, the pathogenesis, and the secondary or contributing factors. The relief of pain may then be achieved by removal of the primary cause (e.g., cure of an infection), neutralization of the effect of the stimulus (e.g., emollients for an ulcer), relief of discomfort (e.g., biofeedback), suppression of the disease process (e.g., antiinflammatory agents), and dulling or obliteration of the sense of pain (e.g., analgesics or acupuncture).' Although the medical profession has chosen to emphasize the pharmacologic methods of pain control, many nonpharmacological options are available. Their applicability and efficacy are documented here. (Although this chapter liberally utilizes pain control in

childbirth, the examples and concepts can be generalized to any situation involving acute and/or chronic pain.)

THE EXPERIENCE OF PAIN A Psychological Model Pain is generally acknowledged to be a complex physiologic/ psychological phenomenon. It involves motivational and emotional components and conceptual interpretation, which may or may not have their basis in actual nociception. Verbal reports of pain and associated behavioral responses are controlled, at least in part, by psychological, cultural, and situational factors. For acute pain, such as that of childbirth, in which the painful experience can be directly related to nociceptive input, a multiprocess feedback model can be considered. However, one must keep in mind the complexity of the psychological processes intervening between sensory event and observable response, ranging from the physiologic to the social aspects of personality. These include elements of the following: Information processing Performance ability Attention Memory Expectancy Attitudes and beliefs Secondary gain 431

Therapeutic Modalities Self-concept Designated sick roles

In the psychological model, the brain infers information from bodily signs and integrates it with existing personal and situational variables to direct behavior. When consideration must also be given to the interactions with interested observers, such as physicians, family members, and birth attendants, who influence the interpretation with their own experiences and attitudes about pain, the complexity becomes even greater. According to this model, which does not differ in essence from a general model of stress, a primary appraisal of the personal danger or threat posed by the painful stressor is followed by a secondary appraisal of one's ability to cope, based on emotional feedback, and contributions of situational and sociocultural response factors. On this basis, a woman in labor could choose to regard pain as "positive," "functional," or "creative"; "pain with a purpose"; or, alternatively, "part of a process involving injury."2 In the course of a pain management program carried out with 84 patients with low back pain, those who more strongly endorsed "organic" concepts about the nature and treatment of pain reported higher levels of disability, whereas reductions in reported "organic" pain beliefs improved reported disability, and endorsement of "psychological" concepts about the nature and treatment of pain was not associated with di~ability.~ Several studies indicate that "catastrophizing" predicts pain or is associated with lower pain tolerance.4$This conceptualization of painful stress suggests that intervention could be successful at several levels: cognitive patterning, physiologic arousal associated with emotional stress, and control of environmental stimuli. Examples of appropriate strategies are cognitive coping skills such as restructuring and utilization of preparatory information and attention shifts; muscular relaxation, physical or electrical stimulation, and biofeedback techniques; and structuring of the environment in a way conducive to effective coping (such as by making it nonthreatening and comfortable).6

Neuropsychological Mechanisms of Pain According to research on the mechanisms of pain, pain can be treated not only by anesthetic blocks, surgical intervention, and the like but also by influencing the motivational-affective and cognitive factor^.^ The traditional specificity theory of pain, first enunciated by Descartes in the seventeenth century, holds that pain messages are conducted from specific pain receptors at the periphery through discrete pathways to pain centers in the brain. However, there are individual differences in pain responses, pain is not consistently stopped by cutting or blocking of the "pain pathway," and it is now known that nonpainful types of stimulation activate the

A-delta and C fibers (see next paragraph) that are associated with pain. Therefore, later modifications of pain theory took into account patterning of nerve impulses over time to reflect differences in degree and intensity of stimuli and summation of signals from an extended area.8 The currently accepted view of pain is the gate control theory, which Melzack and Wall9formulated in 1965. Based on neurologic data and a categorization of the words used to describe pain, this theory conceptualizes the pain experience as having sensory-discriminative, motivational-affective, and cognitive-evaluative components or modalities, corresponding to different patterns of nervous impulses. Neurologically, a specialized cluster of nerve cells in the substantia gelatinosa of the spinal column is thought to operate like a valve or gate, controlling nerve signals before they evoke the perception of, and response to, pain. Besides this monitoring of sensory data in the central nervous system, gating is also influenced by the relative amount of activity in large-diameter (A-beta) and small-diameter (Adelta and C ) nerve fibers. The large fibers tend to inhibit transmission, or close the gate, preventing pain, and the small fibers tend to facilitate transmission, or open the gate, resulting in pain. The fact that large fibers are activated by pressure, touch, massage, and vibration suggests a mechanism for such pain control techniques as acupressure, acupuncture, and transcutaneous electrical nerve stimulation (TENS). Such stimulation apparently closes the spinal gate via the large-fiber system. Melzack and Casey' expanded this theory by proposing the possibility of a higher-level gate, in the reticular or limbic structures of the brain, that probably mediates the drive to escape from unpleasant stimuli. At central nervous system levels, the biochemical mechanisms of gate control may involve the endorphins, natural morphinelike substances that have been implicated in the pain-controlling effects produced by acupuncture.'"

Pain in Childbirth A psychological/social learning approach to pain emphasizes control of motivation, expectation, focus of attention, stress, and feelings of anxiety, depression, and helplessness. Factors specifically operative in labor pain involve these as well as social support and the physiologic factors of hunger, rest, and muscular tension." All of these factors can contribute to the interpretation of pain being placed on the nociceptive message provided by uterine contractions. The influence of motivation on labor pain was effectively demonstrated in a prospective study of maternal attitudes toward pregnancy in 8000 American women. One of the factors found to be strongly related to maternal attitude toward having a baby was the need for analgesics in labor.I2

NonpharmacologicalControl of Pain

Cultural conditioning may also be fundamental to the labeling of childbirth as painful. Throughout most of the world, analgesics are not required for labor; in fact, a Japanese anesthesiologistsuggests that the idea of "painless delivery" is a strange one to his culture.13 American women, on the other hand, "live through a largely self-fulfilling prophecy of birth as a painful, terrifying ordeal, and/or as a medical, drugged process over which they have no control."" This idea relates to body fantasies of injury, brought about in a hospital environment where distress is an expected response to the expulsive reflex.2

PAIN CONTROL Moderating Variables and Psychological Techniques Psychological Strategies The psychological strategies recommended for control of labor pain, many of them part of prepared childbirth programs, generally aim to provide control, communication, relaxation, attention focus, and support as well as physical counterstimuli. Considerable psychological research supports the use of these strategies in the development of pain tolerance. The significance of various characteristics of an individual's psychological profile has been studied by evaluating the effects on pain perception of such parameters as the following:

Introversion-extr~version~~-~~ Augmenters-reducersl7 9 Field dependen~e'~.'~ Repression-sensitizationz@z 9

For example, on the repression-sensitizationaxis, repressors may be characterized as people who avoid having to cope with pain. Sensitizers, however, have an obsessive need to cope; they like to be informed in advance about the situation and to have control over it. The superior initial tolerance exhibited by repressors in response to heat and pressure stimuli disappears in repeated trials, showing that the sensitizers' predilection for challenge enables them to endure long-term pain better. The importance of individual difference variables is also illustrated by the observation that one third of patients undergoing surgical operations do not request pain-killing medi~ation.2~ This common ability to suppress pain indicates that not all surgical patients consider themselves passive victims. In fact, during the postoperative period, pain persists longer for those who accept medication.

Cognitive Strategies The impetus for devising cognitive strategies to promote tolerance of pain has been particularly supported by

investigations showing that pain tolerance increases with greater predictability and perception of ~ o n t r o l . ~ ~ - ~ ~ Similarly, preparatory communications and information received before the onset of experimental or surgical pain consistently decreases the subjects' perception of ~ain.*~ Animal - ~ l studies have demonstrated higher rates of instrumental responses when painful shocks are signaled than when they are u n ~ i g n a l e d Kanfer . ~ ~ and S e i d r ~ e found r ~ ~ that subjects who could advance slides of travel pictures at their own rate tolerated iced-water immersion of the hand longer than yoked subjects whose slides were changed by the experimenter. When surgical patients were given a sense of control by being provided with preparatory information about postoperative discomforts and operative care, in combination with training in rehearsal of realistic, positive aspects of the surgical experience, they showed a significant reduction in postoperative anxiety (as indicated by nurses' observations),requests for sedatives, and length of hospital stayMFurthermore, preparation for second periodontal procedures by auditory and visual messages classified as "control enhancement" was associated with reduction of pain after a second operation.35Subjects who could cognitively redefine a threat of electric shocks as interesting new physiologic sensations also reduced stress to a greater extent than subjects not provided with this coping strategy.36 A typical cognitive behavioral procedure utilizes "stress inoculation," beginning with an educational phase (in which the client is given a conceptual framework for understanding the nature of his or her stressful reactions), followed by rehearsal of behavioral and cognitive coping skills, based on a set of coping self-statements generated by the client in collaboration with the therapist. Such cognitive-behavioral techniques, sometimes in combination with electromyography (EMG) biofeedback control, have been found successful in treatment of chronic low back pain.37-39 Also, cognitive-behavioral strategies have been effective in alleviating the pain of irritable bowel syndrome,4O temporomandibular joint syndr0rne,4~,~~ cancer,43migraine headaches,44rheumatic conditions,"537 fibromyalgia,mand complex regional pain syndr0me.4~ This emphasis on conceptualization, preparatory information, and cognitive transformation seems to have been incorporated into the Read method of natural childbirth, which replaces fear with knowledge about birth.lz Sheila Kitzinger: in her method of prepared childbirth, similarly emphasizes the necessity of "acquiring knowledge and understanding of what labor involves, the terminology used by obstetricians and midwives, and information about what happens in hospitals." A study by Stevens and Heide50 conducted at the University of Wisconsin used iced water to test perception and endurance of pain in subjects who had been taught methods used in childbirth education classes.

The control subjects for this training and an additional control group were offered only distraction during the tests. Those who had been taught the techniques reported only about half the pain of that reported by control subjects and endured it 2.5 times longer. The prepared childbirth strategies improved with practice, were effective for pain lasting longer than most contractions in labor, and were more effective than distraction techniques.” However, this last finding introduces some confusion, because some prepared childbirth methods include either distraction techniques or some other deliberate disposition of one’s attention.

Attention-Focusing Distraction or focused attention, mostly utilizing the rhythms of the breath, is essential to the Lamaze method, the most popular prepared childbirth program in America, and is important in the Bradley and other methods. Sheila Kitzinger2 describes the controlled attention focusing as:

. . . concentrationon what is happening, one‘s response to it as a task, and visualization of what is being achieved by the work of the uterus during contractions. The focus may be on the fantasy of the contractions as a shape provided by actual objects (furniture, architectural details, flowers, a painting) in the room, or a combination of these factors. Stevens and HeideWfound that attention-focusing functions effectively as an analgesia for labor pain. Such strategies are strongly supported by much psychological research. Hospitalized children with chronic illnesses who were taught distraction techniques were able to reduce measures of distress before and during medical procedures such as intramuscular and intravenous inject i o n ~In . ~a~study of patients with bum pain, sensory focusing techniques were more successful than distraction techniques in controlling pain, and both were more successful than standard care.52The focus may be on a competing response, as in a study by Kanfer and GoldfooP3showing that when attention was directed to self-presented external slides, individuals were able to increase their tolerance of the pain of cold water. Focus on a competing response is also shown in the use of hypnosis as an analgesic and in the meditative states of Raj yogis, who pinpoint attention on the tip of the nose or a point on the back of the skull, and then do not react physiologically to cold water, bright lights, or sudden s 0 u n d s . ~ 5Other ~ adepts in unusual feats of pain tolerance, such as having spikes stuck through the skin, either maintain an unfocused attitude, without evaluation, or pinpoint attention totally on the pain, but without e ~ a l u a t i o nIn . ~ ~such cases, the attitude of detachment from the pain can be reflected by an undisturbed electroencephalography (EEG) pattern of alpha or beta waves throughout performance of the feat.

Relaxation Training Relaxation training, another essential element of pain control, is found in all childbirth training programs. A considerable body of literature supports its importance in pain control, because a state of lowered autonomic arousal is incompatible with anxiety. Although progressive muscular relaxation, systematic desensitization, and autogenic training are all well-established physiologic approaches to muscular relaxation, meditation traditions provide quicker methods to achieve what B e n ~ o has n~~ called, the “relaxation response.” One of the simplest meditation practices-maintaining a focal awareness of the flow of the breath-is taught by Rahima Baldwin” in Special Delivery and is identical to the ancient Buddhist practice of vipassarza, or insight meditation.

Hypnosis Hypnosis or autohypnosis is another method utilized to induce deep relaxation for pain control. It incorporates many of the therapeutic elements already referred tofocused attention, positive expectation, and a supportive or permissive attitude-in making suggestions that alleviate anxiety. Thus, its success in pain management may be viewed from a cognitive-behavioral perspective.%In one technique, “glove anesthesia” is induced in one hand and the “numb, heavy wooden feeling” so produced is transferred to the other hand, the face, and eventually to the abdomen in order to “relieve the discomfort” of uterine contractions (the word ”pain” is never used, because its use would be countersuggestive).59 Pain modulation in “high hypnotizable” subjects has been confirmed through brain measurement of somatosensory event-related potentials (SEWS)to noxious stimuli, with highest amplitudes for these subjects recorded at frontal and temporal scalp sites.60

Control of Environmental Stress KitzingerZ cites animal research to show how environmental stress can interfere with the physiologic processes of labor and delivery. Education for childbirth therefore promotes verbal and nonverbal support from husband, obstetrician, midwife, or anyone else who is part of the birthing environment. Touch relaxation and coaching techniques combine the essential elements of relaxation, massage counterstimulus, and the direct supportive communication of a partner.” Several studies agree that comfort in labor is also enhanced by a more vertical position, such as the squatting posture that is adopted in many other

Counterstimulus Methods: Massage, Acupuncture, Transcutaneous Electrical Nerve Stimulation The hand reflexology method of grasping combs during labor to activate points on the fingertips and balls of the

Nonpharmacological Control of Pain ~~

hand that relate to uterine functioning is one example of counterstimulus strategy.” Foot reflexology, acupressure, acupuncture, and TENS might also share a common autonomic nervous mode of operation.

Transcutaneous Electrical Nerve Stimulation The use of TENS to control pain during delivery has been evaluated by several studies. The method used in a Swedish study,64which was subsequently replicated in Germany and Britain, was originally developed in the United States by Shealy and MaureP for the control of acute and chronic pain. In a controlled study of experimentally induced cold-pressor pain, the effect of electrical stimulation with TENS electrodes at two traditional acupoints in 20 subjects had an analgesic effect with statistical significance comparable to that of morphine, and the combined effect of TENS with morphine was stronger than TENS alone.66A series of controlled randomized double-blind studies on carpal tunnel syndrome pain found that the combination of low-level laser and microcurrent TENS on distant and local points significantly decreased McGill Pain Questionnaire Score, sensory and motor latencies, and Phalen and Tine1 signs, compared with sham treatment.67A British study, investigating the relative hypoalgesic effects of different TENS parameters upon experimentally induced mechanical pain, found that low-frequency, high-intensity, extrasegmental stimulation (i.e., over an acupuncture point rather than over a nerve distribution) produced a rapid-onset hypoalgesic effect, which increased during the stimulation period and was sustained for 30 minutes after stimulation.68 Generally in TENS, the electrodes are placed over the painful area in order to stimulate the cutaneous nerves in that area. For use in labor, four electrodes are placed on either side of the midline of the spine to stimulate the posterior primary rami of the spinal segments (T11-Ll and S2-s4) receiving the painful stimuli during labor. It is interesting to note that these are the loci of acupuncture points (BL-20, BL-27, and BL-28) that are traditionally thought to reflect female reproductive function. The selection of this area for stimulation is based on Bonica’s account of the neurologic mechanism of delivery pain.69 During the first stage, pain receptors are assumed to be activated by contractions of the uterus and dilation of the cervix. The evoked impulses are mediated in afferents that run in the hypogastric nerves and reach the spinal cord via the dorsal roots T10-L1. The pain is referred to large areas of the abdomen and back. During the second stage, pain is also caused by distention and stretching of the delivery canal, the pelvic floor, the vulva, and the perineum. The pain is localized, and the impulses reach the spinal cord mainly via the pudendal nerves and the dorsal roots S2-s4. The pain during the first stage is characterized as an ache considered to

be mediated in small-diameter C fibers. During the second stage, the pain has the more localized intensive nature usually identified with the delta afferent fiber~.6~*~O In the typical application of this technique for control of pain during labor, low-intensity stimulation is given continuously and a high-intensity stimulation can be initiated by the parturient herself whenever pain increases. Stimulation via the thoracic electrodes is maintained throughout the delivery at an amplitude that is maximal for a pleasant sensation, whereas sacral stimulation is added from the later part of the first stage. Table 42-1 summarizes the uniformly good results that have been reported. Those patients who complained of backache have especially appreciated it. An Austrian study compared the analgesic effects of TENS, pethidine, and placebos on labor pain in 30 parturient women during the first stage of labor. No sigruficant difference was found between the placebo, unspecific TENS, and control groups in the increase in pain during the test period. Patients who had received pethidine and those who had been given TENS experienced considerable relief of pain.” It is curious that apart from a passing reference by Shealy and M a ~ r e to r ~its ~ use in labor, no research on the obstetric application of TENS appeared for many years in any of the U.S. literature. A 1996 review of 30 studies on TENS stimulation of acupuncture points in labor substantiated the conclusions of earlier research.76 In view of the relatively good results and lack of complications, the consensus of all the preceding studies is that the TENS method is recommended as a primary pain-relieving measure, to which conventional methods can be added as needed. Robson7 comments that TENS is noninvasive and is believed to be safe for both mother and baby. It is easy to apply and can be operated throughout labor by the doctor, midwife, father, or mother. Augustinsson et al.a were most impressed by the lack of complications, because the conventional methods, including analgesic and sedative drugs, nitrous oxide

Results (%)

Study

No. of patients

Good

Moderate

Augustinsson et aIw

147

44

44

12

Andersson et aI7’

27

48

37

15

~ Kanfer & G ~ l d f o o t ~ 35

20

62

18

Stewart72

31

56

13

67

None

Kubista et a173

102

55

24

21

Bundsen et a174

347

47

42

11

inhalation, epidural anesthesia, and local blockades, all possess a varying level of potential risk.6.’ Another advantage is that TENS, because it does not give complete analgesia, does not eliminate pain as a diagnostic tool; it can be interrupted whenever needed for clinical evaluation. More important, perhaps, from the point of view of the woman in labor is the fact that her consciousness is not altered to the point of excluding her own active participation in, and experience of, the delivery. Both Stewartn and Augustinsson et al.65 reported TENS alone to be inadequate for analgesia in the second stage of labor. The second group of researchers regards this difference as possible support for the assumption that C fiber-mediated pain is more amenable to blocking by electrical stimulation than A fiber-mediated pain. Stewart72mentions simply that many women did not wish to use the stimulator at that stage because it proved a distraction from their efforts to bear down. In this connection, it is interesting to note that “those who were well prepared and keen on natural childbirth were not always the most enthusiastic and, in fact, two of the early failures were patients who had been to relaxation cla~ses.’”~ Robsonn explains that TENS could distract some patients from their breathing or other focus of attention learned in childbirth preparation classes. A related issue in the TENS literature is introduced by the comment of Anderson et al.71that there was a correlation between the level of hypnotizability and that of pain relief in their subjects. Such a correlation may, of course, imply only a susceptibility to any type of therapeutic effect. Neumark et al.” tested this effect by including a placebo group that was given no current through the electrodes; these researchers found that the result for the placebo group was not different from that of TENS applied nonspecifically (i.e., incorrectly) but was sigruficantly different from the effect of TENS placed over the relevant nerve distribution and from that of pethidine. Robson,= although making no attempt to assess a patient’s level of susceptibility to hypnosis, switched off the TENS machine for at least two contractions. All patients asked for it to be switched on again, indicating that the technique was providing pain relief. Augustinsson et a1.@consider the suggestive effect, if it occurs, to be of minor sigruficance,because several investigators have found the pain-reducing effect of TENS to be achieved through demonstrable neurophysiologic mechanisms.Stewartn points out that the greater personal contact between patient and attendant essential to the use of this method may introduce an element of suggestibility or distraction that affects the pain experience.

Acupuncture Hundreds of studies have investigated the efficacy and mechanisms of acupuncture analgesia for acute and chronic pain, in surgical operations, and in childbirth.

In a review article of 24 studies, Lewith and found that the typical clinical trial showed a 70%efficacy of acupuncture compared with placebo treatment. Reichmanis and B e ~ k e found r ~ ~ similar results in a review of 17 studies of acupuncture analgesia in experimentally induced pain. On the basis of a thorough review of the clinical and experimental research on acupuncture pain control, Stux and PomerantzsO concluded that acupuncture analgesia helps from 55% to 85% of patients with chronic pain, comparing favorably with the effects of potent pain medication (such as morphine, which is 70% effective), and clearly distinct from the placebo effect, which helps 30%to 35%.80Atthe same time, somatosensory EEG-evoked potential studies have provided objective evidence of the analgesic effect of ac~puncture.~~-~~ Recent randomized and double-blinded controlled studies have demonstrated clinical effectiveness of acupuncture in treating chronic lateral epcondylitiss4 and chronic neck pain.85In the neck pain study, stimulation at distant points of the neck-related meridians were more effective than sham acupuncture points and “dry needle” injections of local myofascial trigger points, reducing motion-related pain by one third after a single treatment. A single-blind randomized controlled trial showed that electroacupuncture ( E N is superior to manual acupuncture in treating patients with tennis elbow.%A review article on treatment of fibromyalgia pain for patients at a hospital in Brazil showed improvement with traditional acupuncture, measured on subjective scales and number of tender points.87Preoperative EA has led to reduction in intraoperative and postoperative requirement of analgesic medications (alfentanil and morphine) in patients receiving gynecologic lower abdomen surgery.88In fact, surgery that requires general anesthesia in Western countries is routinely performed in Chinese hospitals with the combination of acupuncture and local anesthesia for pain control, providing a considerable decrease in risk for surgical patients. Hyodo and Gega13 of the Osaka Medical College have reviewed the literature (summarized in Table 42-2) on acupuncture anesthesia and analgesia in normal delivery and found mixed results. For example, Wallis et a1.90reported that although 19 of their 21 volunteer parturients considered acupuncture unsuccessful in providing analgesia for labor, one third indicated that they would choose acupuncture analgesia in labor again. Some researchers criticize the technique as being inconsistent, unpredictable, incomplete, timeconsuming, and interfering with movement and electronic monitoring. In their own study, Hyodo and Gega13tested 32 patients, equally divided between primaparas and multiparas. Low-frequency electrical current was introduced through

Nonpharmacological Control of Pain EA seems to operate along this pathway.94A study carried out on dogs seems to ver* the traditional theory of points of tonification and sedation, through differential production of sympathomimetic and parasympathResults I%) omimetic effects on the cardiovascular system upon Study No.of patients Good Poor or none stimulation of different points. Carlsson,96 a Swedish Hyodo & Gega13 researcher, concludes that a mechanism for therapeutic 16 62.5 37.5 Primiparas acupuncture must include peripheral events that release Multiparas 16 93.7 7.3 neuropeptides, spinal mechanisms such as gate control, it0*9 80 85 15 and supraspinal mechanisms through the descending pain inhibitory system, the sympathetic nervous system, Wallis et atw 9-33 67-91 and the hypothalamic-pituitary-adrenal (HPA) axis. He Abouleish & Deppgl 80.5 19.5 cautions that much of animal and human experimental acupuncture research shows only short-term hypoalgesia; that almost all such experimental research has been performed with EA rather than the more gentle manual needles at LI-4, ST-36, and SP-6, a standard therapeutic style of therapeutic acupuncture; and that pain threshold repertory for sedation of the reproductive organs. The elevation in human experimental research does not results were assessed from relief noted by the patient necessarily predict the clinical outcome. (subjective scale) as well as from the obstetrician's obserIn a study of labor induction and inhibition by EA, vation (objective scale); among the primiparas, 62.5% Tsuei et al.97utilized SP-6 and SP-4 points, which are found good or excellent effect on the subjective scale, and located in the territory of the L4 dermatome. The spleen 62.6%good or excellent on the objective scale; and among meridian, to which these loci belong, runs across the derthe multiparas, 93.8% subjective relief and 93.7% objecmatomes of LA, W, L2, and L1, and then upward from tive relief. Overall, 90% of the patients experienced relief T12 to T5. Because the sympathetic nerve controlling the of pain within 20 minutes of initiation of acupuncture uterus through the pelvic plexus receives preganglionic anesthesia. These researchers noted the considerable fibers from T5 to L4, Tsuei et al?' concluded that it is disparity in reports of effectiveness of acupuncture from highly possible that stimulation of the electropermeable Japan and America, explaining it as a novelty effect. It is loci within this area may alter the physiologic function natural that in Japan, where no analgesic methods are of the uterus. The LI-4 points of the upper extremities, normally used, the scoring in favor of acupuncture often added to the spleen meridian points in the would be high compared with that in America. acupunctural control of labor pain, perhaps represent Hyodo and Gega13concluded that acupuncture analgethe central approach to the autonomic nervous system, sia is useful for delivery, especially because of its safety, because these loci control pain to the head and neck. even though its results are more erratic and less potent than It should be noted, however, that Motoyama,ss who has those of conventional anesthetic techniques.More recently, attempted to verify the traditional subtle anatomy of a randomized controlled trial investigating acupuncture meridian pathways through tests of electrocutaneous treatment as a complement or an alternative to convenresistance at meridian points, claims that these effects tional analgesia for labor in a Swedish hospital found that cannot be adequately explained in terms of the convenacupuncture sigruficantly reduced the need for epidural tional sympathetic dermatomes but instead imply an analgesia, and parturients receiving acupuncture achieved alternative bioelectric transmission system. a better extent of relaxation than the control g r o ~ p . ~ The discovery of the Head McKenzie sensory A considerable amount of research has focused on zones has shown the possible mediation of the invisible determining a mechanism for acupuncture analgesia. meridians and points of traditional Eastern medicine A 1995 review of studies on acupuncture effects in pain between internal organs and corresponding skin areas. and disease pointed out that, like exercise, acupuncture N a k a t a r ~ was i ~ ~ able to detect the electropermeable produces rhythmic discharges in nerve fibers and causes line as an apparent viscerocutaneous autonomic nerve the release of endogenous opioids and oxytocin. Furtherreflex when organic diseases were involved. Hyodolmhas more, "experimental and clinical evidence suggests that explained acupuncture stimulation as the transmission acupuncture may affect the sympathetic system via of impulses centrally from the reactive electropermeable mechanisms of the hypothalamic and brain-stem loci, via a sympathetic afferent fiber, and that the autolevels."91 Animal studies continue to demonstrate that nomic nerve in the viscera is stimulated to response by acupuncture analgesia is mediated in the central and peripheral nervous systems by opioid ~ e p t i d e s . The 9 ~ ~ ~ the reverse of the McKenzie theory. An exciting recent development in acupuncture research has been the findcortex and hippocampus appear to participate in the ing by functional neuroimagery of neuronal correlates of modulation of chronic pain, and the analgesic action of Results of acupuncture analgesia in the control of labor pain

Therapeutic Modalities

This chapter has presented many of the current nonpharmacological strategies for control of pain. Because

the mechanism of pain perception has been shown to involve both physiologic and psychological components, the optimal treatment might combine psychological factors, such as preparatory information, attention focus, relaxation, and supportive communication, with the physical stimuli of TENS or acupuncture. In fact, such a multidisciplinary approach to patients with chronic back pain was evaluated after a 4-week program that included back schooling, psychological intervention, and treatment by acupuncture, chiropractic, the Alexander technique, and a pain specialist. Significant improvement was maintained for a period of 6 months.lffi Dental researchers of the Pediatric Pain Program of the University of California at Los Angeles School of Medicine searched several databases for reports of randomized, controlled clinical trials of complementary and alternative medical modalities used to treat chronic facial pain. Three acupuncture trials, eight biofeedback trials, and three relaxation trials met the researchers’ inclusion criteria, suggesting that these modalities were comparable to conventional treatment such as an intraoral appliance.lo7 Increasingly, the multidisciplinary pain management team, incorporating a variety of nonpharmacological treatment modalities, is being considered “the optimal method for delivery of comprehensive treatment to patients in pain.”losThe incorporation of ”alternative” forms of pain management, including acupuncture, relaxation techniques, hypnosis, biofeedback, and guided imagery, is acknowledged by the Children’s Hospital of the Medical College of Wisconsin to complement pharmacologic management of children’s pain.Im The selection, balance, and application of these treatment components should be based on consideration of an individual’s coping styles. Such a treatment program could be developed to provide a more consistently effective analgesia than the individual components can provide separately. Relieving the pain of childbirth, for example, without diminishing or distorting the full consciousness of the experience for the mother, would be consistent with the goals of the contemporary physician of natural medicine.

1. Krupp MA, Chatton MJ. Current medical diagnosis and treatment. Los Altos, CA: Lange Medical, 1984:l-5. 2. Kitzinger S. Pain in childbirth.J Med Ethics 1978;4119-121. 3. Walsh DA, Radcliffe JC. Pain beliefs and perceived physical disability of patients with chronic low back pain. Pain 2002;97: 23-31. 4. Haythronthwaite JA, Lawrence JW, Fauerbach JA. Brief cognitive interventions for bum pain. Ann Behav Med 2001;U:42-49. 5. P i a T, Taplin JE, Goodenough B, von Baeyer CL. Cognitive-behavioural predictors of children’s tolerance of laboratory-induced

pain: implications for clinical assessment and future direction. Behav Res Ther 2002;40571-584. 6. Kitaeff R. Cognitive strategies for control of painful stress. Unpublished manuscript, 1979. 7. Melzack R, Casey KC. Sensory, motivational and central control of pain. In Kenshalo DR, ed. The skin senses: proceedings. Springfield, n: Charles C Thomas, 1968:423-443. 8. Feumrstein M, Skjei E. Mastering pain. New York Bantam, 1979:17-21. 9.Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150971-979.

acupuncture stimulation in the human brain. In a controlled study of electroacupuncture (EA) stimulation of GB-34 on the left leg, real EA elicited significantly higher activation over the hypothalamus and primary somatosensory motor cortex than mock and minimal EA, showing that the hypothalamic-limbic system was sigruficantly modulated by EA at acupoints.’”’

Other Methods The scope of this chapter does not permit detailed discussion of other promising methods of pain control, but mention can be made of massage, biofeedback, and nutritional and botanical agents for treatment of pain. A literature search led to the conclusion that massage, particularly acupressure, is effective for low back pain, especially when it is combined with exercises and education, with beneficial effects lasting at least 1 year after the end of treatment.’”*A vast literature is available on biofeedback training for pain. An article suggesting a future direction in pain medicine describes the use of “off-the shelf,” low-cost, and low-bandwidth telemedicine equipment to deliver clinical biofeedback treatment when the patient and provider are in two different locat i o n ~ . In ’ ~a~randomized double-blind trial of 30 patients with chronic maxillofacial pain, significant reduction in pain scores and improvement in tolerance of experimentally induced dental pain were achieved with administration of 3 g daily of the amino acid tryptophan and a high-carbohydrate, low-fat, low-protein diet in comparison with placebo.’04Among botanical agents for pain, corydalis rhizome or tuber (yanhusuo) is well known in the Chinese materia medica for its analgesic effect, containing combined alkaloids found to be 40% as effective as morphine. Acting probably through inhibition of the reticular activating system, corydaline was shown in one clinical study to decrease or relieve pain in 32 of 44 patients with dysrnen~rrhea.’~~

CONCLUSION

NonpharmacologicalControl of Pain 10. Cheng RS, Pomeranz B. Electroacupuncture analgesia could be mediated by at least two pain-relieving mechanisms: endorphin and non-endorphin systems. Life Sci 1979;25:1957-1962. 11. Baldwin R. Special delivery: the complete guide to informed birth. Millbrae, CA: Les Femmes, 1979. 12. Laukaran VH,van den Berg BJ. The relationship of maternal attitude of pregnancy outcomes and obstetric complications: a cohort study of unwanted pregnancy. Am J Obstet Gynecol1980;136374-379. 13. Hyodo M, Gega 0.Use of acupuncture anesthesia for normal delivery. Am J Chin Med 1977;5:63-69. 14. Davidson PO, McDougall CE. The generality of pain tolerance. J Psychosom Res 1969;13:83-89. 15. Eysenck S. Personality and pain assessment in childbirth of married and unmarried mothers. J Mental Sci 1961;107:417429. 16. Levine F, Tursky B, Nichols D. Tolerance for pain, extroversion and neuroticism: failure to replicate results. Percept Mot Skills 1966;23:847-850. 17. Morgan AH, Lezard F, Prytulak S, Hilgard ER. Augmenters, reducers, and their reaction to cold-pressor pain in waking and suggested hypnotic analgesia. J Pers Soc Psychol 1970;16:5-11. 18. Mumford JM, Newton AV, Ley P. Personality, pain perception and pain tolerance. Br J Psychol 1973;64:105-107. 19. Sweeney DR, Fine BJ. Pain reactivity and field dependence. Percept Mot Skills 1965;21:757-758. 20. Andrew J. Coping style, stress-relevant learning and recovery from surgery. Diss Abstr 1968;28:1182-1183. 21. Davidson PO, Bobey MJ. Repressor-sensitizer differences on repeated exposure to pain. Percept Mot Skills 1970;31:711-714. 22. Cohen F, Lazarus R. Active coping processes, coping dispositions, and recovery from surgery. Psychosom Med 1973;35:375-389. 23. Chapman CR. Lecture, University of Washington, October 1979. 24. Bowers K. The effects of UCS temporal uncertainty on heart rate and pain. Psychophysiology 1971;8:382-389. 25. Bandler RJ Jr, Madaras GR, Bem DJ. Self-observation as a source of pain perception. J Pers Soc Psychol 1968;9205-209. 26. Geer JH, Davison GC, Gatchel RI. Reduction of stress in humans through non-veridical perceived control of aversive stimulation. J Pers Soc Psychol 1970;16:731-738. 27.Pervin L. The need to predict and control under conditions of threat. J Pers Soc Psychol 1963;31:570-585. 28. Staub E, Tursky 8 , Schwartz GE. Self-control and predictability: their effects on reactions to aversive stimulation. J Pers Soc Psychol 1971;18:157-162. 29. Johnson JE. Effects of accurate expectations about sensations on the sensory and distress components of pain. J Pers Soc Psychol 1973;27261-275. 30.Neufeld RW, Davidson PO. The effects of vicarious and cognitive rehearsal on pain tolerance. J Psychosom Res 1971;15 329-335. 31. Staub E, Kellett DS.Increasing pain tolerance by information about aversive stimuli. J Pers Soc Psychol 1972;21:198-203. 32. Seligman M, Maier S, Solomon R. Unpredictable and uncontrollable aversive events. In Brush F, ed. Aversive conditioning and learning. New York: Academic Press, 1969. 33. Kanfer FH, Seidner ML. Self-control: factors enhancing and tolerance of noxious stimulation. J Pers Soc Psychol 1973;25: 381-389. 34. Langer E, Janis I, Wolfer J. Effects of cognitive device and preparatory information on psychological stress in surgical patients. Unpublished manuscript, 1973. 35. Croog SH, Baume RM, Nalbandian J. Pain response after psychological preparation for repeated periodontal surgery. J Am Dent ASSW1994;1251353-1360. 36. Holmes DS,Houston BK. Effectiveness of situation redefinition and affective isolation in coping with stress. J Pers SOCPsychol 1974;29:212-218.

37. Newton-John TR, Spence SH, Schotte D. Cognitive-behavioural therapy versus EMG biofeedback in the treatment of chronic low back pain. Ekhav Res Ther 1995;33691-697. 38. Vlaeyen JW, Haazen IW, Schuerman JA, et al. Behavioural rehabilitation of chronic low back pain: comparison of an operant treatment, an operant-cognitive treatment and an operant-respondent treatment. Br J Clin Psychol 1995;34:95-118. 39. Turner JA, Jensen MP. Efficacy of cognitive therapy for chronic low back pain. Pain 1993;52169-177. 40. van Dulmen AM, Fennis JF, Bleijenberg G. Cognitive-behavioral group therapy for irritable bowel syndrome, effects and long-term follow-up. Psychosom Med 1996;58:508-514. 41. Dworkin SF. Behavioral and educational modalities. Oral Surg Oral Med Pathol Oral Radio1 Endod 1997;83:128-133. 42. Gardea MA, Gatchel RJ, Mishra KD. Long-term efficacy of biobehavioral treatment of temporomandibular disorders. J Behav Med 2001;24341-359. 43. Arathuzik D. Effects of cognitive-behavioral strategies on pain in cancer patients. Cancer Nurs 1994;17207-214. 44.Osterhaus So, Passchier J, van der Helm-Hylkema H, et al. Effects of behavioral psychophysiological treatment on school children with migraine in a nonclinical setting: predictors and process variables. J Pediatr Psychol 1993;18:697-715. 45. Basler HD. Group treatment for pain and discomfort. Patient Educ COLUW 1993;20167-175. 46. Sinclair VG, Wallston KA. Predictors of improvement in a cognitive-behavioral intervention for women with rheumatoid arthritis. AM Behav Med 2001;23:291-297. 47. Astin JA, Beckner W, Soekin K, et al. Psychological interventions for rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum 2002,47291-302. 48. Williams DA, Cary MA, Groner KH, et al. Improving physical functional status in patients with fibromyalgia: a brief cognitive behavioral intervention. J Rheumatol2002;29:1280-1286. 49. Lee BH, Scharff L, Sethna NF, et al. Physical therapy and cognitivebehavioral treatment for complex regional pain syndromes. J Pediatr 2002;141:135-140. 50. Stevens RJ, Heide F. Analgesic characteristics of prepared childbirth techniques:attention focusing and systematic relaxation. J Psychosom Res 1977;21:429-438. 51. Dahlquist LM, Busby SM, Slifer KJ, et al. Distraction for children of different ages who undergo repeated needle sticks. J Pediatr Oncol NUIS 2002;19:22-34. 52. Haythronthwaite JA, Lawrence JW, Fauerbach JA. Brief cognitive interventions for bum pain. Ann Behav Med 2001;23:42-49. 53. Kanfer FH, Goldfoot DA. Self-control and tolerance of noxious stimulation. Psychol Rep 1966;18:79-85. 54. Evans MB, Paul GL. Effects of hypnotically suggested analgesia on physiological and subjective responses to cold stress. J Consult Clin Psycho1 1970;35:362-371. 55. Anand BK, Chhina ES, Singh B. Some aspects of electroencephalographic studies in yogis. EEG Clin Neurophysiol 1961; 13~452-456. 56. Pelletier K, Peper E. The chutzpah factor in altered states of consciousness. J Humanis Psych 1977;1763-73. 57. Benson H. The relaxation response. New York: Avon, 1976. 58. Chaves JF. Recent advances in the application of hypnosis to pain management. Am J Clin Hypn 1994;37117-129. 59. Kroger WS. Clinical and experimental hypnosis in medicine, dentistry, and psychology. Philadelphia: Lippincott, 1963:197-198. 60. De Pascalis V, Magurano MR, Bellusci A, Chen AC. Somatosensory event-related potential and autonomic activity to varying pain reduction cognitive strategies in hypnosis. Clin Neurophysiol 2001;112:1475-1485. 61. Dunn PM. Obstetric delivery today: for better or for worse? Lancet 1976;1:790-793.

Therapeutic Modalities 62.Flynn A, Kelly J. Continuous fetal monitoring in the ambulant patient in labour. Br Med J 1976;2:842-843. 63. Liu YC. Effects of an upright position during labor. Am J Nurs 1974j742202-2205. 64.Augustinsson LE, Bohlin P, Bundsen P, et al. Pain relief during delivery by transcutaneous electrical nerve stimulation. Pain 1977;459-65. 65.Shealy CN, Maurer D. Transcutaneous nerve stimulation for control of pain: a preliminary technical note. Surg Neurol 1974;2:45-57. 66. Yuan CS, Attele AS, Dey L, et al. Transcutaneous electrical acupoint stimulation potentiates analgesic effect of morphine. J Clin Pharmacol2002;42:899-903. 67. Naeser MA, Hahn KA, Liebennan BE, Branco KF. Carpal tunnel syndrome pain treated with low-level laser and microamperes transcutaneous electric nerve stimulation: a controlled study. Arch Phys Med Rehabil2002;83:978-988. 68.Chesterton LS, Barlas P, Foster NE, et al. Sensory stimulation (TENS): effect of parameter manipulation on mechanical pain thresholds in healthy human subjects. Pain 2002;99:253-262. 69. Bonica JJ. Fundamental considerations. Vol I, Principles and practice of obstetric analgesia and anesthesia. Philadelphia: FA Davis, 1967. 70. Bonica JJ. The nature of pain in parturition. Clin Obstet Gynecol 1975;2499-516. 71. Andersson SA, Block E, Holmgren E. Lagfrekvent transkutan elektrisk stimulering for smartlindring vid forlassning, Lakartidningen 1976;73:2421-2423. 72. Stewart P.Transcutaneous nerve stimulation as a method of analgesia in labour. Anaesthesia 1979;34:361-364. 73. Kubista E, Kucera H, Riss P. The effect of transcutaneous nerve stimulation on labor pain. Geburtshilfe Frauenheilkd 1978%: 1079-1084. 74.Bundsen P, Carlsson CA, Forssman L, Tyreman NO. Pain relief during delivery by transcutaneous electrical nerve stimulation. Prakt Anaesth 1978;13:20-28. 75.Neumark J, Pauser G, Scherzer W. Pain relief in childbirth: an analysis of the analgesic effects of transcutaneous nerve stimulation (TNS),pethidine and placebos. Prakt Anaesth 1978;13:13-20. 76. Kemp T. The use of transcutaneous electrical nerve stimulation on acupuncture points in labour. Midwives 1996;109:318-320. 77.Robson JE. Transcutaneous nerve stimulation for pain relief in labour. Anaesthesia 1979;34:357-360. 78. Lewith GT, Machin D. On the evaluation of the clinical effects of acupuncture. Pain 1983;16111-127. 79. Reichmanis M, Becker RO. Relief of experimentally-induced pain by stimulation at acupuncture loci: a review. Comp Med East West 1977;5:281-288. 80. Stux G, Pomeranz B. Basics of acupuncture. New York: SpringerVerlag, 1988. 81. Chapman CR, Colpitts YM, Benedetti C, et al. Evoked potential assessment of acupunctural analgesia: attempted reversal with naloxone. Pain 1980;9:183-197. 82.Kumar A, Tandon OP, Bhattarcharya A, et al. Somatosensory evoked potential changes following electreacupuncture therapy in chronic pain patients. Anaesthesia 1995;50:411-414. 83. X u X, Shibasaki H, Shindo K. Effects of acupuncture on somatosensory evoked potentials: a review. J Clin Neurophysiol 1993;10370377. 84. Fink M, Wolkenstein E, Luennemann M, et al. Chronic epicondylitis: effects of real and sham acupuncture treatment: a randomized controlled patient- and examiner-blinded long-term trial. Forsch Komplementarmed Klass Naturheilkd 2002;9:210-215. 85. Imich D, Behrens N, Gleditsch JM, et al. Immediate effects of dry needling and acupuncture at distant points in chronic neck pain: results of a randomized, double-blind, sham-controlled crossover trial. Pain 2002;99:83-89.

86.Tsui P, h u n g MC. Comparison of the effectiveness between manual acupuncture and electreacupuncture on patients with tennis elbow. Acupunct Electrother Res 2002;27107-117. 87. Targino RA, Imamura M, Kaziyama HH, et al. Pain treatment with acupuncture for patients with fibromyalgia. Cum Pain Headache Rep 2002;6379-383. 88. Sim CK, Xu I T , Pua HL, et al. Effects of electroacupuncture on intraoperative and postoperative analgesic requirement. Acupunct Med 2002;20:56-65. 89. It0 T. Painless labor with acupuncture anesthesia. Japan J Anesth 1974;2310-16. 90. Wallis L, Shnider SM, Palahniuk RJ, Spivey HT. An evaluation of acupuncture analgesia in obstetrics. Anesthesiology 1974;41:596-601. 91. Abouleish E, Depp R. Acupuncture in obstetrics. Anesth Analg 1975;54:82-88. 92. Ramnero A, Hanson U, Kihlgren M. Acupuncture treatment during labour: a randomized, controlled trial. Br J Obstet Gynecol 2002;109:637-644. 93. Wu GC, Zhu J, Cao X. Involvement of opioid peptides of the preoptic area during electroacupuncture analgesia. Acupunct Electrother Res 1995;201-6. 94. Zhu L, Li C, Ji C, Li W. The role of OLS in peripheral acupuncture analgesia in arthritic rats. Zhen Ci Yan Jiu [Acupunct Res] 1993;18214-218. 95. Zhou L, Jiang JW, Wu GC, Cao XD. Changes of endogenous opioid peptides content in RFGL during acupuncture analgesia. Sheng Li Xue Bao 1993;45:36-43. 96. Carlsson C. Acupuncture mechanisms for clinically relevant longterm effects: reconsideration and a hypothesis. Acupunct Med 2002;2082-99. 97. Tsuei JJ, Lai Y, Sharma SD. The influence of acupuncture stimulation during pregnancy. Obstet Gynecol1977;50479-448. 98. Motoyama H. How to measure and diagnose the functions of meridians and corresponding internal organs. Tokyo: Institute for Religious Psychology, 1976. 99. Nakatani Y. A guide for application of Ryodoraku autonomous nerve regulatory therapy. Tokyo: Japanese Society of Ryodoraku Autonomic Nervous System, 1972. 100.Hyodo M. New management of pain. Tokyo: Chiyugai Igakushiya, 1970. 101. Wu MT, Sheen JM, Chuang KH, et al. Neuronal specificity of acupuncture response: a fMRI study with electroacupuncture. Neuroimage 2002;161028-1037. 102. Furlan AD, Brosseau L, Imamura M, Irvin E. Massage for low back pain: a systematic review within the framework of the Cochrane Collaboration Back Review Group. Spine 2002271896-1910. 103. Earles J, Folen RA, James LC. Biofeedback using telemedicine: clinical applications and case illustrations. Behav Med 2001;27 77-82. 104. Seltzer S, Dewart D, Pollack RL, Jackson E. The effect of dietary tryptophan on chronic maxillofacial pain and experimental pain tolerance. J Psychiatr Res 1982-83;17181-186. 105. Bensky D, Gamble A. Chinese herbal medicine materia medica. Seattle: Eastland Press, 1986:389. 106. Elkayam 0, Ben Itzhak S, et al. Multidisciplinary approach to chronic back pain: prognostic elements of the outcome. Clin Exp Rheumatol1996;14281-288. 107. Myers CD, White BA, Heft MW. A review of complementary and alternative medicine use for treating chronic facial pain. J Am Dental Assoc 2002;133:1189-1196. 108. Golden BA. A multidisciplinary approach to nonpharmacologic pain management. J Am Osteopath Assoc 2002;102:Sl-S5. 109. Rusy LM, Weisman SJ. Complementary therapies for acute pediatric pain management. Pediatr Clin North Am 2000;47589-599.

Nontransfusion Significance of ABO and ABO -Associated Polymorphisms Peter J. D’Adamo, ND CHAPTER CONTENTS Introduction

441

Background 441 ABH Antigens 441 ABH Secretors and Nonsecretors 442 Blood Group as Self-Declaration and Adhesion Molecules 443 Blood Group Antibodies 444 ABO and Secretor Blood Group Genetics 445 Additional Physiologic Correlations 446 Major Diseases and ABO 447 Cardiovascular Disease 447

INTRODUCTION Concepts without percepts are empty; percepts without concepts -1mmanuel Kant (1724-1804) are blind. Since Landsteiner first described the ABO typing system in 1900, the preeminent clinical role of thisred cell antigenserum antibody system has been the prediction of reactions involving transfused blood and, to a lesser degree, transplanted organs. Despite this exceedingly important role, however, no rational individual should conclude that the proper exchange of blood or other tissues constitutes their primary biologic role. It can be argued that the overwhelming and revolutionizing influence of the ABO system on the history and practice of transfusion medicine and the general reluctance of allopathic medicine to find a workable niche for the nonreducible have had the effect of precluding interest in the nontransfusion sigruficance of ABO polymorphism and, attendant to that, of a lack of any meaningful medical applications. This chapter examines the biologic sigruficance of the ABO blood grouping and the ABH secretor system, with special attention to the effects of ABO expression as a “tipping point” for a variety of physiologic and

Cancer 448 Infection 450

Blood Groups and Dietary Lectins 451 Historical Perspective 451 Actions 453 Role of ABO Blood Groups 455 Clinical Applications of ABO Polymorphism 455 The Blood Type Diet 455 Materia Medica 456 Conclusion 456

pathologic manifestations that may be of interest to the practitioner of natural medicine.

BACKGROUND Although a comprehensive review of the glycobiology of the ABO system is beyond the scope of this work, the brief overview given here should allow the reader to understand the basic mechanics and nomenclature of the system. All humans can be typed for ABO blood group. There are four basic blood types: A, B, AB, and 0.The system is composed of two antigens and two antibodies. The specific combination of these four components determines that individual‘s type. Table 43-1 shows the possible permutations of antigens and antibodies with the corresponding ABO types.

ABH Antigens The ABO blood group antigens are not primary gene products but instead the enzymatic reaction products catalyzed by the enzymes called glycosyltransferases. As depicted in Figure 43-1, they are synthesized from an oligosaccharide intermediate, H substance, which is

441

Possible combinations of antibodies and antigens in the ABO blood grouping system ABO blood tvDe

A antiaen

B antigen

Anti-A antibody

Anti-B antibody

A

Yes

No

No

Yes (IgM)

B

No

Yes

Yes (IgM)

No

0 AB

No

No

Yes (IgM. IgG)

Yes (IgM, IgG)

Yes

Yes

No

No

/g, Immunoglobulin.

produced by the presence of the monosaccharide fucose. Group A or B activity is produced by the addition of a single sugar on the nonreducing end of the H chain. Adding the glycoprotein N-acetyl galactosamine to the end of the chain results in blood group A antigenicity; with blood group B, the terminal carbohydrate and B group antigen is the monosaccharide galactose. There is no true 0 antigen: However, group 0 cells still contain H antigen, so the terminal carbohydrate of 0 (H) antigen is the monosaccharide fucose. Therefore, we identdy the blood types as "ABO but typically refer to the actual antigen system as "ABH." ABH substances manifest quite early in the life process,' appearing in the cell membranes and secretions of human embryos at about 5 weeks' gestational age. The membrane substances are found first in the epithelium and virtually all vascular endothelium.

In endothelial cells the expression of ABH antigen is ubiquitously upregulated in fetal organs and is considered suggestive evidence that blood group antigens serve as early immunomorphologic markers of the endothelial differentiation of mesenchymal cells, specifymg the location of future blood vessels.2 All embryonic epithelia contain the ABH antigen except those of the nervous system, adrenal glands, and liver. The antigens subsequently disappear from epithelia in an orderly and predictable manner as evidence of morphologic differentiation appears, and by about the end of the third intrauterine month, the adult pattern of distribution is achieved. The embryonic expression of ABH antigens may be an important aspect in the pathogenesis of certain diseases: A scrutiny of 2557 medical records for children with type 1 diabetes and controls showed ABO blood group incompatibility in close to 90% of children with diabetes: indicating that maternal-fetal ABO incompatibility may have acted to inhibit normal pancreatic islet formation in the fetus. The expression of ABH antigens in the adult is tightly regulated, and their reappearance in adult tissue normally devoid of them is virtually always a sign of disease. Inappropriate ABH expression is one of the prime manifestations of the aberrant glycosylation state that is a hallmark of malignancy. Instances have been observed indicating that aberrant ABH expression may be paralleled in entirely different organ systems: A link has been demonstrated between ABH antigen expression in normal and neoplastic colonic epithelia and consequent alterations of ABH expression in the thyroid?

ABH Secretors and Nonsecretors

Figure 43-1 Structures of the nonreducing end of the ABH and Lewis blood group antigen determinants.

By 1930 it had been shown that some people do and others do not secrete into their saliva antigens corresponding to their ABO blood group. Persons with these substances in saliva (secretors) have more ABH substances in their tissues than those lacking the substance in their saliva (nonsecretors). The ability to secrete behaved as a simple Mendelian function dominant to nonsecretion. Persons with blood groups A, B, and AB who are secretors secrete the antigens corresponding to

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

their blood groups. Group H persons secrete the H substance, as do all other secretors to a somewhat less extent. ABH secretor status is a major conditioner of the gut mucosa and ecosystem. ABH secretors have greater quantities of free ABH antigens in the makeup of their intestinal secretions, which has sigruficant effects on bacterial and lectin adherence to the gut microvilli. ABH substances are secreted by mucous glands in many organs, including the upper respiratory tract, the gastrointestinal tract from the esophagus through the colon, and the uterine cervix. The secretor gene regulates the synthesis of blood group substances in superficial glands of the gastric and small intestine mucosa. Large amounts of ABH material are found in all secretors.% In the gastric mucosa of healthy individuals the normal mucosa of secretors is characterized by a uniform distribution of blood type antigens in the pits. Healthy mucosa of nonsecretors shows little staining for these blood type antigens? Some ABH expression is independent of secretor status: Glands situated deep in the mucosa of the pylorus and small intestine (Brunner glands) and gastric parietal glands both produce A and B substances without regard to secretor status. ABO type and ABH secretor status together can exert significant effects on several digestive parameters. The most significant are presented here. For a more detailed discussion of the metabolic consequences of ABH secretor status, the reader should refer to my review article specifically on the subject.1°

Brush-Border Hydrolases ABO blood group determines much of the enzyme activity in the tissue (brush border) of the intestine. At least six intestinal hydrolases have ABO blood group antigenic determinants directly related to ABO blood group. Intestinal glycoproteins of blood group A and B individuals express A or B antigens, whereas blood group 0 subjects express the H determinant. The expression of these ABH antigens is under the control of the secretor gene, so these ABH antigens are not detected in the hydrolases of nonsecretor subjects.’l

Intestinal Alkaline Phosphatase Activity The intestinal component of alkaline phosphatase is involved with both the breakdown of dietary cholesterol and the absorption of calcium. The activity of intestinal alkaline phosphatase (IAP) and serum alkaline phosphatase is strongly correlated with ABH secretor phenotypes. Independent of ABO blood group, ABH nonsecretors have lower alkaline phosphatase activity than ABH secretors. It has been estimated that the serum alkaline phosphatase activity of nonsecretors is only about 20% of the activity in the secretor In addition to ABH secretor status, ABO polymorphism is linked to the levels and persistence of IAl?16

Numerous studies have associated group 0 individuals with the highest alkaline phosphatase activity, and group A with the 10west.l~In addition, one study has implied that the group A antigen itself may inactivate IAP.lX

Bacterial Flora The role of the ABO blood group in determining the bacteria making up a healthy gastrointestinal ecosystem is particularly strong in ABH secretors. Because ABH secretor status and ABO blood group dictate the presence and specificity of A, B, and H blood group antigens in human gut mucin glycoproteins, their status can influence the populations of bacteria capable of taking up local residence. This occurs because some of the bacteria in the digestive tract are actually capable of producing enzymes that allow them to degrade the terminal sugar of the ABH blood type antigens for a constant food supply.19 For example, bacteria capable of degrading blood group B antigen produce enzymes that allow them to detach the terminal alpha-D-galactose and use this sugar for food. Blood group A-degrading bacteria would have similar capabilities with respect to N-acetyl galactosamine (GaNAc). Because of this capability, the bacteria that use ABH antigens for food have a competitive advantage and can thrive in the environment created by the preconditioning of ABH secretions. Although comparatively small populations of bacteria produce blood group-degrading enzymes (estimated populations are 108 bacteria per g), the quantity of these bacteria are several orders of magnitude greater in different blood types, and they are much more stable residents. For example, B-degrading bacteria have a population density about 50,000-fold greater in blood group B secretors than in other subjects. Similar bacterial specificity and enzyme activity are found in other blood types.20

Immunity Evidence suggests that ABH nonsecretors have lower levels of immunoglobulin (Ig) G2Ipz and secretory IgA concentrations than s e ~ r e t o r s . ABH ~ ~ , ~nonsecretors ~ appear to have a higher prevalence of a variety of autoimmune diseases, including ankylosing spondylitis, reactive arthritis,psoriatic arthropathy, Sjogren syndrome, multiple sclerosis, and Grave d i s e a ~ e . ~ , ~ ~ - ~ ’

Blood Group as Self-Declaration and Adhesion Molecules In the larger world of glycoproteins, ABH antigens are characterized as 0-linked glycans (glycosylation at serine or threonine residues by GalNAc). All cells and many proteins in nature carry these dense and complex arrays of covalently attached sugar chains. Their biologic roles are particularly important in construction of

Therapeutic Modalities complex multicellular organs and organisms, a process that requires interactions of cells with one another and with the surrounding extracellular matrix. The glycans are typically on the outer surfaces of cellular and secreted macromolecules and are therefore in optimal positions to mediate interactions between organisms and a variety of cell-to-cell and cell-to-matrix interactions crucial to the development and function of a complex multicellular organism. Glycans can have a sigruficant effect on fungal, viral, and bacterial pathogenicity. H substance, a fucosylated glycan, can serve as a ligand in cell adhesion and is a receptor for several microorganisms, most notably Cundida albicans, which produces an adhesin with high H specificity.28 ABH antigens are ubiquitous in nature, found abundantly in foodstuffs (where they are thought to play a role in the induction of opposing blood group antibodies early in life) and in a host of microorganisms. A 1995 study showed that of 833 fungi harvested from 1977 to 1994,422 extracts (47.8%)produced agglutination of human red blood cells (RBCs), equally distributed against type 0, A, and B cells. Obviously, these fungi are not producing agglutinins with the direct intent of clumping human red cells but, rather, are desirous of attaching and infecting seeds or other microbes that possess some "ABO blood type" activity of their ABH antigens appear in secretions by 8 to 9 weeks of age, first in the salivary glands and stomach, then throughout the gastrointestinal and vaginal tracts. The ABH variation of blood group antigen expression on vaginal epithelial cells and mucus has a sigruficant role in susceptibility to urinary tract infections in women.30

Blood Group Antibodies The antibodies in the ABO system (isoagglutinins) are naturally occurring in the sense that they are non-RBCstimulated. Anti-A and anti-B are not normally present at birth because with their underdeveloped immune system and lack of provocation, newborns cannot synthesize immunoglobulins. The antibodies develop between 3 and 6 months of age as a result of unknown antigenic stimuli, presumably bacteria and foodstuffs. In a type 0 child, for example, antibodies begin forming to type A and B RBC antigens as soon as the child starts eating food, because the A and B antigens are actually found in quite a number of plants. So,as soon as the child starts eating plant food, he or she will be exposed to those antigens and start making antibodies against them. Isoagglutinins are typically IgM class antibodies, although group 0 individuals can and do produce IgG class anti-A and anti-B in addition to an IgG antibody to both A and B epitopes (anti-AB).

It has been shown that levels of the anti-blood type isoagglutinins are rising: A French study showed that they are about 50%higher in children in 1979 than was found in 1929.31The researcher suggested that the increased immune reactivity of children observed currently may be due to the greater use of prophylactic vaccinations, although dietary changes may have also played a role. GrundbacheP2 found that isoagglutinins were typically higher in black than in white persons, white persons having higher anti-A than anti-B levels, with the levels being higher in females than in males. In black persons the anti-B levels were almost as high as the levels of anti-A, and little sex difference was found. In another study, one fifth of sera from young, black, group 0 Zimbabwean blood donors were strongly hemolytic for either A or B cells or both.3 ABO blood type incompatibility may be a critical factor in infertility. ABO-incompatible mating couples (a type A male fertilizing a type 0 female) are a common Occurrence in miscarriages, especially very early in the gestational term. One study of 288 miscarriages showed that there was an excess of blood type A and type B in otherwise normal fetuses. The researchers concluded that the ABO incompatibility between mother and fetus is likely to be a cause of early miscarriages, but almost exclusively in chromosomally normal fetuses.%

Infertility In a study of 102 infertile couples, S ~ l i s hfound ~ ~ that 87%were blood type incompatible. The same study also found that in 7 couples with markedly delayed fertility, the 9 children who did result were all blood type 0, and hence would have been compatible with the mother. This researcher suggested that the infertility was due to the presence of antibodies in the secretions of the mother's genital tract or incompatible sperm from the father. In another study, a total of 589 compatible mating couples were compared with 432 incompatible mating couples. The mean number of living children presented a significant difference. There was a 21% deficiency of type A children in the two groups. Similarly, there was a 16% deficiency of type B children in the two groups. It appears that a 31.9%rate of miscarriage is associated with incompatible matings, compared with 17.15% in compatible matings. This finding has led some researchers to theorize that ABO incompatibility results in "cervical hostility" between the man's blood type antigens, which are present in his sperm, and the woman's opposing antibodies, present in her cervical mucus.36

Other Immune Correlates In 1991, DAdamo and Z a m p i e r ~ nreported ~~ that individuals of group 0 blood reporting a previous urticaria

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms or anaphylaxis showed high residual titers of anti-A isoagglutinins. When a score value was assigned to each agglutination reaction to allow for characterization, individualswith these disorders showed remarkably high titration scores compared with controls of the same blood group. In several cases, the subjects’ scores were almost threefold higher. A mild increase was noted for group 0 subjects with severe eczema or asthma, but total scores in these subjects were only marginally greater than those of controls. However, a striking association was shown for group 0 women suffering from end0metriosis.3~

ABO and Secretor Blood Group Genetics ABO System Epstein and Ottenberg suggested that the ABO blood group system could be inherited in 1910.38The determination of ABO status is the result of two codominant alleles and one recessive allele found on chromosome 9q band 34. A and B blood groups are dominant over the 0 blood group, and the A and B group genes are themselves codominant. The ABH antigens are not primary gene products but, instead, the enzymatic reaction products catalyzed by the enzymes called glycosyltransferases. ABO genes consist of at least seven exons, and the coding sequence in the seven coding exons spans more than 18 kb of the genomic DNA. The single nucleotide deletion found in most (but not all) of the 0 alleles and responsible for the loss of the activity of the enzyme is located in exon 6.39

ABH Secretor System The secretor gene (FLIT2 at 19q13.3)codes for the activity of glycosyltransferases needed to assemble (“secrete”) free ABH antigen in places like saliva, semen, vaginal fluid, and goblet and mucous gland cells, resulting in their presence in these bodily fluids and cells. This is accomplished in concert with the gene for group 0, or H (FUTZ). Secretor status is determined by two alleles on FUT2, Se (dominant) and se (recessive),with approximately 80% of the population typing as secretors (SeSe or Sese).

Lewis Blood Groups and Their Association with the ABH Secretor System The ABH secretor system is a major determinant of the Lewis (Le) blood grouping system. This is due to the fact that, in addition to ABH, FUTZ and FUT2 provide the glycans necessary for conversion of Lewis antigens as well. Two broad categories of Lewis blood type exist. These are the “Lewis positive” (either Lea+b or Lea*) and “Lewis negative” (Lea*) phenotypes. Depending on race, between 1%and 8%of the population are Lewis negative. In Lewis-positive phenotypes, Lea is formed initially, and in the case of nonsecretors (lacking the Se gene, FUT2), Lea substance is adsorbed onto the red cell, and they type as Lea. In the case of secretors, the Se gene activates the H gene, which causes an additional sugar to be added to Lea, converting it to Leb(see Figure 43-1). Among Lewis-positiveindividuals, ABH secretors are always Lea* because they convert all their Lea antigen into Leb.Conversely, among Lewis-positive people, ABH nonsecretors are always Lea+b because they lack the FUT2-dependent glycosyltransferase to accomplish this conversion. Thus it is often possible (and quite handy) to use the Lewis groups to infer ABH secretor status, because Lewis typing is fairly quick to perform and easy to master compared with the salivary inhibition test traditionally used. However, using Lewis typing to infer ABH secretor status works only in those individuals who are Lewispositive (about 9 of every 10 patients). Lewis-negative individuals can either be secretors or nonsecretors. However the Lewis-negative patient carries important metabolic consequences of their own, worthy of much attention.’O Table 43-2 shows Lewis blood types and their relationship to ABH secretor/nonsecretor status. Sialylated forms of several Lewis variations (sialyl Lewis A, sialyl Lewis X) are oligosaccharide ligands now considered crucial to the initial adhesion of white blood cells to a site of injury mediated by E-selectins. Large quantities of sialyl Lewis X have also been found on the surfaces of certain tumor and cancer cells and one of its variants (sialyl fj-sulfo Lewis X) appears to be involved in routine homing processes involving a variety of chemokines.

Lewis blood types and their relationship to ABH secretorhonsecretor status Lewis type

Category

ABH secretor status

Leave Lewis a antigen but not Lewis b

Lewis positive

ABH nonsecretor

Lea. Lewis b antigen but not Lewis a

Lewis positive

ABH secretor

Lea-b Neither Lewis a nor Lewis b

Lewis negative

Lewis outcome cannot determine ABH secretor status

Therapeutic Modalities Individuals of blood group 0 phenotype run an approximate 1.5- to 2-fold higher risk for development of acid peptic disease,40although there is no direct correlation between ABO blood group phenotypes and the prevalence of Helicobucter pylori infection. However in addition to H type 1, the Lebantigen is also a binding receptor for H. pyZori, and in this capacity it can best be described as a ”virulence promoting factor.” For virulent strains, Lebantigen binding activity targets the microbes to the epithelial cell surfaces and potentiates the effect of secretion of virulence factors such as the vacuolating cytotoxin and/or neutrophil activating/recruiting factors.41

Linkage When genes occur on the same chromosome, they are inherited as a single unit. Genes inherited in this way are said to be linked. Gene linkage analysis has demonstrated several associations between the ABO locus and several coadjacent genes. For example, there are strong indications that a gene regulating dopamine beta hydroxylase (DBH) activity is linked to the ABO blood group locus.42DBH is a key enzyme in the conversion of dopamine to norepinephrine. This linkage may help explain the continued sigruficance of ABO group as a discreet and sigruficant genetic marker for a variety of affective disorders, including type A behavior in men subsequent to myocardial infarct i ~ and n ~bipolar ~ d e p r e s s i ~ n ,each ~ . ~ of ~ which is associated with blood group 0.The ABO locus shows putative linkage with platelet monoamine oxidase activity,& reduced levels of which have been noted in group 0 healthy men?7 Additional evidence implies that there is a linkage between the ABO gene and the gene that regulates the activity of the enzyme argininosuccinate synthetase, which recycles arginine from citrulline in the production of nitric oxide.&A letter to the editor in the journal Lancet reported differences between ABO groups in their responsiveness to inhaled nitric oxide (NO) therapy, types with a B antigen (B and AB) having less success with this thera~y.4~ Elevated factor VIII (FVIII) levels contribute to venous thrombotic risk. FVIII levels are determined to a large extent by levels of von Willebrand factor (VWF), its carrier protein that protects FWII against proteolysis.m ABO polymorphism is one of the best-characterized genetic modifiers of plasma FVIII; it accounts for approximately 30% of the total genetic effe~t.~’ Subjects with blood group non-0 have higher VWF and FVIII levels than individuals with blood group 0.52

Additional Physiologic Correlations In addition to the previously described variations in IAP and brush border hydrolase activity, several additional circumstances where ABO polymorphism exerts a significant influence on physiology have been reported.

Gastric Acidity Because the prevalence of both pernicious anemia and gastric cancer is higher in individuals of blood group A and that of duodenal ulcer higher in those of group 0, a hypothesis relating blood group effects on acid secretion was i n e ~ i t a b l e Early . ~ ~ work confirmed that acid output tended to be greater in group 0 than in group A subje~ts.~,~~

Gastrin and Pepsinogen In one study, serum pepsinogen A (pepsinogen I) levels were studied in relation to ABO blood group, age, and sex in 700 healthy blood donors. Serum pepsinogen A levels were higher in males than in females and rose with increasing age. Blood group 0 individuals showed higher serum pepsinogen A levels than blood group A individuals.” There is also evidence that the type A antigen in gastric juice binds to pepsin and possibly inactivates it.57A recent study using serum pepsinogen levels as a marker for gastric atrophy showed a high association with blood groups A and B.58 However, possibly owing to the polygenic nature of pepsinogen activity, one study failed to find any sigruficant difference in pepsinogen levels between ABO gr0ups.5~ Another study looking at ABO polymorphism and serum gastrin concentration after stimulation by a glycine drink could find no correlation with ABO blood group.@’ However the study had a simple preprandial and postprandial methodology. In a separate study, the concentrations of gastrin were measured in the blood of 121 fasting healthy Greek volunteers of both sexes and of different ABO blood types, aged between 20 and 70 years. The testing took place after a test meal while the subjects were fasting, and again at 10 minutes and 40 minutes. The researchers found that gastrin levels took 40 minutes to increase after the meal in the blood types A and B subjects but that a sipficant increase had appeared already 10 minutes after the meal in the blood type 0 subjects.61

Cholesterol Although several studies on highly select populations have yielded conflicting results,62,63the general consensus is that blood group A individuals have a significantly higher basal cholesterol level than those in other blood groups. The relationship between ABO blood phenotype and total serum cholesterol level was examined in a Japanese population to determine whether elevated cholesterol values are associated with blood type A. Their results showed that cholesterol levels were very significantly elevated in the blood type A group compared with the non-A group (p < 0.00001).64 In a nationwide sample of more than 6000 black and white adolescents aged 12 to 17 years, ABO blood group and coronary risk factor levels were measured. Blood group A was associated with significantly higher serum

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms total cholesterol levels in white females independent of all other risk factors, in white males independent of age and weight, and in southern black females independent of age and weight.65 A separate study (the Bogalusa Heart Study) looked at 656 white and 371 black adolescents and found the same results with regard to cholesterol (A higher than others) and also showed higher levels of LDLcholesterol in type A adolescents than in the other blood types.% Whether the association between group A and elevated cholesterol values is through linkage or environmental factors, such as diet, remains to be determined. The aforementioned ABO variations in IAP levels have been posited as a potential causative factor.

Stress In addition to the previously mentioned associations between ABO group and affective disorders, several studies have identified difference between ABO group and possible chemical responses to stress. Interestingly, individuals of blood group A appear to have a lower incidence of ”type A per~onality.”~~ A study that evaluated the influence of blood type (A versus 0) coupled with a mirror drawing stressor on very-low-densitylipoprotein (VLDL) toxicity-preventing activity (TxPA) and plasma cortisol levels showed significant ABO variation. Exposure to the stressor significantly decreased TxPA and increased cortisol for the total group of 25 older men. However, the stress response patterns of the 15 blood type A men were different from those of the 10 type 0 subjects. The blood type A group had higher initial levels of TxPA and cortisol as well as quicker stress recovery rates than the type 0 g r o ~ p . ~ Using the act of venipuncture as an inherently stressful event, researchers then proceeded to measure the cortisol and catecholamine response to venisection by humans with different blood groups. Blood group A individuals responded to the stressful situation with higher levels of cortisol and, possibly, of adrenah1e.6~

Rheology Rheology is the science of deformation and flow. One common factor of solids, liquids, and all materials whose behavior is intermediate between solids and liquid is that if a stress or load is applied on any of them, they will deform or strain. For purposes of this discussion, rheology is used to describe the dynamics between blood clotting (moving toward a solid state) and blood thinning (moving toward a liquid state). It might be tempting to substitute the word viscosity for rheology when talking about blood types and clotting. Viscosity, however, does not cover the ”dynamics” of how, when, and why blood can change texture; it only distinguishes one texture state from another.

There is evidence that the rheology of blood may play a role in a variety of chronic anxiety states. When compared to normal subjects, chronic depressive and schizoid patients had very significant differences in their blood rheology and in the ability of their RBCs to aggregate. When patients having schizoid anxiety were compared to those having depressive anxiety, their ratio of albumin to globulin was increased. When patients were divided according to their ABO blood groups, significant differences were found in their albumin/fibrinogen ratio and their blood viscosity. This was particularly true for women who had blood type A and who suffered from depressive anxiety: their blood tended to be substantially ”thicker” and to have higher amounts of serum proteins in it than women with similar depression who had blood type 0.70 Associations between the ABO phenotype and variations in blood rheology have been also reported in high blood pressure?* stress,” diabetes,” heart attack, cancer and thyroid kidney and malignant melanoma.76

Soluble Endothelial Cell Markers Selectins are cell-cell adhesion molecules that are involved in leukocyte+ndothelial cell adhesive interaction, which is required for extravasation at target tissue sites. Three types of selectins have been discovered so far: L-selectins are generally expressed on almost all leukocytes; E-selectins are inducible on vascular endothelium upon stimulation with cytokines; and P-selectins were originally found on activated platelets. Less known is the role of thrombomodulin as a c-type lectin with a domain that interferes with neutrophil adhesion to endothelial cells. Elevated levels of E-selectin (p < 0.001) and thrombomodulin (p < 0.001) are linked with blood type A individuals.n

MAJOR DISEASES AND ABO Cardiovascular Disease Stroke A European study comparing 50 patients with stroke and the standard expected frequency of ABO blood types in the surrounding population showed that the frequency of the blood group A in the patients with stroke was 120% greater than would normally be expected. The percentage of blood type B was even higher (159% of expected rate of occurrence).Patients with blood type 0 were only 85% as likely to experience stroke as those with blood type 0 in the surrounding p ~ p u l a t i o n . ~ ~ A 1979 study of 220 patients with stroke looked at the viscosity of their blood a few hours after the stroke event. About 80% of the patients had blood cells that easily aggregated. What was especially interesting was the discovery by the researchers that the clotting of blood in patients with A and B blood types was due to

Therapeutic Modalities

fibrinogen, whereas in blood types 0 and AB it was caused by other clotting factors.79 Individuals with blood types A and AB have a generalized tendency toward problems associated with blood clotting, whereas problems in those with blood types B and 0 appear to be linked to excessive bleeding and poor clotting. This observation was verified in several studies, the largest being performed in 1460 patients with “stroke” and reported in the journal Lancet. In 329 cases, the cause of death was certified as cerebral thrombosis (brain clot). In the thrombosis cases there was an excess of patients of blood types A and AB and a deficiency of those with blood types 0 and B. In the 482 ”strokes” that were due to cranial bleeding, the reverse was true: There was a significantly higher proportion of patients with blood types 0 and B than of those with blood types A and AB.so

Peripheral Artery Disease and Venous Thromboembolism It is estimated that peripheral artery disease (PAD) occurs in approximately 12%of the adult population, or approximately 22 million Americans. The prevalence of PAD rises with advancing age such that almost 20% of people older than 70 years have the disease. E-selectin and thrombomodulin levels are always elevated in intermittent claudication, a disorder almost always found with PAD and carrying a distinct association with blood type A.81 The ABO blood groups were determined in 125 patients suffering from venous thrombosis in a Brazilian population. A higher than expected proportion of blood group A and a lower than expected proportion of blood group 0 were observed among the patients.s2This is consistent with the previously discussed influence of ABO on a third soluble endothelial product, VWF, and its role in thromboembolism.

Heart Disease There is a clear-cut association with having A and AB phenotypes and an increased risk for heart disease. This association has been reported continuously in the scientific literature over the last 50 years. Individuals who have blood type A have higher rates of heart attack in all age groups, both genders, and all ethnic and national groups. In 1962, the Framingham Heart Study typed the blood of the surviving 4125 members of the original study group of 5209 people first examined in 1948 to 1951. The most striking observance was the lower rates of nonfatal heart disease in men aged 39 to 72 years with blood type 0 than in those with blood type A.mA 1994 Polish study on patients undergoing coronary bypass surgery who had highly advanced arteriosclerosis of the coronary arteries found a sigruficantly higher number of cases with group AB and a lower number of those with group O.@A 1981

German study of 13,175 patients showed a prevalence of blood type A in all types of heart disease examined.85 In a study of 191 coronary artery bypass candidates, investigators paradoxically found an excess of type 0 over type A subjects. After examining the data more closely, they concluded that the tendency of type A subjects for more ready development of blood clots (”thrombotic proneness”) led to a poorer prognosis. In essence, the blood type A subjects were missing from the study because they had already died in greater numbers, leaving a disproportionate number of type 0 subjects among the long-term survivors.86In a study of male survivors of heart disease, researchers found that there were fewer patients who were type A and younger than 55 years than would have been otherwise expe~ted.~’ A 1975 Italian study of 746 patients with high blood pressure, 3258 with congenital heart disease, and 4503 with a history of heart attack found a significant lack of patients with type 0 blood, and a significant excess of blood type A patients in the group with myocardial infarction. The study also showed an excess of blood type A patients with high blood pressure, and a lack of patients who were blood type B.8s A 1983 study of 255 women originally investigating the effects of smoking on the rates of heart attack in women also found several other factors significantly associated with heart attacks in this group, including hypertension, angina pectoris, family history, diabetes mellitus, and blood type A.89 Platt et alWexamined blood type and heart attacks in two different age groups. The patients were divided into two groups: 65 years or older and younger than 65 years. The predominance of blood type A in patients with cardiac infarction was “highly significant” in both age groups (p < 0.005). This study was unique in that it excluded other risk factors, such as smoking, high blood pressure, diabetes, and high cholesterol levels. When the researchers looked specifically at the older group, the predominance of blood group A in those with cardiac infarction was even higher ( p < 0.001). The researchers concluded, ”Our investigation strongly suggests the existence of a genetic factor associated with blood group A and independent of the other risk factors, which is also responsible for a greater incidence of cardiac infarction.”%An 8-year study of 7662 men found that blood type A is linked to the incidence of ischemic heart disease as well as higher total serum cholesterol concentrations?l

Cancer Cancer and Altered Glycosylation Some cancers contain an A-like substance men when they occur in persons who are not A or AB. These observations suggest that in the tissues, both normal and neoplastic, of all persons, there are blood group A-like antigens present at a biochemical level, which are usually inaccessible to the immune system. -AE Mourant (Blood Groups and Disease, 1977)

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

Variation in blood group antigen (BGA) expression in normal and neoplastic tissues of BGAs

Expression of BGAs in malignancy

Colon’

Present

Absent

94

Bladder+

Present

Prostate

Absent Present

Absent

95 96

Liver’

Absent

Present

97

Squamous

Present

Absent

98

Endometrium5

Absent

Present

99 1 00

Normal expression Tissue. oraan

References

Stomach

Present

Absent

Thyroid”

Absent

Present

101

Esophagus

Present

Absent

102

‘Inversely correlated. tBGAs better than all other tumor markers. *BGAs effective at predicting hepatitis transformation to malignancy. §Vast majority of BGAs secreted are H antigen.

Tumor development is usually associated with changes in cell surface carbohydrates. The changes are often divided into those related to terminal carbohydrate structures, which include incomplete synthesis and modification of normally existing carbohydrates, and those in the carbohydrate core structure. Cell glycosylation depends on the expression and function of various glycosyltransferases and glycosidases. Numerous data demonstrate that malignant transformation is associated with various and complex alterations in the glycosylation process. These changes provide a selective advantage for tumor cells during their progression to more invasive and metastatic forms. The blood group-related carbohydrate structures Le(x), sialyl-Le(x), ABH, and Le(y) are examples of terminal carbohydrate structures that are related to tumor prognosis. These structures are of increasing interest because they may function as adhesion molecules or motility Deletion, reduction, or inappropriate expression of blood group A or B antigen in tumors of blood type A or B individuals is clearly correlated with the level of malignancy and metastatic p0tential.9~The most significant variations are summarized in Table 43-3. A and B blood group antigens are present on carcinoma cells at the early stages of carcinogenesis and tend to disappear at later stages. The blood group A antigen may render malignant cells resistant to apoptosis; in animal studies, the faster tumor growth of the A antigenpositive cells in immunocompetent animals was due to their higher ability to escape immune control, which was associated with their higher degree of resistance to apoptosis.lo3 Lewis blood groups can modulate the expression of several tumor-associated antigens, including DU-PAN9

and CA19-9, and some researchers have suggested that taking into account Lewis secretor status in order to establish reference ranges for the tumor antigen measurements might actually be a way to improve their clinical utility. This relationship is shown in Table 43-4.

Thomsen-Friedenreich Antigen Many malignant cells (such as those found in breast and stomach cancers) develop a tumor marker called the Friedenreich-Friedenreich(T) antigen (also called TFA). This antigen is encrypted in normal healthy cells, much like a rock is covered over by water at high tide. T antigen becomes “unsuppressed” only as a cell moves toward malignancy, much like the covered rock example is uncovered as the tide moves out. It has been estimated that T antigen (or its precursor, Tn antigen) is expressed and uncovered in about 90% of all cancers, earning it the appellation “pancarcinoma associated antigen.”lD4As a general rule, an orderly expression of T antigens on a cancer cell usually indicates

Correlation of CA19-9 and DU-PAN-9 expression in colorectal cancer with Lewis type Lewis phenotype

CA19-9 expression’

DU-PAN-9 expression

Le (a+b-)

Highest levels

Lower levels

Le (a-b-t)

High levels

Lower levels

Le (a-b-)

Zero to very low levels

Highest levels

‘Individuals having homozygous inactive Se alleles (sese) and homozygous active Le alleles (LeLe), exhibited the highest mean CA19-9 value. All of the Lewis-negative individuals (/e/e genotype) had complete absence of CA19-9, irrespective of the Se genotype.1°

a cancer with a relatively favorable outlook. However, a prevalence of Tn antigens (a less well-developed T antigen) on a cancer cell usually denotes a highly aggressive, metastatic cancer, irrespective of the organ involved and the form of cancer. It is so rare to find the Tn antigen in healthy tissue that most people produce antibodies (TFA agglutinins) to itprobably in response to cross-induction by the gut flora. ABO blood group appears to influence the amount and activity of these antibodies against T and Tn antigens. Although derived from the M blood type antigen, Tn antigen shows structural homology to the A antigen. Antibodies against Tn antigen cross-react with A glycolipids. Because Tn antigen and A glycolipids share terminal GalNAc, Tn antigen was concluded to be an A-like antigen in a broad sense. "A-like" is actually considered an antigenic entity, a substance not A and not Tn but capable of sharing antigenic sensibility with them.Io5 That blood group A patients with gastric cancer have the greatest and most uniform suppression of the level of TFA agglutinins, irmpective of age, cancer stage, or tumor morphology, and lower levels of anti-B isohemagglutinins'06 strongly supports the notion. The association of group A with gastric carcinoma is quite old, having first been demonstrated by Aird et allw in 1953. One hypothetical mechanism behind the association between blood group A and gastric carcinoma is that the carcinoma cells produce an antigen immunologically related to blood group A, which may have a protective effect, particularly in blood group 0 individuals, by prevention of the growth and spread of the tumor.'08 It appears that the progression of stomach cells to stomach cancer involves a necessary mutation at the ABO gene, the result of which is the production of A antigen, even if this is not the person's blood type. This "A-like" antigen may not be the true A antigen but rather, what one researcher has called "tumorassociated, A cross-reacting antigens occurring in a wide variety of human adenocarcinomasof hosts belonging to all ABO blood groups."'Og Breast cancer researchers have given this aberrant glycosylation moiety the moniker "ligand-like complex" (LLC), which by virtue of altered antigenicity both allows for metastatic egress from the regional lymph nodes and detachment from the extracellular matrix and thus is associated with cancers with poor prognosis.110I believe that LLC may well be the "A-like," pan-carcinoma crossreacting antigen, because of observations that the GalNac binding lectin from the Roman snail, Helix pomatia agglutinin (HPA), appears to identify this oligosaccharide"' and because of separate reports that "Springer's vaccine" (human group 0 RBC membrane-derived T/Tn antigen containing traces of phosphoglycolipid A hyperantigen) has had significant effect as an immune modulator in breast carcinoma of even advanced stage.'I2

Epidermal Growth Factor The epidermal growth factor receptor (EGF-R) bears an antigenic determinant that is closely related to the human blood group A carbohydrate structure. A higher number of high-affinity EGF binding sites was observed in donors with blood group A1 erythrocytes than in donors with blood groups 0 and B.'I3 That the blood group A antigen can also bind to EGFRs is now well documented. So it is not unlikely that free A antigen in individuals with blood groups A and AB (especially if they are secretors) can find their way onto these excess EGF-Rs and act to simulate cell growth. As with VWF and factor VIII, excessive activation of the EGF-R results in cancer cells that become more mobile and better able to develop new and additional blood supplies (angiogenesis).'I4 One reason that low stomach acid is linked to type A blood may have to do with the role of EGF discussed in the previous section on saliva. As described, the EGF-R has a high affinity for the type A antigen, and although the major action of EGF is to stimulate repair of the digestive lining, it has also been shown to decrease acid production in the stomach.

Infection The previous section appears to imply a selection disadvantage for group A individuals, and it has been argued that under present-day civilized living conditions, blood type 0 carriers have a preservation advantage over blood group A carries.l15 This may be the result of the deletion of the selection factor "infectious disease," which may nevertheless regain importance if environmental changes occur.116 To a great extent, infectious diseases, especially the worldwide epidemic diseases, have selective effects. This is demonstrated inter alia in the different "selection values" in the ABO blood group system. During the eons before antimicrobial intervention, selection variability via ABO polymorphism was the preeminent natural survival mechanism. Historically, some of the most catastrophic epidemic and endemic diseases are ABO selective and in many instances demonstrate ABO variation in morbidity, mortality, or microcharacteristics such as substrain preferentiality and level of inflammatory response. They include cholera (0),smallpox (A), malaria (A), and influenza (variable subsets depending on strain). The influence of ABO polymorphism on infectious disease appears to stem from a multitude of unique factors. These are encapsulated in Table 43-5. A morbidity and mortality variation among the ABO and secretor groups is presented in Table 43-6. A special examination of polymorphic differences in uropathic infectious disease is presented in Table 43-7.

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

Mechanisms of ABO influence on infectious disease Class

Mechanism

Description

Example

Selectivity

Adhesion kinetics

Adhesin or lectin specificities of the infectious agent based on particular ABH glycosylation Inadequate production or activity of isoagglutinin Infectious agent is antigenically similar to host's ABO group

Candida albicans (group 0 )

Humoral dynamics Molecular mimicry Response variability

Neisseria gonorrhoeae (group B) Giardia lamblia (group A)

Host response

Variation in severity of disease through unique biologic response (examples: inappropriate inflammatory response, rosette formation)

Cholera (group 0) Dengue fever (group B) Malaria (group A)

Substrain susceptibility

Different ABO groups often show variations in susceptibilityto individual bacterial, fungal, or parasitic species or viral strains

Influenza (all groups) Malaria (group 0 versus group A)

For a more detailed examination of particular infectious scenarios, the reader is referred to my comprehensive survey."'

BLOOD GROUPS AND DIETARY LECTINS ABO polymorphism is one of the prime determinants of the glycosylation variability of gut mucin. As such, it affords insight into the actions of a class of carbohydrate-binding dietary proteins called lectins, which are increasingly the subject of interest for nutritional researchers.

Historical Perspective Stillmark at the University of Dorpat in Estonia first identified lectins in 1888. While investigating the toxic effects on blood of castor bean extract (Ricinus cornrnunis), he noticed that the RBCs were being agglutinated. He isolated the material responsible for the agglutination and called it ricin. In 1945, William Boyd of the Boston University School of Medicine discovered that lectins can be blood group specific, being able to agglutinate the RBCs of one type but not those of another. He discovered that h a bean lectin would agglutinate RBCs of human blood type A

Influence of ABO polymorphismon susceptibilityto various infectious agents Strain

Susceptible phenotype(s1

Amoebic dysentery

0,A

Blood type B and AB persons have a degree of resistance against development of severe or acute dysentery, especially the amoebic forms.

Candida carriage

0, nonsecretor

Candida carriage was associated with blood group 0 (p < 0.001) and, independently, with nonsecretion of blood group antigens (p < 0.01). Candida albicans extracellular polymeric material (EP)contains a mannoprotein adhesin with a lectin-like affinity for H (type 2) blood group antigen. There were a significantly higher number of nonsecretors (48.9%) among 174 patients with either oral or vaginal Candida infections than in the local population (26.6%). Nonsecretorsaliva actually seemed to enhance Candida attachment.

Cholera

0, AB

Blood type 0 individuals have a greater risk of infection with cholera and have the most severe and life-threateningforms of this illness, as documented in several studies. Patients with type 0 had more diarrhea-likestools per day than persons of other blood groups, were more likely to report vomiting and muscle cramps, and were almost eight times more likely to require hospital treatment. Type AB persons, on the other hand, appear to have the highest degree of protection from cholera infections.

Coccidioidomycosis

B

Blood type B individuals are more prone to disseminated disease after exposure.

Dengue fever

B

According to researchers, blood type B is strongly associated with the severe form of dengue fever known as dengue hemorrhagic fever.

Comments

Continued

Influence of ABO polymorphismon susceptibility to various infectious agent-ont'd Strain

Susceptible phenotype(s)

Dermatophytosis

A

The fungus Trichophyton rubrum, isolated from 54.5% of the patients tested, was more common in individuals in blood group A.

Escherichia coli

Variable subsets

Giadia

A

It appears that many forms of E. coli capable of causing diarrhea are immunologically "B-like."This results in a substantially higher number of cases of diarrhea among individuals of Mood types B and AB. However, when it comes to the overall severity of infection with E. coli, individuals with type B, AB and 0 also are most likely to have a severe form of diarrhea. Persons with blood group A are more susceptible to giardiasis, especially the asymptomatic form, whereas those with blood group B are less susceptible.

Helicobacter pylori

0, nonsecretor

Comments

H. pylorivariants produce a variety of blood group antigens, including A, Lewis (a), and a variety of type 1 H-like antigens (0). Blood group 0 would be a moderate risk factor for infection by H. pylori, with more severe cases in men. Persons with blood group 0 have a more pronounced inflammatory reaction to H. py/ori. Group 0 cells release significantly more interleukin-6and tumor necrosis factor in response to H. pylori infection. The Le (a*) nonsecretor phenotype and blood group 0 are relevant genetic markers of peptic ulcer. The Lewis (a*) nonsecretor phenotype and blood group A are also positively associated with esophageal adenocarcinoma. with concurrent H. pylori infection.

Hookworm

0

A 1972 Egyptian study correlated type 0 with higher incidence of hookworm and strongyloidiasis.

Influenza

Variable subsets

Blood group A individuals generate a quick and substantial antibody response against influenza type A(H1 N1) and especially A(H3N2). The antibody response against influenza B is not quite as dramatic. Blood group AB types have a relatively poor ability to generate high antibody levels against any of the influenza viruses. Blood group B persons show a reasonable, but not great ability to generate an antibody response against influenza A (H1N1) and the slowest (3-5 months) and weakest ability to generate antibodies against influenza A (H3N2 'Hong Kong") of any Mood type.Against influenza B virus, Mood group B has a significant advantage, respondingdifferently from blood groups A and 0; the blood type B immune response happens much earlier and persists longer. Blood group 0 shows a moderate ability to generate antibody response against influenza A(H1N1) and A(H3N2) viruses. Antibody response against influenza B is not as dramatic as that of blood type B.

Malaria

A, AB

Evidence suggests that blood types A and 0 individuals might have a higher predispositionto infection with the Plasmodium viva species and that blood type B individuals tend toward higher infection rates with Plasmodium falciparum. Malaria-infectedred blood cells sometimes bind to uninfected red blood cells (RBCs) to form dumps called rosettes. The rosettes can obstruct flow in small blood vessels, leading to tissue damage and severe malarial disease. The tendency for malaria to be worse among individuals with blood types A and AB is due primarily to a greater degree of rosette formation by RBCs with these antigens. von Willebrand factor, always elevated in type A, also enhances rosette formation.

Neisseria gononhoeae

B

The relation of infection with N. gonorhoeae to the blood groups A, B, AB, and 0 was examined in 584 women attending a prenatal clinic. The occurrence of gonorrhea was significantly higher in black patients with blood group B than in those with blood groups A, AB, or 0. Depending on the ABO blood group, gonorrhea may affect the titers of isohemagglutininscompared with those of uninfected controls. The isohemagglutinin titers in group 0 patients were significantly increased (p < 0.001) against erythrocytes A, B, and AB. In group A patients, only the titer against AB erythrocytes was significantly increased. In group B patients, the titer against AB erythrocytes was significantly lower (p < 0.001) than that in sera of healthy persons.

Norwalk virus (norovirus)

0

It appears that group 0 RBCs are most easily bound by noroviruses, whereas group B RBCs are apparently little bound at all. Individuals with an 0 phenotype are more likely to be infected with Norwalk virus. The preferred binding site is apparently the H type 2 antigen, which functions as the viral receptor on human type 0 RBCs.The Lewis B antigen (found in secretors) is also a binding site.

Nontransfusion Significance of ABO and ABO-Associated Polyrnorphisms Influence of ABO polymorphism on susceptibility to various infectious agents-ont’d Strain

Susceptible phenotype(s)

Schistosomiasis

A

Group A individuals tend to be more susceptible to infection, tend to have more intense symptoms after infection, and are much more likely to have damage to organs (such as the liver) after infection.

Shigellosis

B, AB

There is a strong association between blood type B (and AB to a slightly lesser degree) and shigellosis.

Smallpox

A

Group A persons have higher mortality from smallpox infection; also have more reactions to smallpox vaccination. The leukocytesof peripheral blood in group A individuals show a poorer binding capacity with respect to the smallpox vaccine virus. Blood group A also shows a high rate of chromosomal aberration after vaccination, resulting to some extent from increased proliferative ability of the cells.

Staphylococcus aureus

A

Persons with blood type A are much more likely to be chronic carriers of S.aureus, partly because they have a lower ability to mount an aggressive antibody (or immune) response against this organism.

Streptococcus (group B)

B

A blood type connection with neonatal group B streptococci infection exists for blood type B. Mothers with blood group B have double the risk for infection among their infants.

Strongyloidiasis

0

A 1972 Egyptian study correlated type 0 with higher incidence of hookworm and strongyloidiasis.

Tuberculosis

0

Group 0 blood has a much higher rate of infection with tuberculosis (particularly true in individuals of European descent). Tuberculosis runs a much more aggressive and detrimental course in patients with blood type 0, whereas those with type A are afforded the highest degree of protection. Typically, during the first 2 years of infection with bacillary tuberculosis, individuals with blood types 0 and AB have a significantly higher rate of infection.

Comments

but not those of 0 or B. The seeds of Lotus tetragonolobus can agglutinate group 0 specifically, and Bundeirueu sirnplicifoliu is specific to group 8.The specificity of lectins is so sharply defined that they can differentiate among blood subgroups. Dolichos bifZorens lectin reacts more vigorously with blood group Al than with A2. Influence of ABO polymorphism on susceptibility to various uropathic infectious agents Blood type

Uropathogenic strains

A

Staphylococcussaprophyticus

B

Klebsiella pneumoniae Proteus spp. Pseudomonas sp. K. pneumoniae Proteus spp. Pseudomonas spp. S.saprophyticus Uropathogenic Escherichia coli

AB

Nonsecretor

As a general rule: Blood type B is most plagued by chronic or recurrent urinary tract infections

(UTls). Type AB is next on the susceptibility list, followed by type A. Type 0 is the most protected. Nonsecretorsare much more prone to repeated and severe UTls.

The word lectin was proposed by William Boyd in 1954 to describe a class of blood type-specific agglutinins that had been found in certain plants. The word is allegorical to a degree, because it derives from a Latin word meaning ”to choose.”

Actions The surface epithelium of the gut is extensively glycosylated,l18 mainly because most membrane proteins, including hormone and growth factor receptors, transport proteins, and brush-border enzymes, are glycosylated before being embedded in the brush-border membrane. Membrane lipids and gangliosides are also glycosylated, and all secreted mucins are carbohydraterich glycoproteins. Thus the scope of potential lectincarbohydrate interactions is quite wide. However, not all lectins react with the epithelium, and even those that do react vary in their ability to recognize and bind to specific types of carbohydrate receptors. Because lectin reactions are quite specific, it is imperative that the correct carbohydrate structures be present on the surface of the gut mucosa. Factors that are known to influence lectin activity are summarized in Box 43-1. Lectins can have a variety of biologic effects, including: induction of mitosis in lymphocytes, cellular agglutination via cross-linking of membrane sugars, preferential agglutination of malignant cells, precipitation

Therapeutic Modalities

Animal species Blood group specificity Age Particular area of the small intestine Position along the villi State of cell maturation Diet Bacterial status Sickness or pathology Modified from PusztaiA, BardouS.Trends GlycoxiGlycotechnol1996;8:149-165.

of polysaccharides and glycoproteins, and activation of complement. The variety of reported effects resulting from the ingestion of dietary lectins is summarized in Table 43-8. Most lectins in the U.S. diet are resistant to breakdown during gut passage and are bound and endocytosed

by epithelial cells. These lectins are powerful exogenous growth factors for the small intestine, and they can induce dramatic shifts in its bacterial flora and interfere with its hormone secretion. In addition, lectins that are transported across the gut wall into the systemic circulation can modulate the body’s hormone balance, metabolism, and health. In contrast to dietary proteins, lectins resist degradation in the small intestine and are also resistant to breakdown by most gut bacteria. Thus, most lectins survive, at least in part, the passage through the digestive tract in an immunologically and functionally intact form.12’ Although lectin binding is most commonly studied in the small intestine, similar binding can OCCUT throughout the entire digestive tract, from the stomach to the distal colon. However, surface glycosylation varies in the different functional parts of the gut, so lectin binding is not uniform in the digestive tract. Binding of lectins and their endocytosis by enterocytes occur throughout the gut, although endocytosis in the small intestine

Reported effects of dietary lectins Action

Description

Induction of interleukins (ILs)

Dietary lectins are known to induce interleukins IL-4 and IL-13. Because lectins can enter the circulation after oral uptake, they might play a role in inducing the so-called early IL-4 required to switch the immune response toward a helper T cell type 2 response and type I allergy.llg

Induction of autoimmunity

The interaction of dietary lectins with enterocytes and lymphocytes may facilitate the translocation of both dietary and gut-derived pathogenic antigens to peripheral tissues, which in turn causes persistent peripheral antigenic stimulation. In genetically susceptible individuals, this antigenic stimulation may ultimately result in the expression of autoimmune disease.lm

Interference with protein digestion

Aminopeptidase activity (the enzyme that breaks down polypeptides into amino acids) is inhibited by several dietary lectins.121

Interaction with the brush-border membrane

Lectins, which bind avidly to the brush-border membrane, are potent hyperplastic growth factors for the gut.lZ Binding of lectins to the epithelium is obligatory for growth stimulation, and their growth factor activity is determined mainly by the strength and intensity of their binding.lZ3

Antinutrient effects

Rats fed a diet composed principally of raw navy bean flour were smaller and had 50% less ability to absorb glucose and utilize dietary protein than a control group that was fed navy beans in which the lectin had been inactivated.lZ4

Enhancement of gut permeability

In one study, rats fed on diets containing kidney beans showed greater intestinal permeabilityto serum proteins that had been injected into the blood stream. After challenge with kidney bean proteins, the protein injected into the blood stream was detected in both the lumen (open space) and the walls of the small intestine. The researchers suggested that dietary lectins may, at least in part, be responsible for loss of serum proteins and may contribute to other food intolerance secondary to the loss of gut integrity.lZ5

Activation of gut hormones

Cholecystokininis induced by several dietary lectins.lZ6

Hormone and growth factor mimicry

Because surface membrane receptors of cells are glycosylated, lectins are good mimics of the effects of endogenous growth factors, hormones, and cytokines in all types of cells.127Lectins can mimic the effect of the natural ligands and induce similar physiologic reactions. It is also possible that bound lectin induces conformationalchanges in the receptor and/or physically blocks the active site of the receptor, thereby attenuating or completely abolishing the physiologic effect of the natural ligand.

Mucotractive effects

Many lectins stimulate the production of mucus. This is possibly a protective function or an allergic response and was for a time thought to be an action of lectins that promised some therapeutic benefit that could be applied in patients with cystic fibrosis.lZ8

Mitogenic effects

Several foodstuffs and herbal medicines are known to contain lectins that are capable of inducing T- or 6-cell blastogenesis.

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

I

Primary and secondary much glycosides known to be associated with ABO polymorphism

CLINICAL APPLICATIONS OF ABO POLYMORPHISM The BloodType Diet

The advantage of a low-lectin diet can be exemplified by the best known application of the ABO polymorA phisms, The Blood Type Diet, popularized by publication Glycophorin AI3* Galactosyl-A glyc01ipid.s~~~ in 1997 of my New York Times bestseller Eat Right 4 Your "Band 3"lM Type. Eat Right 4 Your Type was the first "diet b o o k that B Galactose KNeuraminic Glycophorin B1= both looked at foods as medicine tailored to the individKAcetyl g1ucosamine136138 ual rather than simply as part of a generic single-purpose 0 Fucose mechanism (i.e., weight loss, cholesterol control). Like the very antigens that it uses for its determination, The Blood Type Diet is "nonreducing," meaning that the food value system is essentially stateless: A food that becomes appreciable only in the presence of large nummight cause difficulties in one ABO phenotype may well bers of commensal bacteria. As expected, endocytosis of possess therapeutic value in another, a concept that lectins is more extensive in the colon, where bacterial harkens back to the observation of the Roman philosocounts are high.Iz8 pher Lucretius, "What is food to one man may be fierce How prevalent are lectins in the diet? A superficial poison to others." survey done in the early 1980s implied that they are The Blood Type Diet inventories a variety of paramequite extensively distributed in our food supply.1z9 ters, including the physiologic and pathologic distincIn this study, the edible parts of 29 of 88 foods tested, tions between the blood groups as reported in the including common salad ingredients, fresh fruits, roasted literature, lectin, and agglutinin characterizations (both nuts, and processed cereals, were found to possess sigrufmine and others'), and variations in isoagglutinin titer icant lectin-like activity as assessed with blood agglutiand reactivity with regard to food challenge (both nation and bacterial agglutination assays. in vitro and in vivo). It also provides specific recommenLectin content is a prime area of manipulation for the dations regarding foods that should be considered beneproduction of transgenic foods,130so they will probably ficial and should be emphasized and others that may be continue to occupy the attention of nutritionally oriented problematic and might better be avoided. physicians well into the future. One advantage conferred by the theory is the notion Role of ABO Blood Groups that certain individuals may be better suited to Paleolithic or vegetarian diets. Despite certain locutions Because ABO blood group is a prime determinant of glyand circumlocutionsoffered by proponents of one system cosylation, it is not surprising that a substantial number or the other, most clinicians have ample experience with of food lectins show ABO specificity. However, equally the simple fact that certain patients make better vegetariimportant, but not typically recognized, is my observaans or carnivores than others. Conversely, the ability to tion that ABO status appears to influence variability in identify particular individuals at risk of an adverse reacsecondary glycosides, which are not integral to the ABO tion to high-protein/low-carbohydratediets can lead to type of the hosts. These secondary glycosides appear actions aimed at the prevention of such consequences. to provide additional conditioning of the much manuFor example, high-protein diets are known to upregufactured by the particular ABO type, perhaps offering late soluble endothelial adhesion factors,140whereas a some explanation for the apparent effects of panhemagsoy-based, lipid-lowering diet is known to decrease glutinins and other non-ABO specific lectins on one endothelial adhesion factors, including VWF, E-selectin, particular ABO type over another. These effects are listed in Table 43-9. and intercellular adhesion molecule (ICAM).141-143 Because individuals with blood group A have been The ability to use the ABO groups as a predictive reported to have increased levels of all three endothelial device in narrowing down potential food reactions in adhesion factors and, perhaps consequently, a higher sensitive subjects lies in its low cost to the patient and incidence of cardiovascular disease, a modified Asian/ the clinician's ability to discern interactions that are Mediterranean, plant-based diet would appear ideal for not easily testable via standard food allergy isolation this phenotype. methods. A useful resource for clinicians seeking more Conversely, in 1998, I examined serum cholesterol information on lectins is Lectser, the world's most complete lectin characterization database, available at my levels in small number of group 0 subjects after a minimum of one month of the blood type diet recommended ~ebsite.~~~ Blood arouD

Primarv qlvcoside Secondarv alvcosidels) NAcetyl galactosamine MannoseI3l

for that phenotype.'@Group 0 individuals following the "Type 0 Diet" (higher protein, lower carbohydrate) showed a consistent drop in serum cholesterol (n = 14; average 237.3 mg/dl before diet, 200.2 mg/dl withdiet); in subjects with elevated serum triglyceride values, the results were more pronounced (n = 6; average 387.1 mg/dl before diet, 168.8 mg/dl with diet). The Blood Type Diet has produced an extensive library of works, at a various levels of information density. Eat Right 4 Your Type has been translated into more than 60 languages, and well over 3 million individuals follow the system.145

Materia Medica ABO polymorphism and its clinical expression have led to new or rediscovered applications and contraindications for several traditional naturopathic treatment modalities. The most significant are summarized in Table 43-10.

CONCLUSIONS It is my sincere hope that this abbreviated survey proves sufficient to persuade the reader that ABO and ABOrelated polymorphisms, in both genotypic and phenotypic

Modalities known to exert effects at least partially preferentialto ABO group Agenffspecies

Common names

Actions

Notes

References

Fucus vesiculosus

Bladderwrack kelp

Anti-adhesive Candicidal

Best suited for 0, nonsecretors

146-148

Bapfisia tinctoralis

Wild indigo

Induces anti-Tn or cross-reacting antibodies

Best suited for A, AB

149, 150

Urfica dioica rhizome

Stinging nettle root

'Superantigen" lectin T-cell mitogen (CD& and CD8+) Candicidal

Not useful in B or AB

151,152

Helix pornafia agglutinin

Roman or escargot snail

Contains Tn-, LLC-, and "A-like"specific lectins

Best suited for A, AB

110,111

Agaricus bisporus

Domestic mushroom

Lectin stimulates insulin release by pancreatic islets Lectin binds Tn antigen; stimulates differentiation of undifferentiated colon cancer cells; inhibits proliferation of epithelial cell lines

Best suited for A

153,154

Marrubium spp.

Horehound

Contains Tn-specific lectins

Best suited for A, AB

155

Salvia spp.

Sage

Contains Tn-specific lectins Attenuates soluble endothelial adhesion factors

Best suited for A. AB

155,156

Vicia faba

Fava bean

VFA stimulated an undifferentiated colon cancer cell line to differentiate into glandlike structures. The adhesion molecule epCAM is involved in this process. Dietary or therapeutic VFA may slow progression of colon cancer

Best suited for A; can be used by 0,B

157

Griffonia (Bandeiraea) simplicifolia

African legume from which 5-HTP is extracted

Griffonia contains 5 isolectins, at least 3 of which are blood group agglutinating GSA &Q is a serologically Lewis b (Lebkactive binding lectin claimed to be blood group B specific as well The "&-rich lectin preferentially agglutinates blood group A, and the "B"-rich lectin preferentially agglutinates blood group B cells and is specific for alpha-galactose residues

Not useful in A, AB, B or secretors

158-160

Artocarpus integrifolia

Jackfruit seeds

Contains T- and Tn-specific lectin (jacalin)

Best suited for A, AB; can be used by 0, B

161

~~

epCAM, Epithelial cell adhesion molecule; GSA. Grihbnia simplicifolia agglutinin; LLC. ligand-like complex; VFA. Vicia faba agglutinin.

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms

expression, exert biologic sigruficance far beyond the surface of an erythrocyte, and that this expression is worth factoring into the everyday algorithms of a nutritional practice. Perhaps the advent and acceptance of the newly emerging science of "nutrigenomics" might provide the conceptual framework needed to allow

the nontransfusion significance of ABO and secretor polymorphism to parse into meaningful scientific dialogue. At that point, natural medicine could be considered to have the rational beginnings to delivering its long-awaited promise, "Treating the patient, not the disease."

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the fecal population density of certain enteric bacteria. J Clin Invest 1976;577482. 20. Hoskins LC, Boulding ET. Degradation of blood group antigens in human colon ecosystems. I. In vitro production of ABH blood group-degrading enzymes by enteric bacteria. J Clin Invest 1976;5763-73. 21. Al-Agidi SK, Shukri SM. Association between immunoglobulin levels and known genetic markers in an Iraqi population. Ann Hum Biol1982;9:565-569. 22. Shinebaum R. ABO blood group and secretor status in the spondyloarthropathies. FEMS Microbiol Immunol1989;1:389-395. 23. Grundbacher FJ. Immunoglobulins, secretor status, and the incidence of rheumatic fever and rheumatic heart disease. Hum Hered 1972;22:399-404. 24. Grundbacher FJ. Genetic aspects of selective immunoglobulin A deficiency.J Med Genet 1972;9:344-347. 25. Pal A, Hill M, Wordsworth P, Brown M. Secretor status and ankylosing spondylitis. J Rheumatol 1998;25:318-319. 26. Manthorpe R, Staub Nielsen L, et al. Lewis blood type frequency in patients with primary Sjogren's syndrome. A prospective study including analyses for AlA2B0, secretor, MNSs, P, Duffy, Kell, Lutheran and rhesus blood groups. Scand J Rheumatol 1985;14: 159-162. 27. Toft AD, Blackwell CC, Saadi AT, et al. Secretor status and infection in patients with Graves' disease. Autoimmunity 1990;7279-289. 28. Tosh FD, Douglas LJ. Characterization of a fucoside-binding adhesin of Candida albicuns. Infect Immun 1992;60:4734-4739. 29. Furukawa K, Ying R, Nakajima T, Matsuki T. Hemagglutinins in fungus extracts and their blood group specificity. Exp Clin Immunogenet 1995;12223-231. 30.Navas EL, Venegas MF, Duncan JL, et al. Blood group antigen expression on vaginal and buccal epithelial cells and mucus in secretor and nonsecretor women. J Urol1993;1491492-1498. 31. Godzisz J. [Synthesis of natural allohemagglutinins of the ABO system in healthy children aged 3 months to 3 years]. Rev Fr Transfus Immunohematol1979;22:399-412. 32. Grundbacher FJ. Genetics of anti-A and anti-B levels. Transfusion 1976;16:48-55. 33. Adewuyi JO, Gwanzura C, Mvere D. Characteristics of anti-A and anti-B in black Zimbabweans. Vox Sang 1994;67307-309. 34. Lauritsen JG, Grunnet N, Jensen OM. Matemo-fetal ABO incompatibility as a cause of spontaneous abortion. Clin Genet 1975;7308-316. 35. Solish GI. Distribution of ABO isohaemagglutinins among fertile and infertile women. J Reprod Fertil1969;18:459-474. 36. Cantuaria AA. Blood group incompatibility and cervical hostility in relation to sterility. Obstet Gynecol1978;51:193-197. 37. DAdamo PJ, Zampieron ER. Does ABO "bias" in natural immunity imply an innate difference in T-cell response? J Naturopath Med 1991;2:11-17. 38. Greenwalt TJ. A short history of transfusion medicine. Transfusion 1997;37550-563. 39. Yamamoto F. Blood group antigen gene mutation database. The Bumham Institute. Available online at www.bioc.aecorn.yu.edu/bgmut/ abo.htm (accessed 27 March 2004).

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63. Tarjan Z, Tonelli M, Duba J, Zorandi A. Correlation between ABO and Rh blood groups, serum cholesterol and ischemic heart disease in patients undergoing coronarography. Orv Hetil1995;136767-769. 64.Wong FL, Kodama K, Sasaki H, et al. Longitudinal study of the association between ABO phenotype and total serum cholesterol level in a Japanese cohort. Genet Epidemiol1992;9405-418. 65. Gillum RF. Blood groups, serum cholesterol, serum uric acid, blood pressure, and obesity in adolescents. J Natl Med Assoc 1991;83 682-688. 66. Fox MH, Webber LS,Thurmon m,Berenson GS. ABO blood p u p associations with cardiovascular risk factor variables. II. Blood pressure, obesity, and their anthropometric covariables. The Bogalusa Heart Study. Hum Biol1986;58549-584. 67. Mao X, Xu M, Mu S, et al. [Study on relationship between human ABO blood groups and type A behavior pattern]. Hua Xi Yi e Da Xue Xue Bao 1991;22:93-96. 68.Neumann JK, Arbogast BW, Chi DS,Arbogast LY. Effects of stress and blood type on cortisol and VLDL toxicity preventing activity. Psychosom Med 1992;54:612-619. 69. Locong AH, Roberge AG. Cortisol and catecholamines response to V enisection by humans with M e r e n t blood groups. Clin Biochem 1985;1867-69. 70. Dintenfass L, Zador I. Blood rheology in patients with depressive and schizoid anxiety. Biorheology 1976;13:33-36. 71. Dintenfass L, Bauer GE. Dynamic blood coagulation and viscosity and degradation of artificial thrombi in patients with hypertension. Cardiovasc Res 1970;4:50-60. 72.Dintenfass L, Zador I. Effect of stress and anxiety on thrombus formation and blood viscosity factors. Bib1 Haematol1975;41:133-139. 73. Dintenfass L, Davis E. Genetic and ethnic influences on blood viscosity and capillaries in diabetes mellitus. Microvasc Res 1977; 14161-172. 74. Dintenfass L, Forbes CD. Effect of fibrinogen on aggregation of red cells and on apparent viscosity of artificial thrombi in haemophilia, myocardial infarction, thyroid disease, cancer and control systems: effect of ABO blood groups. Microvasc Res 1975;9107-118. 75. Dintenfass L, Steward JH. Formation, consistency and degradation of artificial thrombi in severe renal failure: effect of ABO blood groups. Thromb Diath Haemorrh 1968;20:267-284. 76.Dintenfass L. Some aspects of haemorrheology of metastasis in malignant melanoma. Haematologia (Budap) 1977;11:301-307. 77. Blann AD, Daly RJ, Amiral J. The influence of age, gender and ABO blood group on soluble endothelial cell markers and adhesion molecules.Br J Haematol1996;92498-500. 78. Sostaric V, Bozicevic D, Brinar V, Grbavac Z. Hereditary antigen characteristics of blood in ischemic cerebrovascular accident. Neurol Croat 1991;40:3-11. 79. Ionescu DA, Ghitescu M, Marcu I, Xenakis A. Erythrocyte rheology in acute cerebral thrombosis: effects of ABO blood groups. Blut 1979;39:351-357. 80.Ionescu DA, Marcu I, Bicescu E. Cerebral thrombosis, cerebral haemorrhage, and ABO blood-groups. Lancet 1976;1:278-280. 81. Horby J, Gyrtrup HJ, Grande P, Vestergaard A. Relation of serum lipoproteins and lipids to the ABO blood groups in patients with intermittent claudication.J Cardiovasc Surg (Torino) 19893: 533-537. 82. Robinson WM, Roisenberg I. Venous thromboembolism and ABO blood groups in a Brazilian population. Hum Genet 1980;55:129-131. 83. Havlik RJ, Feinleib M, Garrison RJ, Kannel WB. Blood-groups and coronary heart-disease. Lancet 1969;2:269-270. 84.Slipko Z, Latuchowska B, Wojtkowska E. [Body structure and ABO and Rh blood groups in patients with advanced coronary heart disease after aorto-coronary by-pass surgery]. Pol Arch Med Wewn 1994;91:55-60. 85.Meshalkin EN, Okuneva GN, Vlasov IuA, Vel'tmander NN. [ABO and Rh blood groups in cardiovascular pathology]. Kardiologiia 1981;21:46-50.

Nontransfusion Significance of ABO and ABO-Associated Polymorphisms 86. Erikssen J, Thaulow E, Stormorken H, et al. ABO blood groups and coronary heart disease (CHD): a study in subjects with severe and latent CHD. Thromb Haemost 1980;43137-140. 87. Allan TM. ABO blood groups, age and work in ischaemic heart disease. Atherosclerosis 1975;21:459461. 88. Galeazzi L, Gualandri V. [ABO blood-group phenotypes and pathogenesis of cardiovascular diseases. Congenital, rheumatic and coronaric heart disease and arterial hypertension (author’s transl)]. G Ital Cardiol 1975;5744751. 89. Rosenberg L, Miller DR, Kaufinan DW, et al. Myocardial infarction in women under 50 years of age. JAMA 1983;250:2801-2806. 90. Platt D, Muhlberg W, Kiehl L, Schmitt-Ruth R. ABO blood group system, age, sex, risk factors and cardiac infarction. Arch Gerontol Geriatr 1985;4241-249. 91. Whincup PH, Cook DG, Phillips AN, Shaper AG. ABO blood group and ischaemic heart disease in British men. BMJ 1990;300:1679-1682. 92. Dabelsteen E. Cell surface carbohydrates as prognostic markers in human carcinomas. J Pathol 1996;179358-369. 93. Ichikawa D, Handa K, Hakomori S. Histo-blood group A/B antigen deletion/reduction vs. continuous expression in human tumor cells as correlated with their malignancy. Int J Cancer 1998;76284249. 94. Cooper HS, Marshall C, Ruggiero F, Steplewski Z. Hyperplastic polyps of the colon and rectum. An immunohistochemical study with monoclonal antibodies against blood groups antigens (sialosyl-Lea, Leb, Lex, Ley, A, B, H). Lab Invest 1987;57:421-428. 95. Saegusa M. [Isoantigens ABH in bladder tumors as an indicator of malignant potential a combined study with CEA, BMG, Leu-M1 and H-Ag]. Hinyokika Kiyo 1989;351311-1321. 96. Abel PD, Marsh C, Henderson D, et al. Detection of blood group antigens in frozen sections of prostatic epithelium. Br J Urol 1987;59:430435. 97. Lin XS. [The expression and siguficance of blood group antigens (BGA) A, B, H, Le(a) and Le(b) in hepatocellular carcinoma and chronic hepatitis] Zhonghua Sing Li Xue Za Zhi 1992;21:2426. 98. Robey-Cafferty S, El Naggar AK, Sahin AA, et al. Prognostic factors in esophageal squamous carcinoma. A study of histologic features, blood group expression, and DNA ploidy. Am J Clin Pathol 1991;95:844849. 99. Inoue M, Sasagawa T, Saito J, et al. Expression of blood group antigens A, B, H, Lewis-a, and Lewis-b in fetal, normal, and malignant tissues of the uterine endometrium. Cancer 1987;60:2985-2993. 100. Matias-Guiu X, Giux M. ABO (H) blood group antigen expression in gastric mucosa. Pathol Res Pract 1988;183:476-480. 101. Larena A, Vierbuchen M, Fischer R. Blood p u p antigen expression in malignant tumors of the thyroid a parallel between medullary and nonmedullary carcinomas. Langenbecks Arch Chir 1995;380: 269-272. 102. Tauchi K, Kakudo K, Machimura T, et al. Immunohistochemical studies of blood group-related antigens in human superficial esophageal carcinomas. Cancer 1991;673042-3050. 103. Marionneau S, Le Moullac-Vaidye 8, Le Pendu J. Expression of histo-blood group A antigen increases resistance to apoptosis and facilitates escape from immune control of rat colon carcinoma cells. Glycobiology 2002;12851-856. 104. Springer GF. T and Tn pancarcinoma markers: autoantigenic adhesion molecules in pathogenesis, prebiopsy carcinoma-detection, and long-term breast carcinoma immunotherapy. Crit Rev Oncog 1995;657-85. 105. Garratty G. Blood group antigens as tumor markers, parasitic/ acterial/viral receptors, and their association with immunologically important proteins? Immunol Invest 1995;24213-232. 106. Kurtenkov 0,Klaamas K, Miljukhina L. The lower level of natural anti-Thomsen-Friedenreichantigen (TFA) agglutinins in sera of patients with gastric cancer related to ABO(H) blood-group phenotype. Int J Cancer 1995;60:781-785.

107. Aird I, Bentall HH, Roberts JA. A relationship between cancer of stomach and the ABO blood groups. Br Med J 1953;1:799-801. 108. Beckman L, Angqvist KA. On the mechanism behind the association between ABO blood groups and gastric carcinoma. Hum Hered 1987;37140-143. 109. Hirohashi S, Clausen H, Yamada T, et al. Blood group A crossreacting epitope defined by monoclonal antibodies NCC-LU-35 and -81 expressed in cancer of blood group 0 or B individuals: its identification as Tn antigen. Proc Natl Acad Sci U S A 1985; 82:7039-7043. 110. Brooks SA, Leathem AJ. Prediction of lymph node involvement in breast cancer by detection of altered glycosylation in the primary tumour. Lancet 1991;338:71-74. 111. Brooks SA, Hall DM, Buley I. GalNAc glycoprotein expression by breast cell lines, primary breast cancer and normal breast epithelial membrane. Br J Cancer 2001;851014-1022. 112. Springer GF. Immunoreactive T and Tn epitopes in cancer diagnosis, prognosis, and immunotherapy. J Mol Med 1997;75: 594602. 113. Defize LH, Amdt-Jovin DJ, Jovin TM, et al. A431 cell variants lacking the blood group A antigen display increased high affinity epidermal growth factor-receptor number, protein-tyrosine b a s e activity, and receptor turnover. J Cell Biol1988;107939-949. 114. Engelmann 8, Schumacher U, Haen E. Epidermal growth factor binding sites on human erythrocytes in donors with different ABO blood groups. Am J Hematol1992;39239-241. 115. Jorgensen G. [ABO blood groups in physicians more than 75 years old: on the hypothesis concerning “little more fitness of blood group 0 1 . MMW Munch Med Wochenschr 1974;116649-652. 116. Jorgensen G. [Human genetics and infectious diseases (author’s transl)] . M M W Munch Med Wochenschr 1981;1231447-1452. 117. D’Adamo P. The complete blood type encyclopedia: the A-Z reference guide for the blood type connection to symptoms, disease, conditions, vitamins, supplements, herbs, and food. New York Riverhead Books, 2002. 118. Pusztai A, Bardou S. Biological effects of plant lectins on the gastrointestinal tract: metabolic consequences and applications. Trends Glycosci Glycotechnol 1996;8:149-165. 119. Haas H, Falcone FH, Schramm G, et al. Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils. Eur J Immunol1999;2991&927. 120. Cordain L, Toohey L, Smith MJ, Hickey MS. Modulation of immune function by dietary lectins in rheumatoid arthritis. Br J Nutr 2000;83207-217. 121. Erickson RH, Kim J, Sleisenger MH, Kim YS. Effect of lectins on the activity of brush border membrane-bound enzymes of rat small intestine. J Pediatr Gastroenterol Nutr 1985;4984-991. 122. Pusztai, A. Plant lectins. Cambridge: Cambridge University Press, 1991. 123. Pusztai A, Ewen SWB, Grant G, et al. Relationshipbetween survival and binding of plant lectins during small intestinal passage and their effectiveness as growth factors. Digestion 1990;46:30&316. 124. Weinman MD, Allan CH, Trier JS, Hagen SJ. Repair of microvilli in the rat small intestine after damage with lectins contained in the red kidney bean. Gastroenterology 1989;971193-1204. 125. Greer F, Pusztai A. Toxicity of kidney bean (Phaseolus vulgaris) in rats: changes in intestinal permeability. Digestion 1985;32:42-46. 126. Jordinson M, Playford RJ, C a l m J. Effects of a panel of dietary lectins on cholecystokinin release in rats. Am J Physiol 1997;273:G946-G950. 127. Pusztai A. Dietary lectins are metabolic signals for the gut and modulate immune and hormone functions. Eur J Clin Nutr 1993;47691-699. 128. Freed DJ. Dietary lectins. In Brostoff J, Challacombe S, eds. Food allergy and intolerance. Philadelphia: Bailliere Tmdall Publishers, 1987.

129. Bardocz S, Grant G, Ewen SW, et al. Reversible effect of phytohaemagglutinin on the growth and metabolism of rat gastrointestinal tract. Gut 1995;37353-360. 130. Nachbar MS, Oppenheim JD.Lectins in the United States diet: a survey of lectins in commonly consumed foods and a review of the literature. Am J Clin Nutr 1980;332338-2345. 131. Ewen SW, Pusztai A. Health risks of genetically modified foods. Lancet 1999;354:684. 132. Czirok E, Marton A, Csik M, Solt M. Virulence factors of Escherichia coli. I. Mannose resistant haemagglutinating capacity is associated with serogroup but not with site of infection. Acta Microbiol Hung 1984;31:187-195. 133. Podbielska M, Krotkiewski H. Identification of blood group Aand B antigens in human glycophorin. Arch Immunol Ther Exp (Warsz) 2ooO;48:211-221. 134.Clausen H, Stroud M, Parker J, et al. Monoclonal antibodies directed to the blood group A associated structure, galactosyl-A: specificity and relation to the Thomsen-Friedenreich antigen. Mol h~n011988;25:199-204. 135. Slomiany BL, Murty VL,Slomiany A. Structural features of carbohydrate chains in human salivary mucins. Int J Biochem 1993; 25:259-265. 136. Kochetkov NK,Derevitskaya VA, Arbatsky NP. The structure of pentasaccharides and hexasaccharides from blood group substance H. Eur J Biochem 1976;67:129-136. 137. Johansson I, Bratt P, Hay DI, et al. Adhesion of Candida albicans, but not Candida krusei, to salivary statherin and mimicking host molecules. Oral Microbiol Immunol2000;15:112-118. 138. Schulte BA, Poon KC, Rao KF,' Spicer SS. Lectin histochemistry of complex carbohydrates in human cervix. Histochem J 1985;17 627-654. 139. DAdamo P. LECster 2.3. Eat right 4 your type. Available online at wwu.dadamo.com/7ecster2/lecster.cgi[accessed 27 March 20041. 140. Fleming RM. The effect of high-protein diets on coronary blood flow. Angi010g~2000;51:817-826. 141. Blann AD, Jackson P, Bath PM, Watts GF. von Willebrand factor, a possible indicator of endothelial cell damage, decreases during long-term compliance with a lipid-lowering diet. J Intern Med 1995;237:557-561. 142. Yildirir A, Tokgozoglu SL, Oduncu T, et al. Soy protein diet significantly improves endothelial function and lipid parameters. Clin Cardiol2001;24:711-716. 143. Fuentes F, Lopez-Miranda J, Sanchez E, et al. Mediterranean and low-fat diets improve endothelial function in hypercholesterolemic men. Ann Intern Med 2001;132.1115-1119.

144. DAdamo P. Unpublished results. Some data available online a t uuw.dadamo.com/outcome-l998.htm/ 145. More information, including an extensive knowledge base, is available at the author's primary internet portal: uuw.dadamo.com/ 146. Ferreiros CM, Criado MT. Purification and partial characterization of a Fucus vesiculosus agglutinin. Rev Esp Fisiol 1983;39:51-59. 147. Roberts DD, Ginsburg V. Sulfated glycolipids and cell adhesion. Arch Biochem Biophys 1988;267405-415. 148.Criado MT, Ferreiros CM. Selective interaction of a Fwcus vesiculosus lectin-like mucopolysaccharide with several Candida species. Ann Microbiol (Pans) 1983;134A:149-154. 149. Boericke W. Pocket materia medica. San Francisco, 1927. 150. Jenkin CR, Jackson GD. Artificial antigens and immunity to infectious disease. Prog Immunobiol Stand 1970;4493-504. 151. Galelli A, Truffa-BachiP. Urtica dioica agglutinin: a superantigenic lectin from stinging nettle rhizome. J hunol1993;151:1821-1831. 152. DAdamo P. Unpublished observations, 1987-1994. 153. Gray AM, Flatt PR. Insulin-releasing and insulin-like activity of Agaricus carnpestris (mushroom). J Endocrinol 1998;157 259-266. 154. Yu LG, Femig DG, White MR, et al. Edible mushroom (Agaricus bisporus) lectin, which reversibly inhibits epithelial cell proliferation, blocks nuclear localization sequence-dependent nuclear protein import. J Biol Chem 1999;2744890-4899. 155. Bird GW, Wingham J. More Tn-specific lectins from seeds of the genus Labiatae: Hyptis sp. Chan, Salvia lyrata and Marrubium velutinum. Clin Lab Haematol 1982;4403-404. 156. Ren de C, Du GH, Zhang JT. Inhibitory effect of the water-soluble extract of Salvia miltiorrhiza on neutrophil-endothelial adhesion. Jpn J Pharmacol2002;90:276-280. 157. Jordinson M, El-Hariry I, CaInan D, et al. Vicia faba agglutinin, the lectin present in broad beans, stimulates differentiation of undifferentiated colon cancer cells. Gut 1999;44:709-714. 158. Khan F, Khan RH, Shenvani A, et al. Lectins as markers for blood grouping. Med Sci Monit 2002;8:RA293-RA300. 159. Ito N, Nishi K, Kawahara S, et al. Difference in the ability of blood group-specific lectins and monoclonal antibodies to recognize the ABH antigens in human tissues. Histochem J 1990; 22~604-614. 160. Vandonselaar M, Delbaere LT, Spohr U, Lemieux RU. Crystallization of the lectin IV of Griflonia simplicifolia and its complexes with the Lewis b and Y human blood group determinants. J Biol Chem 1987;26210848-10849. 161. Wu AM, Wu JH, Lin LH, et al. Binding profile of Artocarpus integrifolia agglutinin (Jacalin). Life Sci 2003;72:2285-2302.

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Nutritional Medicine Michael T. Murray, ND Joseph E. Pizzorno Jr, ND C HA PTE K C 0N TE NT S Introduction

461

Evolutionary Aspects in Human Nutrition 461 A Look at Our Closest Wild Relatives 461 Hunter-Gatherer Diets 462 The Importance of a Plant-Based Diet 462 The Pioneering Work of Burkitt and Trowell

462

Trends in U.S. Food Consumption 463

2. Reduce Exposure to Pesticides and Food Additives 466 3. Eat to Support Blood Sugar Control 467 4. Reduce Intake of Meat and Other Animal Foods 468 5. Eat the Right Type of Fats 468 6. Keep Salt Intake Low, Potassium Intake High 469 7. Avoid Food Additives 470 8. Take Measures to Reduce Foodborne Illness 470 9. Drink Sufficient Amounts of Water Each Day 471

The Government and Nutrition Education 463 Nutritional Supplementation 471 The Optimal Health Food Pyramid 465 1. Eat a “Rainbow” Assortment of Fruits and Vegetables 465

Let your food be your medicine and let your medicine be your food. -Hippocrates

INTRODUCTION Nutritional medicine, as described in this textbook, consists of the use of diet and nutritional supplementation as therapeutic modalities. The foundation of nutritional medicine is a health-promoting diet that focuses on the consumption of whole, natural foods. Nutritional supplements are used in the overall context of nutritional medicine as complementary agents, not as sole primary medicines. Diet is always primary, and supplementation secondary.

EVOLUTIONARY ASPECTS IN HUMAN NUTRITION Although the human gastrointestinal tract is capable of digesting both animal and plant foods, a number of physical characteristics indicate that Homo sapiens evolved to digest primarily plant foods. Specifically,our teeth are composed of 20 molars, which are perfect for crushing and grinding plant foods, along with eight

Final Comments 472

front incisors, which are well suited for biting into fruits and vegetables. Only our front four canine teeth are designed for meat eating. Our jaws swing both vertically to tear and laterally to crush, but carnivores’ jaws swing only vertically. Additional evidence that support the body’s preference for plant foods is the long length of the human intestinal tract. Carnivores typically have a short bowel, and herbivores have a bowel length proportionally comparable to that of humans. Thus the human bowel length favors plant f0ods.l

A Look at Our Closest Wild Relatives To answer the question “What should humans eat?“ many researchers look to other primates, such as chimpanzees, monkeys, and gorillas. Nonhuman wild primates are also omnivores or, as often described, herbivores and opportunistic carnivores. They eat mainly fruits and vegetables but may also eat small animals, lizards, and eggs if given the opportunity. Only 1%and 2%, respectively, of the total calories consumed by gorillas and orangutans are animal foods. The remainder of their diet is from plant foods. Because humans are between the weights of the gorilla and orangutan, it has been suggested that humans are designed to eat 461

Therapeutic Modalities

around 1.5% of their diet as animal foods.2 Most Americans derive well over 50% of their calories from animal foods. Although most primates eat a considerable amount of fruit, it is critical to point out that the cultivated fruit in American supermarkets is far different from the highly nutritious wild fruits these animals rely on. Wild fruits have slightly higher protein contents and a higher content of certain essential vitamins and minerals, but cultivated fruits tend to be higher in sugars. Cultivated fruits are therefore very tasty to humans, but because they have a higher sugar composition and also lack the fibrous pulp and multiple seeds found in wild fruit that slow down the digestion and absorption of sugars, cultivated fruits raise blood sugar levels much more quickly than their wild counterparts. Wild primates fill up not only on fruit but also on other highly nutritious plant foods. As a result, wild primates weighing Ho as much as a typical human ingest nearly 10 times the level of vitamin C and much higher amounts of many other vitamins and minerals. Other differences in the wild primate diet are also important to point out, such as a higher ratio of alpha-linolenic acid, the essential omega3 faty acid, to linoleic acid, the essential omega4 fatty acid2(Table 44-1).

Hunter-Gatherer Diets Determining what foods humans are best suited for may not be as simple as looking at the diet of wild primates. There are some structural and physiologic differences between humans and apes. The key difference may be a larger, more metabolically active brain. In fact, it has been theorized that a shift in dietary intake to more animal foods may have produced the stimulus for brain growth. The shift itself was probably the result of limited food availability that forced early humans to hunt grazing mammals such as antelope and gazelle. Archeologic data supports this association: The brains of humans started to grow and become more developed at about the

Mineral Calcium Phosphorus Potassium Sodium Magnesium

Total daily intake of 7-kg adult monkey (ma) 4571 728 6419

Recommended daily allowance for 70-kg man (ma) 800 800

The Importance of a Plant-Based Diet The evidence supporting diet‘s role in chronic degenerative diseases is substantial and overwhelming. There are two basic facts linking the diet-disease connection: (1)a diet rich in plant foods (i.e., whole grains, legumes, fruits, and vegetables) is protective against many diseases that are extremely common in so-called Western society, and (2) a diet providing a low intake of plant foods is a causative factor in the development of these diseases and provides conditions under which other causative factors are more active.

1600-2000

182

500

1323

350 10

Iron

38.5

Manganese

18.2

2.0-5.0

2.8

1.5-3.0

Copper

same time as evidence shows an increase in bones of animals butchered with stone tools at sites of early villages. Improved dietary quality alone cannot M y explain why human brains grew, but it definitely appears to have played a critical role. With a bigger brain, early humans were able to engage in more complex social behavior, which led to improved foraging and hunting tactics, which in turn led to even higher quality food intake, fostering additional brain evolution. Data from anthropologists looking at hunter-gatherer cultures are providing much insight as to what humans are designed to eat; however, it is very important to point out that these groups were not entirely free to determine their diets. Instead, their diets were molded by what was available to them. For example, the diet of the Inuit Eskimos is far different from that of the Australian aborigines. It may not be appropriate to answer the question “What should humans eat?” simply by looking at these studies. Nonetheless, it is important to point out that regardless of whether hunter-gatherer communities relied on animal or plant foods, the rate of diseases of civilization, such as heart disease and cancer, is extremely low in such communities? It should also be pointed out that the meat that our ancestors consumed was much different from the meat found in supermarkets today. Domesticated animals have always had higher fat levels than their wild counterparts, but the desire for tender meat has led to the breeding of cattle that produce meat with a fat content of 25% to 30% or more, compared with less than 4% for free-living animals and wild game. In addition, the type of fat is considerably different. Domestic beef contains primarily saturated fats and virtually undetectable amounts of omega3 fatty acids. In contrast, the fat of wild animals contains more than five times more polyunsaturated fat per gram and has good amounts of beneficial omega3 fatty acids (approximately 4%).4

The Pioneering Work of Burkitt and Trowell Much of the link between diet and chronic disease originated from the work of two medical pioneers Denis Burkitt, MD, and Hugh Trowell, MD, authors of Western Diseases: Their Emergence and Prevention, first published in 1981.5Although now extremely well-recognized,

Nutritional Medicine

their work is actually a continuation of the landmark work of Weston A. Price, a dentist and author of Nutrition and Physical Degeneration. In the early 1900s, Dr. Price traveled the world observing changes in teeth and palate (orthodontic) structure as various cultures discarded traditional dietary practices in favor of a more “civilized” diet. Price was able to follow individuals as well as cultures over periods of 20 to 40 years and carefully documented the onset of degenerative diseases as their diets changed. On the basis of extensive studies examining the rate of diseases in various populations (epidemiologic data) and his own observations of primitive cultures, Burkitt formulated the following sequence of events:

First stage. In cultures consuming a traditional diet consisting of whole, unprocessed foods, the rate of chronic diseases like heart disease, diabetes, and cancer is quite low. Second stage. Commencing with eating a more “Western” diet, there is a sharp rise in the number of individuals with obesity and diabetes. Third stage. As more and more people abandon their traditional diet, conditions that were once quite rare become extremely common. Examples are constipation, hemorrhoids, varicose veins, and appendicitis. Fourth stage. Finally, with full westernization of the diet, other chronic degenerative or potentially lethal diseases, such as heart disease, cancer, osteoarthritis, rheumatoid arthritis, and gout, become extremely common. Since Burkitt and Trowell’s pioneering research, a virtual landslide of data has continually verified the role of the Western diet as the key factor in virtually every chronic disease, especially obesity and diabetes. Box 44-1 lists diseases with convincinglinksto a diet low

-

Metabolic Obesity, gout, diabetes, kidney stones, gallstones Cardiovascular High blood pressure, strokes, heart disease, varicose veins, deep vein thrombosis, pulmonary embolism Colonic Constipation, appendicitis, diverticulitis, diverticulosis, hemorrhoids, colon cancer, irritable bowel syndrome, ulcerative colitis, Crohn’s disease Other Dental caries, autoimmune disorders, pernicious anemia, multiple sclerosis, thyrotoxicosis, psoriasis, acne

in plant foods. Many of these now common diseases were extremely rare before the twentieth century.

TRENDS IN U.S. FOOD CONSUMPTION During the twentieth century, food consumption patterns changed dramatically (Table 44-2). Total dietary fat intake has risen from 32%of the calories in 1909 to 43% by the end of the century. Overall carbohydrate intake dropped from 57% to 46%; and protein intake has remained fairly stable at about 11%. Compounding these detrimental changes are the individual food choices accounting for the changes. The biggest changes were in sigruficant rises in the consumption of meat, fats and oils, and sugars and sweeteners in conjunction with the decreased consumption of noncitrus fruits, vegetables, and whole-grain products. The absolutely largest change in the last 100 years of human nutrition is the switch from a diet with a high level of complex carbohydrates, as found naturally occurring in grains and vegetables, to a tremendous and dramatic increase in the number of calories consumed from simple sugars. Currently, more than half of the carbohydrates being consumed are in the form of sugars (sucrose, corn syrup, etc.) being added to foods as sweetening agents. High consumption of refined sugars is linked to many chronic diseases, including obesity, diabetes, heart disease, and cancer.

THE GOVERNMENT AND NUTRITION EDUCATION Throughout the years, various governmental organizations have published dietary guidelines, but the recommendations of the United States Department of Agriculture (USDA) have become the most widely known. In 1956, the USDA published Foodfor Fitness-A Daily Food Guide. This became popularly known as the Basic Four Food Groups. The Basic Four were composed of the following: 1. The Milk Group: milk, cheese, ice cream, and other milk-based foods 2. The Meat Group: meat, fish, poultry, eggs, with dried legumes and nuts as alternatives 3. The Fruit and Vegetable Group 4.The Breads and Cereals Group

One of the major problems with the Basic Four Food Groups model was that it graphically suggested that the food groups are equal in health value. The result was overconsumption of animal products, dietary fat, and refined carbohydrates, and insufficient consumption of fiber-rich foods like fruits, vegetables, and legumes. This in turn has resulted in diet’s being responsible for many premature deaths, chronic diseases, and increased health care costs.

Therapeutic Modalities

Foods Meat, poultry, and fish: Beef Pork Poultry Fish

1909

1967

1985

1999

54 62 18 12 -

81 61 46 15

73 62 70 19

66 50 68 15 -

~

~

146

203

224

199

37

40

32

32

223

47 -

232 44 15 159 -

122 112 26 190 -

112 101 30 210 -

339

450

450

453

18 1 8 12 2

6 10 16 5 16

5 11 23 46 25

5 8 22 29 -

41

53

68

70

17

60

72

79

154 8

73 35

87

115

34

37 -

179

168

193

231

46 34

36 25

38 31

55 39

136 8

87 35

96 34

126 39 -

TOTAL

224

183

199

259

Potatoes, white Fresh Processed

182 0

67 19

55 28

TOTAL

Eggs Dairy products: Whole milk Low-fat milk Cheese Other TOTAL

Fats and oils: Butter Margarine Shortening Lard and tallow Salad and cooking oil TOTAL

Fruits: Citrus Noncitrus Fresh Processed TOTAL

Vegetables: Tomatoes Dark green and yellow Other Fresh Processed

64 5

49 91

As the Basic Four Food Groups became outdated, various other governmental as well as medical organizations developed guidelines of their own designed to reduce the risk of either a specific chronic degenerative disease, such as cancer or heart disease, or of all chronic diseases. In an attempt to create a new model in nutrition education, the USDA first published the “Eating Right Pyramid” in 1992. Since that time it has received harsh criticisms from numerous experts and other organizations. One big question that should be asked is ”Is it appropriate to have the USDA making these recommendations?” After all, the USDA serves two somewhat conflicting roles: (1)it represents the food industry and (2) it is in charge of educating consumers about nutrition. Many people believe that the pyramid was weighted more toward dairy products, red meat, and grains because of influence from the dairy, beef, and grain farming and processing industries. In other words, the pyramid was designed not to improve the health of Americans but rather to promote the USDA agenda of supporting multinational agrifoods giants (Figure 44-1). One of the main criticisms of the Eating Right Pyramid is that is does not stress strongly enough the importance of quality food choices. For example, the bottom of the pyramid represents the foods that the USDA thinks should make up the bulk of a healthy diet: the Bread, Cereal, Rice, and Pasta Group. Eating 6 to 11 servings a day from this group is supposedly the path to a healthier life. In thisway, the pyramid sets a person up for insulin resistance, obesity, and adult-onset diabetes if he or she consistently chooses refined rather than whole-grain products in this important category. This is one example of how the Eating Right Pyramid does not take into consideration how quickly blood glucose levels rise after eating a certain type of food-an effect referred to as the food’sglycmic index (GI). The GI is a numerical scale used to indicate how fast and how high a particular food raises blood glucose (blood

~

TOTAL

Dry beans, peas, nuts, and soybeans Grain products: Wheat products Corn Other grains TOTAL

Sugar and sweeteners: Refined sugar Syrups and other sweeteners TOTAL

182

86

83

140

16

16

18

22

216 56 19

116 15 13

122 17 26

150 28 24 -

291

144

165

202

77 14

100 22

63 90

68 91

91

122

153

159

Modified from United States Department of AgricuRure. Food Review 2000; 2318-1 5.

Figure 44-1

U.S. Department of Agriculture Food Pyramid.

Nutritional Medicine

sugar) levels. There are two versions of the GI, one based on a standard of comparison with glucose as 100, and the other based on white bread. Foods are tested against the results of the selected standard. Foods with a lower GI create a slower rise in blood sugar, whereas foods with a higher GI create a faster rise in blood sugar. One of the major problems with the Eating Right Pyramid is that the glycemic indices of some of the foods that the pyramid is directing Americans to eat more of, such as breads, cereals, rice, and pasta, can greatly stress blood sugar control, especially if derived from refined grains, and are now being linked to an increased risk for obesity, diabetes, and cancer. As a result, the goal of the Eating Right Pyramid was to improve the health of Americans and, hopefully, slow down the growing trend toward obesity and diet-related disease, but because of poor individual food choices within the categories, the pyramid has only worsened the problem.

THE OPTIMAL HEALTH FOOD PYRAMID On the basis of existing evidence we have created The Optimal Health Food Pyramid (Figure 44-2). The major difference from the USDA pyramid is that the Optimal Health Food Pyramid incorporates the best of two of the most healthful diets ever studied-the traditional Mediterranean diet (see later) and the traditional Asian diet. In addition, the Optimal Health Food Pyramid more clearly defines what the healthy components within the categories are and stresses the importance of vegetable oils and regular fish consumption as part of a healthful diet. Appendix 8 provides a patient handout

that clearly defines the components of the Optimal Health Food Pyramid. We based the Optimal Health Food Diet on the following nine principles: 1. Eat a ”rainbow” assortment of fruits and vegetables. 2. Reduce exposure to pesticides. 3. Eat to support blood sugar control. 4.Do not overconsume animal foods. 5. Eat the right types of fats. 6 . Keep salt intake low, potassium intake high. 7. Avoid food additives. 8. Take measures to reduce foodborne illness. 9. Drink sufficient amounts of water each day.

1. Eat a “Rainbow” Assortment of Fruits and Vegetables A diet rich in fruits and vegetables is the best bet for preventing virtually every chronic disease. That fact has been established time and again in scientific studies on large numbers of people. The evidence in support of this recommendation is so strong that it has been endorsed by U.S. government health agencies and by virtually every major medical organization, including the American Cancer Society. “Rainbow” simply means that selecting colorful foods-red, orange, yellow, green, blue, and purple-provides the body the full spectrum of pigments with powerful antioxidant effects as well as the nutrients it needs for optimal function and protection against disease (Box 44-2). Fruits and vegetables are so important in the battle against cancer that some experts have said, and we believe, that cancer is a result of a ”maladaptation” over

Red

Dark Green-cont’d

Apples (red) Bell peppers (red) Cherries Cranberries Grapefruit Grapes (red) Plums (red) Radishes Raspberries Strawberries Tomatoes Watermelon

Bell peppers (green) Broccoli Brussels sprouts Chard Collard greens Cucumber Grapes (green) Green beans Honeydew melons Kale Leeks Lettuce (dark green types) Mustard greens Peas Spinach Turnip greens

Dark Green Exercise Daily

TEAM:; watching

Pure Water 8-12 glasses

Flgure 44-2 The Optimal Health Food Pyramid.

Artichoke Asparagus

Continued

Therapeutic Modalities

Yellow and Light Green

Orange-cont’d

Apples (green or yellow) Avocado Banana Bell peppers (yellow) Bok choy Cabbage Cauliflower Celery Fennel Kiwi fruit Lemons Lettuce (light green types) Limes Onions Pears (green or yellow) Pineapple Squash (yellow) Zucchini (yellow)

Cantaloupe Carrots Mangoes Oranges Papaya Pumpkin Sweet potatoes Yams

Orange Apricots Bell peppers (orange) Butternut squash

Purple Beets Blackberries Blueberries Cabbage (purple) Cherries Currants Eggplant Grapes (purple) Onions (red) Pears (red) Plums (purple) Radishes

time to a reduced level of intake of fruits and vegetables. As a study published in the medical journal Cancer Causes and Control put it, ”Vegetablesand fruit contain the anticarcinogenic cocktail to which we are adapted. We abandon it at our peril.”6 A vast number of substances found in fruits and vegetables are known to protect against Some experts refer to these as “chemopreventers,” but they are better known to many as phytochemicals (Table 44-3). Phytochemicals include pigments such as carotenes, chlorophyll, and flavonoids; dietary fiber; enzymes; vitamin-like compounds; and other minor dietary constituents. Although they work in harmony with antioxidants like vitamin C, vitamin E, and selenium, phytochemicals exert considerably greater protection against cancer than these simple nutrients. Among the most important groups of phytochemicals are pigments such as chlorophyll, carotenes, and flavonoids.

2. Reduce Exposure to Pesticides and Food Additives In the United States, more than 1.2 billion pounds of pesticides and herbicides are sprayed on or added to food crops each year. That is roughly 5 lb of pesticides for each man, woman, and child. There is a growing concern that in addition to the sigruficant number of cancers caused by the pesticides directly, exposure to these chemicals damages the body’s detoxification mechanisms, thereby raising the risk of cancer and other diseases. To illustrate

Examples of anticancer phytochemicals Phytochemical

Action(s)

Sources

Carotenes

Antioxidants Enhance immune functions

Dark-colored vegetables such as carrots, squash, spinach, kale, tomatoes, yams, sweet potatoes; fruits such as cantaloupe, apricots, citrus fruits

Coumarin

Antitumor properties Enhances immune functions Stimulates antioxidant mechanisms

Carrots, celery, fennel, beets, citrus fruits

Dithiolthiones, glucosinolates. and thiocyanates

Block cancer-causing compounds from damaging cells Enhance detoxification

Cabbage-familyvegetables-broccoli, Brussels sprouts, kale, etc.

Flavonoids

Antioxidants Direct antitumor effects Immune-enhancingproperties

Fruits, particularly darker fruits such as berries, cherries, citrus fruits; also tomatoes, peppers, greens

lsoflavonoids

Block estrogen receptors

Soy and other legumes

Lignans

Antioxidants Modulate hormone receptors

Flax seed and flax seed oil; whole grains, nuts, seeds

Limonoids

Enhance detoxification Block carcinogens

Citrus fruits, celery

Polyphenols

Antioxidants Block carcinogen formation Modulate hormone receptors

Green tea, chocolate, red wine

Sterols

Block production of carcinogens Modulate hormone receptors

Soy, nuts, seeds

Modified from Steinmetz KA, Potter JD. J Am Diet Assoc 1996;96:1027-1039

Nutritional Medicine

just how problematic pesticides can be, one can take a quick look at the health problems of the farmer. The lifestyle of farmers is generally healthy: Compared with city dwellers, farmers have access to lots of fresh food; they breathe clean air, work hard, and have a lower rate of cigarette smoking and alcohol use. Yet studies show that farmers have a higher risk of lymphomas, leukemias, and cancers of the stomach, prostate, brain, and Exposure to pesticides may explain this occurrance. Perhaps the most problematic pesticides are the family of halogenated hydrocarbons, such as 1,l-dichloro-2,2bis(4-chloropheny1)ethylene (DDE), polychlorinated biphenyl (PCB), pentachlorophenol (PCP), dieldrin, and chlordane. These chemicals persist almost indefinitely in the environment. A similar pesticide, dichlorodiphenyltrichlorethane (DDT),has been banned for nearly 30 years yet it can still be found in the soil and root vegetables such as carrots and potatoes. The human body also has a tough time detoxlfylng and eliminating these compounds. Instead, they end up being stored in fat cells. Moreover, inside the body these chemicals can act like the hormone estrogen. They are thus suspected as a major cause of the growing epidemic of estrogen-related health problems, including breast cancer. Some evidence also suggests that these chemicals raise the risk of lymphomas, leukemia, and pancreatic cancer as well as play a role in low sperm counts and reduced fertility in men.I4 Avoiding pesticides is especially important in children of preschool age. Children are at greater risk for two reasons: they eat more food relative to body mass, and they consume more foods higher in pesticide residue-uch as juices, fresh fruits, and vegetables. A recent University of Washington study15that analyzed levels of breakdown products of organophosphoruspesticides (a class of insecticides that disrupt the nervous system) in the urine of 39 urban and suburban children aged 2 to 4 years found that concentrationsof pesticide metaboliteswere six times lower in the children who ate organic fruits and vegetables than in those who ate conventional produce. After conducting an analysis of USDA pesticide residue data for all pesticides for 1999 and 2000, Consumers Union16warned parents of small children to limit or avoid conventionally grown foods known to have high pesticide residues, such as cantaloupes, green beans (canned or frozen), pears, strawberries, tomatoes (Mexican grown), and winter squash. The University of Washington study added apples to this list.

Recommendations for Patients to Avoid Pesticides in the Diet Patients can avoid consuming pesticides in their foods by following these recommended practices: 1.Do not overconsume foods that have a tendency to

concentrate pesticides, such as animal fat, meat, eggs, cheese, and milk.

2. Buy organic produce, which is grown without the aid of synthetic pesticides and fertilizers. Although less than 3% of the total produce in the United States is grown without pesticides, organic produce is widely available. 3. Develop a good relationship with your local grocery store produce manager. Explain your desire to reduce your exposure to pesticides and waxes. Ask what measures the store takes to ensure that pesticide residues are within approved limits. Ask where the store obtains its produce; make sure the store is aware that foreign produce is much more likely to contain excessive levels of pesticides as well as pesticides that have been banned in the United States. 4.Try to buy local produce, in season. 5. Peeling off the skin or removing the outer layer of leaves of some produce may be all you need to do reduce pesticide levels. The downside is that many of the nutritional benefits of fruits and vegetables are concentrated in the skin and outer layers. An alternative measure is to remove surface pesticide residues, waxes, fungicides, and fertilizers by soaking the item in a mild solution of additive-free soap such as Ivory or pure Castile soap. All-natural, biodegradable cleansers are also available at most health food stores. To use, spray the food with the cleanser, gently scrub, and rinse.

3. Eat to Support Blood Sugar Control Refined sugars, white flour products, and other sources of simple sugars are quickly absorbed into the blood stream, causing a rapid rise in blood sugar. In response, the body boosts secretion of insulin by the pancreas. High-sugar, "junk food" diets definitely lead to poor blood sugar regulation, obesity, and ultimately type 2 diabetes and heart di~ease.''-*~The stress on the body that they cause, however, including secretion of too much insulin,can promote the growth of cancer and increases the risk of heart disease as well. As already discussed, the GI of a food refers to how quickly blood sugar levels will rise after it is eaten. However, the GI does not tell how much.of that carbohydrate is in a typical serving of a particular food, so another tool is needed. The glycerrzic loud (GL) is a relatively new way to assess the effect of carbohydrate consumption that takes the GI into account but gives a fuller picture of the effect that a food has on blood sugar levels than GI alone. A GL of 20 or more is high, a GL of 11 to 19 inclusive is medium, and a GL of 10 or less is low. For example, beets have a high GI, but a low GL. Although the carbohydrate in beet root has a high GI, the amount of carbohydrate is low, so a typical serving of cooked beet root has a relatively low GI (about 5). Thus as long one eats a reasonable portion of a low-GL food, the impact on blood sugar is acceptable, even if the food has

Therapeutic Modalities a high GI. For example, a diabetic can enjoy some watermelon (GI 72) as long as he or she keeps the serving size reasonable; the GL for 120 g watermelon is only 4. In essence, foods that are mostly water (e.g., apple, watermelon), fiber ( e g , beet root, carrot) or air (e.g., popcorn) will not cause a steep rise in blood sugar even if their GIs are high as long as portion sizes are moderate. To help design a healthy diet, we provide a list of the GI, fiber content, and GL of common foods in Appendix 6.

4. Reduce Intake of Meat and Other Animal Foods Study after study seems to indicate that the higher the intake of meat and other animal products, the higher the risk of heart disease and cancer, especially the major cancers like those of the colon, breast, prostate, and lung, whereas a diet focusing on plant foods exerts the opposite effect."*21 There are many reasons for this association. Meat lacks the antioxidants and phytochemicals that protect from cancer. At the same time, it contains lots of saturated fat and other potentially carcinogenic compounds-including pesticide residues, heterocyclic amines, and polycyclic aromatic hydrocarbons, which form when meat is grilled, fried, or broiled. The more well done the meat, the higher level of amines.' Some proponents of a diet high in meats claim that people should eat the way their "caveman" ancestors did. That argument does not really hold up. As already discussed, the meat of wild animals that early humans consumed had a fat content of less than 4%. The demand for tender meat has led to the breeding of cattle whose meat contains 25% to 30% or more fat. Domestic beef contains primarily saturated fats and virtually no beneficial omega-3 fatty acids (discussed later), whereas the fat of wild animals contains more than five times the polyunsaturated fat per gram and has substantial amounts (about 4%) of omega-3 fatty acids. Range-fed animals also contain ten times as much conjugated linoleic acid (CLA) as grain-fed animals. CLA is a slightly altered form of the essential fatty acid linoleic acid. It occurs naturally in meat and d a q products. CLA was discovered in 1978, when researchers at the University of Wisconsin were looking for cancer-causing compounds that result from cooking. Instead, they found CLA, which appears to be an anticancer compound. Preliminary studies show that CLA might reduce the risk of heart disease and cancer.u Particularly harmful to human health are cured or smoked meats, such as ham, hot dogs, bacon, and jerky, that contain sodium nitrate and/or sodium nitritescompounds that keep the food from spoiling but that dramatically raise the risk of cancer. These chemicals react with amino acids in foods in the stomach to form highly carcinogenic compounds known as nitrusarnines.

Research in adults makes a convincing argument to avoid these foods. Even more compelling is the evidence linking consumption of nitrates to a sigruficantlyincreased risk of the major childhood cancers (leukemias, lymphomas, and brain cancers), as follows: '

Children who eat 12 hot dogs per month have nearly ten times the risk of leukemia in children who do not eat hot dogs.24 Children who eat hot dogs once a week double their chances of brain tumors; eating hot dogs twice a week triples the risk.24 Pregnant women who eat two servings per day of any cured meat have more than double the risk of bearing children who have brain cancer.25 Kids who eat the most ham, bacon, and sausage have three times the risk of lymphoma." In addition, kids who eat ground meat once a week have twice the risk of acute lymphocytic leukemia compared with those who ate none; eating two or more hamburgers weekly triples the risk.24 Fortunately, vegetarian alternatives to these standard components of the American diet are now widely available, and many of them actually taste quite good. Consumers can find soy hot dogs, soy sausage, soy bacon, and even soy pastrami at their local health food stores as well as in many mainstream grocery stores.

5. Eat the RightType of Fats There is no room for debate: A diet high in fat, particularly saturated fat and cholesterol, has been linked to numerous cancers. Both the American Cancer Society and the National Cancer Institute recommend a diet that supplies less than 30%of calories as fat. However, just as important as the amount of fat is the type of fat consumed. The goal is to decrease total fat intake (especially intake of saturated fats, trans fatty acids, and omega-6 fats) while increasing intake of omega-3 fatty acids and monounsaturated fatty acids. What makes a fat "bad" or "good" has a lot to do with the function of fats in the body's cellular membranes. Membranes are made mostly of fatty acids. What determines the type of fatty acid present in the cell membrane is the type of fat consumed. A diet composed mostly of saturated fat, animal fatty acids, and trans fatty acids (from margarine, shortening, and other sources of hydrogenated vegetable oils) and high in cholesterol results in membranes that are much less fluid in nature than a diet with optimal levels of unsaturated fatty acids. Modem pathology clearly indicates that an alteration in cell membrane function is the central factor in the development of virtually every disease. As it relates to diabetes, abnormal cell membrane structure due to eating the wrong types of fats leads to impaired action of insulin.

Nutritional Medicine Without a healthy membrane, cells lose their ability to hold water, vital nutrients, and electrolytes. They also lose their ability to communicate with other cells and to be controlled by regulating hormones, including insulin. Without the right type of fats in cell membranes, cells simply do not function properly. Considerable evidence indicates that cell membrane dysfunction is a critical factor in the development of many diseases. The type of dietary fat profile that is linked to many diseases is an abundance of saturated fat and trans fatty acids (hydrogenated vegetable oils) along with a relative insufficiency of monounsaturated and omega-3 fatty acids. One of the key reasons appears to be that because dietary fat determines cell membrane composition, such a dietary pattern leads to reduced membrane fluidity, which in turn causes reduced insulin binding to receptors on cellular membranes and/or reduced insulin action. Particularly harmful to cell membrane function are margarine, vegetable oil shortening, and other foods containing trans fatty acids and partially hydrogenated oils. These "unnatural" forms of fatty acids interfere with the body's ability to utilize important essential fatty acids and are now linked to an increased risk for heart disease, diabetes, and cancer. Just the opposite effect has been shown for diets high in monounsaturated fats and omega-3 fatty One diet that appears to be representative of a way of eating that that provides an optimal intake of the right types of fat is the traditional Mediterranean dieta term with a specific meaning. It reflects food patterns typical of some Mediterranean regions in the early 1960s, such as Crete, parts of the rest of Greece, and southern Italy. The traditional Mediterranean diet has shown tremendous benefit in fighting heart disease and cancer as well as diabetes.30 It has the following characteristics:

agents that may also account for some of its health benefits. Olive oil is particularly valued for its protection against heart disease. It lowers the harmful low-density lipoprotein (LDL) cholesterol and increases the level of protective high-density lipoprotein (HDL) cholesterol. It also helps circulating LDL cholesterol from becoming damaged by free radicals and has been proved to contribute to a better control of the elevated blood triglycerides that is so common in diabetes.30

6. Keep Salt Intake Low, Potassium Intake High The electrolytes-potassium, sodium, chloride, and magnesium-are mineral salts that can conduct electricity when dissolved in water. For optimal health, it is important to consume these nutrients in the proper balance. Too much sodium in the diet from salt (sodium chloride) can disrupt this balance. Many people know that a high-sodium, low-potassium diet can cause high blood pressure and that doing the opposite can lower blood pressure13132but not as many are aware that the former diet also raises the risk of ~ancer.3~ In modem Western society, only 5% of sodium intake comes from the natural ingredients in food. Prepared foods contribute 45% of our sodium intake; 45%is added in cooking, and another 5%is added as a condiment. Patients can reduce their salt intake by following these tips:

Olive oil is the principal source of fat. It centers on an abundance of plant food (fruit, vegetables, breads, pasta, potatoes, beans, nuts, and seeds). Foods are minimally processed, and there is a focus on seasonally fresh and locally grown foods. Fresh fruit is the typical daily dessert, sweets containing concentrated sugars or honey being consumed a few times per week at the most. Dairy products (principally cheese and yogurt) are consumed daily in low to moderate amounts. Fish is consumed on a regular basis. Poultry and eggs are consumed in moderate amounts (1-4 times weekly) or not at all. Red meat is consumed in low amounts. Wine is consumed in low to moderate amounts, normally with meals.

1.Take the salt shaker off the table. 2. Omit added salt from recipes and food preparation. 3. If you absolutely must have the taste of salt, try the salt substitutes such as NoSalt and Nu-Salt. These products are made with potassium chloride and taste very similar to sodium chloride. 4. Learn to enjoy the flavors of unsalted foods. 5. Try flavoring foods with herbs, spices, and lemon juice. 6 . Read food labels carefully to determine the amounts of sodium. Learn to recognize ingredients that contain sodium. Salt, soy sauce, salt brine, and any ingredient with "sodium" (such as monosodium glutamate) or "baking soda" (sodium bicarbonate) as part of its name contains sodium. 7. In reading labels and menus, look for words that signal high sodium content, such as smoked, barbecued, pickled, broth, soy sauce, teriyaki, Creole sauce, marinated, cocktail sauce, tomato base, Parmesan, and mustard sauce. 8. Do not eat canned vegetables or soups, which are often extremely high in sodium. 9. Choose low-salt (reduced-sodium) products when available.

Olive oil consists not only of the monounsaturated fatty acid oleic acid; it also contains several antioxidant

Most Americans have a potassium/sodium (K:Na) ratio of less than 1:2.In other words, they ingest twice as

much sodium as potassium. But experts believe that the optimal dietary potassium/sodium ratio is greater than 5:l-ten times higher than the average intake. However, even this may not be optimal. A natural diet rich in fruits and vegetables can easily produce much higher KNa ratios, because most fruits and vegetables have a K:Na ratio of at least 50:l. The average K:Na ratios for several common fresh fruits and vegetables are as follows: Carrots: 75:l Potatoes: 11O:l Apples: 90:l Bananas: 44O:l Oranges: 260:l

7. Avoid Food Additives Food additives are used to prevent spoiling or to enhance flavor; they include such substances as preservatives, artificial colors, artificial flavorings, and acidifiers. Although the government has banned many synthetic food additives, it should not be assumed that all the additives currently used in the U.S. food supply are safe. A great number of synthetic food additives remain in use that are being linked to such diseases as depression, asthma or other allergy, hyperactivity or learning disabilities in children, and migraine headaches.g37 The U.S. Food and Drug Administration (FDA) has approved the use of more than 2800 different food additives. It is estimated that the per capita daily consumption of these food additives is approximately 13 to 15 g. This amount is astounding and leads to many questions. Which food additives are safe? Which should be avoided? An extremist might argue that no food additive is safe. However, many food additives fulfill important functions in the modem food supply. Many compounds approved as additives are natural in origin and possess healthpromoting properties, whereas others are synthetic compounds with known cancer-causing effects. Obviously, the most sensible approach is to focus on whole, natural foods and avoid foods that are highly processed. An illustration of the problem with food additives, is one of the most widely used synthetic food colors, FD&C (Food, Drug and Cosmetic Act) yellow dye no. 5, or tartrazine. Tartrazine is added to almost every packaged food as well as to many drugs, including some antihistamines, antibiotics, steroids, and sedatives. In the United States, the average daily per capita consumption of certified dyes is 15 mg, of which 85% is tartrazine; among children, consumption is usually much higher. Although the overall rate of allergic reactions to tartrazine is quite low in the general population, allergic reactions to tartrazine are extremely common (20% to 50%) in individuals sensitive to aspirin as well as other allergic individuals. Like aspirin, tartrazine is a known inducer of asthma, hives, and other allergic conditions,

particularly in children. In addition, tartrazine, as well as benzoate and aspirin, increases the production of a compound that raises the number of mast cells in the body. Mast cells are involved in producing histamine and other allergic compounds. A person with more mast cells in the body is typically more prone to allergies. For example, examination of patients with hives shows that more than 95% have a higher than normal number of mast cells. In studies using provocation tests to determine sensitivity to tartrazine and other food additives in patients with hives, results have ranged from 5% to 46%. Diets eliminating tartrazine as well as other food additives in sensitive individuals have, in many cases, been shown to be of great benefit in patients with hives and other allergic conditions, such as asthma and eczema.

8.Take Measures to Reduce Foodborne Illness Foodborne illness is caused by consumption of contaminated foods or beverages. Although the food supply in the United States is one of the safest in the world, the Centers for Disease Control and Prevention estimates that 76 million people get sick, more than 300,000 are hospitalized, and 5000 Americans die each year from foodborne illness.38The microbe or toxin enters the body through the gastrointestinal tract and often causes the first symptoms there, so nausea, vomiting, abdominal cramps, and diarrhea are common symptoms in many foodbome diseases. Most cases of foodbome illness are mild, but serious diarrheal disease or other complications may occur. More than 250 different organisms have been documented as being capable of causing foodborne illne~s.3~ Most of these cases are infections by a variety of bacteria, viruses, and parasites, but poisonings can also occur as a result of ingestion of harmful toxins or chemicals from organisms that have contaminated the food; for example, botulism occurs when the bacterium Clostridiurn botuliizurn grows and produces a powerful paralytic toxin in foods. The botulism toxin can produce illness even if the bacteria are no longer present. Most of the common causes of foodbome infections are microorganisms frequently present in the intestinal tracts of healthy animals. Meat and poultry can become contaminated during slaughter by contact with small amounts of intestinal contents, and fresh fruits and vegetables can be contaminated if they are washed or imgated with water that is contaminated with animal manure or human sewage. The most common causes of foodbome infections are the bacteria Carnpylobacter, Salmonella, and Escherichia coli 0157:H7 and a group of viruses called caliciviruses, also known as the Norwalk and Norwalk-like viruses. Undercooked meat and poultry, raw eggs, unpasteurized

Nutritional Medicine milk, and raw shellfish are the most common sources of these organisms. Curnpylobacter is a bacterial pathogen that causes fever, diarrhea, and abdominal cramps. It is the most commonly identified bacterial cause of diarrheal illness in the world. These bacteria live in the intestines of healthy birds, and most raw poultry meat has Cumpylobacter on it. Eating undercooked chicken or other food that has been contaminated with juices dripping from raw chicken is the most common source of this infection. Salmonella is widespread in the intestines of birds, reptiles, and mammals. It can spread to humans via a variety of different foods of animal origin. The illness it causes, salmonellosis, typically involves fever, diarrhea, and abdominal cramps. In persons with poor underlying health or weakened immune systems, the organism can invade the bloodstream and cause life-threatening illness. E. coli 0157H7 is a bacterial pathogen with a reservoir in cattle and other similar animals. Human illness typically follows consumption of food or water that has been contaminated with microscopic amounts of cow feces. The illness it causes is often a severe and typically provokes bloody diarrhea and painful abdominal cramps, without much fever. In 3%to 5%of cases, a complication called hemolytic-uremic syndrome (HUS) can occur several weeks after the initial symptoms. This severe complication consists of temporary anemia, profuse bleeding, and kidney failure. Calicivirus, or Norwalk-like virus, is an extremely common cause of foodborne illness, though it is rarely diagnosed because the laboratory test for its detection is not widely available. The v h s causes an acute gastrointestinal illness, usually with more vomiting than diarrhea, that usually resolves within 2 days. It is believed that unlike many foodborne pathogens that have animal reservoirs, Norwalk-like viruses spread primarily from one infected person to another. Infected kitchen workers can contaminate a salad or sandwich as they prepare it, if they have the virus on their hands. Infected fishermen have contaminated oysters as they harvested them. The foremost measure to reduce the risk of foodborne illness is to cook meat, poultry, and eggs thoroughly. Using a thermometer to measure the internal temperature of meat is a good way to be sure that it is cooked sufficiently to kill bacteria. For example, ground beef should be cooked to an internal temperature of 160" F, poultry should reach a temperature of 185" F, and an egg should be cooked until the yolk is firm. One must also take care to avoid contaminating foods by making sure to wash hands, utensils, and cutting boards after they have been in contact with raw meat or poultry and before they touch another food. Cooked meat should be served on a clean platter, rather than back on one that held the raw meat. To prepare produce,

one should wash fresh fruits and vegetables in running tap water. A soft-bristle brush with a little a mild soap can be used. Greens can be soaked in cold water as many times as needed to get them clean.

9. Drink Sufficient Amounts of Water Each Day Water is essential for life. The average amount of water in the human body is about 10 gallons. The recommendation to drink at least 48 ounces of water per day to replace the water that is lost through urination, sweat, and breathing is valid. Even mild dehydration impairs physiologic and performance Many nutrients dissolve in water so they can be absorbed more easily in the digestive tract. Similarly, many metabolic processes need to occur in water. Water is a component of blood and thus is important for transporting chemicals and nutrients to cells and tissues. Each cell is constantly bathed in a watery fluid. Water also carries waste materials from cells to the kidneys for filtering and elimination.Water absorbs and transports heat. For example, heat produced by muscle cells during exercise is carried by water in the blood to the surface, helping to maintain the right temperature balance. The skin cells also release water as perspiration, which helps maintain body temperature. Several factors are thought to increase the likelihood of chronic mild dehydration: a faulty thirst "alarm" in the brain; dissatisfaction with the taste of water; regular exercise that increases the amount of water lost through sweat; living in a hot, dry climate; and consumption of the natural diuretics caffeine and alcohol. There is currently a great concern over the U.S. water supply. It is becoming increasingly difficult to find pure water. Most of the water supply is full of chemicals, including not only chlorine and fluoride, which are routinely added, but also a wide range of toxic organic compounds and chemicals, such as PCBs, pesticide residues, and nitrates, and heavy metals such as lead, mercury, and cadmium. It is estimated that lead alone may contaminate the water of more than 40 million Americans. Patients should be encouraged to determine the safety of their tap or well water by contacting their local water companies; most cities have quality assurance programs that perform routine analyses. Patients can simply ask for the most recent analysis.

NUTRITIONAL SUPPLEMENTATION Nutritional supplementation-the use of vitamins, minerals, and other food factors to support good health as well as preventing or treating illness-is an important component of nutritional medicine. The key functions of nutrients like vitamins and minerals in the human body revolve around their role as essential components in

Therapeutic Modalities

enzymes and coenzymes. One of the key concepts in nutritional medicine is to supply the necessary support or nutrients to allow the enzymes of a particular tissue to work at their optimum levels. The concept of “biochemical individuality” was coined by nutritional biochemist Roger Williams in the 1970s to recognize the wide range in enzymatic activity and nutritional needs of humans. These observations also provided the basis for ”orthomolecular medicine” as envisioned by two-time Nobel laureate Linus Pauling. In addition to serving as necessary components in enzymes and coenzymes, many nutrients appear to exert pharmacologic effects. Most of these effects appear to be the result of enzyme induction. In other words, when used at supraphysiologic levels, nutrients can induce the manufacture of enzymes, induce enzymes to become more active, or even inhibit enzyme action. For example, the B vitamin niacin (nicotinic acid) is well known as a lipid-lowering agent when given at high dosages (2-6 g/day in divided doses). Its mechanism of action is quite diverse but appears to occur via inhibition of enzymes that manufacture of very-low-density

lipoprotein (VLDL) while stimulating the production or activity of enzymes that take up LDL in the liver. The advantage of using nutrients at pharmacologic dosages is that they are more recognizable and better metabolized by the body, as evidenced by a broader therapeutic index. Even so, the use of nutrients as pharmacologic agents is closely akin to drug therapy. That being the case, it is imperative that they be used and monitored appropriately.

1. Ryde D. What should humans eat? Practitioner 1985;232:415-418. 2. Milton K. Nutritional characteristics of wild primate food: d o the diets of our closest living relatives have lessons for us? Nutrition 1999;1548&498. 3.Cordain L, Eaton SB, Miller JB, et al. The paradoxical nature of hunter-gatherer diets: meat-based, yet non-atherogenic. Eur J Clin Nutr 2002;56(S~ppll):S42-S52. 4. Eaton SB, Eaton SB 3rd. Paleolithic vs. modem diets-seleded pathophysiological implications. Eur J Nutr 2OOO;39:67-70. 5. Trowell H, Burkitt D. Westem diseases: their emergence and prevention. Cambridge, MA: Harvard University Press, 1981. 6. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. 11. Mechanisms. Cancer Causes Control 1991;2:427-442. 7. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc 1996;96:1027-1039. 8. La Vecchia C, Tavani A. Fruit and vegetables, and human cancer. Eur J Cancer Prev 1998;73-8. 9. Van Duyn MA, Pivonka E. Overview of the health benefits of fruit and vegetable consumption for the dietetics professional: selected literature. J Am Diet Assoc 2OOO;100:1511-1521. 10. Aronson KJ, Miller AB, Woolcott CG, et al. Breast adipose tissue concentrations of polychlorinated biphenyls and other organochlorines and breast cancer risk. Cancer Epidemiol Biomarkers Prev 2000;955-63. 11. Baris D, Zahm SH. Epidemiology of lymphomas. Curr Opin Oncol 2OOO;12:383-394. 12. Blair A, Zahm SH. Agricultural exposures and cancer. Environ Health Perspect. 1995;103(Suppl8):205-208. 13. Mao Y, Hu J, Ugnat AM, White K. Non-Hodgkin’s lymphoma and occupational exposure to chemicals in Canada. Canadian Cancer Registries Epidemiology Research Group. Ann Oncol 2000;ll (SUPPI1):69-73. 14. Jaga K, Brosius D. Pesticide exposure: human cancers on the horizon.Rev Environ Health 1999;1439-50.

15.Lu C, Knutson DE, Fisker-Andersen J, Fenske RA. Biological monitoring survey of organophosphorus pesticide exposure among preschool children in the Seattle metropolitan area. Environ Health Perspect 2001;109(3):299-303. 16. Consumers Union of United States, Inc. Do you know what you’re eating? An analysis of U.S. government of data of pesticide residues in foods. Washington, DC:Consumers Union, February 1999. 17. Jenkins DJ, Kendall CW, Augustin LS, et al. Glycemic index: overview of implications in health and disease. Am J Clin Nutr 2002;76:266S2673S. 18. Willett W, Manson J, Liu S. Glycemic index, glycemic load, and risk of type 2 diabetes. Am J Clin Nutr 2002;76274S2805. 19. Liu S, Willett WC, Stampfer MJ, et al. A prospective study of dietary glycemic load, carbohydrate intake, and risk of coronary heart disease in US women. Am J Clin Nutr 2000;71:1455-1461. 20. Bingham SA. High-meat diets and cancer risk. Proc Nutr Soc 1999;58:243-248. 21. Segasothy M, Phillips PA. Vegetarian diet: panacea for modem lifestyle diseases? QTM 1999;92:531-544. 22. Zheng W, Gustafson DR, S i a R, et al. Well-done meat intake and the risk of breast cancer. J Natl Cancer Inst 1998;901724-1729. 23. Whigham LD, Cook ME, Atkinson RL. Conjugated linoleic acid: implications for human health. Pharmacol Res 2000;42.503-510. 24. Blot WJ, Henderson BE, Boice JD Jr. Childhood cancer in relation to cured meat intake: review of the epidemiological evidence. Nutr Cancer 1999;34:111- 118. 25. Preston-Martin S, Pogoda JM, Mueller BA, et al. Maternal consumption of cured meats and vitamins in relation to pediatric brain tumors. Cancer Epidemiol Biomarkers Prev 1996;5599-605. 26. Bougnoux P. n-3 polyunsaturated fatty acids and cancer. Curr Opin Clin Nutr Metab Care 1999;2:121-126. 27. Bucher HC, Hengstler P, Schindler C, Meier G. N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials. Am J Med 2002;112:298-304.

FINAL COMMENTS The dietary guidelines and principles that are detailed in this chapter represent our answer to the hotly debated question “What is the best diet?“ After a review of every popular diet in detail as well as thousands of scientific articles on the role of diet in human health, our offering here is based on the evolutionary understanding of what constitutes the optimal diet. The bottom line for a healthpromoting diet is to reduce the intake of potentially harmful substances-foods laden with empty calories, additives, and artificial sweeteners-and replace them with natural foods, preferably organically grown.

Nutritional Medicine 28. Fraser GE. Nut consumption, lipids, and risk of a coronary event. Clin Cardiol1999;22(Suppl):ll-15. 29. Jiang R, Manson JE,Stampfer MJ, et al. Nut and peanut butter consumption and risk of type 2 diabetes in women. JAMA 2002;288: 2554-2560. 30.Alarcon de la Lastra C, Barranco MD, Motilva V, Herrerias JM. Mediterranean diet and health: biological importance of olive oil. Cum Phan-n Des 2001;7933-950. 31. Whelton PK, He J. Potassium in preventing and treating high blood pressure. Semin Nephrol1999;19494-499. 32. Sacks FM,Svetkey LP, Vollmer Wh4, et al.Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 2001;344:3-10. 33. Jansson B. Potassium, sodium, and cancer: A review. J Env Pathol TOX~COI On~011996;15:65-73.

34. Boris M, Mandel FS.Foods and additives are common causes of the attention deficit hyperactive disorder in children. Ann Allergy 1994;72462-468. 35.Lessof MH. Reactions to food additives. Clin Exp Allergy 1995;25(S~ppl1):27-28. 36. Groten JP, Butler W, Feron VJ,et al. An analysis of the possibility for health implications of joint actions and interactions between food additives. Re@ Toxic01 Pharmacol2000;31:77-91. 37. Simon RA. Adverse reactions to food additives. Curr Allergy Asthma Rep 2003;3:62-66. 38. Lasky T. Foodborne illness-old problem, new relevance. Epidemiology 2002;13:593-598. 39. Tauxe RV. Emerging foodbome pathogens. Int J Food Microbiol 2002;78:3141. 40. Kleiner SM. Water: an essential but overlooked nutrient. J Am Diet ASSW1999;99:200-206.

Peat Therapeutics and Balneotherapy Mark D. Groven, ND CHAPTER CONTENTS Introduction 475 Balneology 476 History 476 Balneotherapy in Combination with Other Therapies 476 Physiologic Effects 476 Circadian Rhythms 477 Peat Therapeutics 477 History 477 Skin Response 477 Physiologic Effects 478 Hyperthermia 478 Clinical Applications 479 Discopathy 479 Myopathy 479 Scoliosis 479 Arthritis 479 Headache 479

INTRODUCTION Nature has provided many gifts of healing. One of the most outstanding and exciting is peat. The use of organic peat and its constituents is ancient, yet people with pain, injury, and dermatologic, rheumatic, and other conditions are benefiting from modern peat therapy today. This pleasant and safe healing discovery has brought relief and cure for many.'-'* BaZneoZogy is the study of the art and science of bathing. Balneotherapy is the use of natural thermal mineral waters, additive baths, peloids, and other natural substances as well as various atmospheric or environmental elements singly or in combination for the prevention and treatment of disease. The aim of balneotherapy is to change regulation and reactive functions, leading to improvement of capacity, adaptation, and ~elf-healing.'~ Peloid refers to the pulp of a substance that is applied to the body. It may be in pack form or bath, either local or whole body. The concentration of peloidal solutions

Hamstring Strain 479 Ankle Sprain 479 Molluscum Contagiosum 479 Hypertension 480 Dermatologic Problems 480 Scleroderma 480 Human Papillomavirus 480 Herpes Virus 480 Infertility 480 Ankylosing Spondylitis 480 Hematoma 480 Immune Stimulation 480 Clinical Procedures 481 Hyperthermic Medicinal Peat Bath 481 Medicinal Peat Peloid 483 Partial-Immersion Medicinal Peat Bath 484 Combination Full Bath and Peat Pack 484 Conclusion 484

can vary and should be applied to the skin in a specific manner for a specific condition to optimize results. Common peloids are peat pulp, lake or sea muds, and plant substances. For many conditions balneotherapy works synergistically with peloid therapy, and the percutaneous absorption of their constituents along with the physiological and psychologic effects provides an excellent therapy for people who can no longer tolerate oral or injectable pharmaceuticals and are suffering from chronic degenerative diseases. Life is stressful, and our society is aging. We would be wise to utilize the positive benefits of balneotherapy in the conventional treatment of pain and illness as well as in health maintenance and prevention of disease. The purpose of this chapter is to describe the general concept of balneotherapy with emphasis on the therapeutic application of peat. There certainly is a distinction between the application of peat and the application of other muds such as lake mud or clay. 475

Vitally important are the characteristics of the specific peat mud constituents being used as well as the manner of their application.*

BALNEOLOGY History Therapeutic bathing is an ancient art and probably the oldest of medical procedures. Hippocrates wrote on the application of therapeutic bath in 400 BC and how it soothed pain in the side, improved respiration, soothed the joints and skin, was diuretic, and removed heaviness of the head. It was suited for those who benefited but could be unsuitable if applied in the wrong way. It enjoyed tremendous popularity until about 75 years ago when, along with other natural techniques, it fell out of favor as conventional medicine produced its modem successes. Since then, the large corpus of empirical wisdom has been expanded on and much scientific evidence has contributed to the advancement of balneology as a science. Regular research continues in this field. Every 4 years a conference of the International Society of Medical Hydrology and Climatology (ISMH)presents new scientific research and validates its findings. World Peat Congresses meet to discuss the medical use of peat, and symposiums are held on peat therapeutics and its application in health care?6 Many institutions are teaching hydrotherapy and balneologic techniques, and many spas have wonderful programs for people to utilize. It is not hard to imagine that the reason this art has survived and improved is because it can better people’s health. Balneotherapy’s modem-day roots lie predominantly in European spas, which have some of the longest continuously running histories of any medical institution. Millions of patients flock to clinics throughout Europe and the world each year for treatment in hydrology departments under the supervision of physicians and their staffs. Such clinics provide a variety of balneotherapeutic techniques. Spa therapy is a term used for the combination of balneotherapy and other techniques usually delivered at a resort setting. The effects of spa therapy are influenced positively by the pleasure of being in a beautiful setting with the stresses of home and work removed. Medical spas are often in an area where earth’s elements enter in. The pristine air, the ambient temperature, the humidity or amount of light, nourishing food, and exercise can affect a change in the spirit, mind, and body.”

Balneotherapy in Combination with Other Therapies Many therapies work well together, such as phototherapy and mud therapy in the treatment of psoriasis. ‘References7. 10. 11. 13. 16.18-25.

Mud pack therapy, peloidotherapy, massage, soft and osseous tissue manipulation, iontophoresis, phonophoresis, and exercise work t0gether.2~The combination of buoyancy and heat in the water make sense,for example, in underwater traction bath and massage, which have been shown to reduce the levels of analgesic consumption in patients.ls In my own experiences with patients, hydrotherapy with and without mud in combinationwith other treatments such as naturopathic manipulation can work like nothing else to help people heal and stay healthy. A multitude of conditions can be treated with balneotherapeutic methods--pain, injury, and dermatologic and rheumatic conditions rank high?JyBBUnder the right conditions and with the right application, balneotherapy stimulates healing and speeds recovery. Contrast bath in the treatment of obesity may function to promote homeostasis when used in combination with exercise. Promotion of thermogenesis mechanisms may help obese patients begin to lose weight, enhance lipid metabolism, and improve some aspects of hypertension. Contrast bath enhances the positive effects of dietary changes; when these methods are given in combination patients have the best results.3o

Physiologic Effects Balneotherapeuticsinduce direct and indirect actions on the body. The direct actions of balneotherapy take into consideration the physical actions of water on the body, such as hydrostatic pressure, buoyancy, viscosity, and frictional resistance, as well as thermal effects and the chemical and pharmacologic effects of the percutaneous absorption of the substance being used. Such substances are hot spring waters of various types, such as carbon dioxide, hydrogen sulfide, chloride, sulfate, iron, acid, and radon. Mineral waters contain cations such as Na+, K+, Ca+,and Mg+ and anions SO4-, C1-, and HC03-. The concentrations of these ions are usually significantly high (1 g/L). In spring water, levels of nitrogen compounds such as NO3, NO2,and NO are very low and the water is free of or low in bacteria.17 Peat muds, plant preparations, and mineral-containing muds are also used. In Europe, peat bath and peloids are traditional. These applications are used in combination with exercise, aquatics, steam bath, sauna therapy, climatotherapy, physical therapy, and pharmacotherapy, among others, with important consideration being given during treatment to the chronobiologic and circadian rhythmic phases of the body.1J4,U,25-28 The indirect actions of balneotherapy arise from the repeated application of therapeutic stimulation, such as climatic exposure to the elements, training effects of exercises, and social and psychological effects arising from changes in environment. These elements act as a complex stimulation in a nonspecific manner of the

Peat Therapeutics and Balneotherapy

physiologic function of the organism's central nervous system, autonomic nervous system, endocrine system, immune system, and so on. The result of these stimulations is a reactive response by the body, leading to activation and improvement of capacity, adaptation, and self-healing potential. In other words balneotherapy has a normalizing effect on the body's systems and rhythms.*

Circadian Rhythms Biorhythms are important in the expression of many cond i t i ~ n s . Sunlight, ~ , ~ ~ mealtimes, and seasonal changes are external cues that, together with internal cues such as blood pressure and respiration, affect the hypothalamus or master clock. This part of the brain then signals hormones, enzymes, and other substances to facilitate healing, produce cells, or cause pain and symptoms. It has been shown that different times of day affect the amount of muscle torque potential, body temperature, and clockgene messenger RNA (mRNA)expression.42A cold or hot foot bath can induce rise in temperature of oral mucosa up to 1"C, but the extent of the oral temperature increase depends on the body's reaction to this stimulus, which is influenced by the body's own internal clock.' Conditions such as arthritis have pain with varying cycles.43It is thought that some of these cycles are in synchrony with the moon and the sun. Heart attacks, asthma, and rheumatoid arthritis joint pain are early morning diseases, so medication and treatment can be tailored for different times of day when it is sigruficantly more helpful and less wasteful when not needed. Serum adrenocorticotropic hormone (ACTH), prolactin, luteinizing hormones, and immune parameters such as plasma levels of soluble p75 tumor necrosis factor (sTNF-R75)and tumor necrosis factor-alpha (TNF-a)vary in 24hour rhythms in the body? These may be affected through balneotherapy, as may melatonin production and expression. Melatonin affects the organization and expression of biorhythms and is easily susceptible to oxidative stress. Symptom remission in some conditions coincides with a normalization of circadian rhythms promoted by balneotherapeutic treatment.4447In a European study, the combination of carbon dioxide bath and mud bath was shown to downregulate the systolic pressure in hypertension while having a balancing effect on biologic clocks.48A study on patients fibromyalgia in whom altered reactivity of the hypothalamic-pituitaryadrenal (HPA) axis was observed supports the theory that mud pack therapy works in synergy with antidepressant treatment to decrease pain and improve depression. Balneotherapy can promote the body's

*References 2, 4, 7, 10, 11, 15, 31-39.

response systems, such as the stress response system, to achieve homeo~tasis.4~

PEAT THERAPEUTICS History The ancients used peat extract baths, and the antiseptic properties of peat mud were recognized in World War I when it was applied directly to wounds to prevent infe~tion.4~ Native used mud externally and internally. Peat has been used as a medicinal preparation in baths and peloid packs extensively in Europe for the past 200 years. This unique substance contains many chemical constituents that can interact with organic and inorganic compounds.20The scientific basis for the physical, chemical, and pharmacologic effects of peat baths has been long known, and such baths have been used extensively in balneotherapeutic applications in Europe and other parts of the world to treat rheumatic diseases, gynecologic disorders, osteoarthritis, lumbago, sciatica, skin diseases, trauma and its sequelae, and many other aliments and afflictions. The many substances in peat offer a vast possibility of medicinal cure a p p l i ~ a t i o n s . 5 ~ ~ ~ It is important to consider the region and origin of the peat being used for medicinal purposes. Low moor peat has been shown to contain higher concentrations of nitrous substances, which are thought to contain a higher content of biologically active substances than the high moor peats or peats taken from a shallower depth. It is not just high nitrous content that makes a certain peat more medically useful, but the quality, type, and amount of the biologically active substances it contains that are the determining factors in medicinal effect. In Germany these types of peats are now a national resource.

Skin Response The skin is a reflex, metabolic, immune, and excretory organ. It affects the autonomic, immune, and circulatory systems and participates in the biosynthesis of not only vitamin D but also acetylcholine, histamine, and serot ~ n i n . ~ ,Sigruficantly ~ J ~ J ~ higher concentrationsof minerals and medicaments can be attained in the epidermis with baths than with systemic flooding via the vascular system. There is percutaneous uptake of many substances by the skin but not in large amounts for most natural substances. Permeation into the dermis does occur especially for humic acids, and uptake beyond the stratum corneum is exemplified by measurable urinary excretion rates.60,61 The primary effects of bath components take place within the skin. For instance, hydrogen sulfide acts as a trap for oxygen radicals, functioning to reduce inflammation. It is thought that the action comes from the effect

of sulfur on the Langerhans cells, which play a role in immune presentation and inflammation modulation. In this way, skin responses can act as transmitter-activating helper functions. Sulfur-containing peat baths demonstrate a pain-reducing and healing effect on rheumatic and degenerative diseases. One reason may be the reduction in Langerhans cell activity in producing cytokines that results from the combination of the components within peat and thermal radiation.*

Physiologic Effects Peat has a structure containing micropores, which accounts for its spongelike watercarrying capacity and its ability to maintain either hot or cold temperatures. When applied, peat produces a gradient rise or fall in temperature, which is especially desirable in a therapeutic bath. A peat formulation bath influences and neuromuscular, endocrine, and pulmonary functions,kidney hemodynamics, depending on the consistency and volume of the partial or full bath?JOPeat has well-documented effects such as tissue dilatation and increases in strokevolume, metabolism, and immunologic stimulation. Peat bath may be preferable to water bath if one considers the gradient rise and fall of temperature, increased buoyancy, and prevention of heat loss during a bath and the possible positive chemical and pharmacologic effects of the constituents of peat.59a Those who have experienced a therapeutic bath can appreciate the feelings of exhilaration and deep relaxation induced by a bath that contains an additive such as peat. The response is affected by the constituents in the water, the temperature of the bath, and the time of day the stimulus is given.63 The patient’s genetics and physical capacity are also important. Peat bath enhances circulation significantly longer than water bath.21 Microcirculatory vasodilatation in the skin has been shown to increase even without hyperthermia. The peripheral and deeper arteries such as the intrauterine vessels have shown prolonged increased flow after peat bath. The effects of peat constituents can occur without heat, but heat increases the effect on the body. The antirheumatic activity of thermal muds has a precise pharmacologic character. Therapy can be prescribed according to the characteristics of the mud for specific For example, specific muds work better with phototherapy for psoriasis and atopic dermatitis. The length of time that the peat mud has undergone humificaton and maturation lends unique characteristics. Maturation of peat muds increases their thermoinsulating, hydration, and, importantly, biochemical characteristics. The sulfoglycolipid content of mature mud differentiates a natural remedy from a specific

‘References 2, 7, 15. 19. 22. 49, 62.

application with a precise pharmacologic character. These sulfoglycolipids are absorbed through the skin and stimulate an antirheumatic effect.65 Several peat substances are able to permeate the skin.61Their absorption and action have been documented by the comparisons of placebo, water bath, and peat bath using Doppler ultrasound measurement. One study that measured circulation in the uterine artery after bath therapy showed that only the peat bath achieved the physiologic effect of prolonged vasodilatation and circulation. This effect lasts for several hours after the treatment. It is thought that absorption of peat substances takes place through the hair follicles and apocrine glands via diffusion and partial pinocytosis.21”8The fractions of peat components that penetrate the skin include the humic acid fractions, fulvic, ulmic, and volvic. The excitatory effect of humic acid fractions such as fulvic acid impact the reactivity of a2 and D2 receptors of smooth muscle cells.62 The functions of peat in medicinal applications are antimicrobial, antiviral, antiinflammatory, and antineoplastic, to name a few.63Many biochemical effects have been demonstrated in humans and animals. The antiinflammatory effect of peat mud has been attributed to a sulfoglycolipid associated with a decrease in serum interleukin-1 (IL-1) in patients with arthritis.” The effects of mud applications include elevation of protein synthesis, reduction of arachidonic acid, and inhibition of inflammatory mediators such as leukotrienes, prostaglandins, and thromboxane. Biologic activity is ascribed to peat ingredients such as sulfur compounds, magnesium, manganese, iron, and humic acids.* Mud pack therapy decreases the proinflammation factors IL-1 and TNF-a and also increases serum levels of insulin-like growth factor 1(IGF-l), which is cartilage protective. Humic substances spread widely in nature and found mainly in highly degraded peat have been shown to have a proliferative effect on certain leukocytes. Water-soluble oxihumate, given orally or dermally, increases the proliferative response in mononuclear leukocytes as well as production and expression of IL-2.2,49

Hyperthermia The thermal properties of peat mud applications have been shown to be much greater than those of waterbath because of the former’s dynamic viscosity, decreased convective cooling, and a protective effect on the skin with hot applications? Whole-body, extracorporal, and local infrared applications of hyperthermia have uses in cancer therapy. Hyperthermic effects include changes in heat shock proteins (HSP) and upregulation of heart antioxidant defense proteins such as manganese superoxide d i ~ m u t a s eAlso . ~ ~ plasma B-endorphins rise

’References 6, 7, 10, 11, 16. 19, 24

Peat Therapeutics and Balneotherapy

in response to hot water bathing and may be responsible for the euphoric feeling the bath may bring.& In a study of patients with cancer, hyperthermia was shown to create the same endorphin rise both after sauna bath and in whole-body infrared hyperthermia. Whole-body hyperthermia (WBH) stimulates an increase in T cells such as monocytes and absolute numbers of white blood cells.& There is an increase in homing response to different tissues of lymphocytes, which contributes to antitumor activity. Hyperthermia may increase lymphocyte migration into inflamed tissue or lymphoid tissues such as lymph nodes and Peyer’s patches; this effect may help generate the cellular immune response. TNF-a and IL-6 are regulated by the stimulus of h y p e r t h e ~ - r n i aHSPs . ~ ~ ~produced ~ by hyperthermia can provide protection against the muscle damage that occurs through a pathologic increase in intracellular calcium or uncoupling of the mitochondria1 respiratory chain. Hyperthermia provides protection to typical damage from reperfusion after ischemia or with excessive exercise damage. Calcium homeostasis, energy loss, increased free radical-mediated reactions, and activation of apoptosis pathways are affected. I use a thermal application of the partial or full peat-additive bath for the treatment of back pain, musculoskeletal disorders, skin problems, viral illnesses, and more. The use of heat in the right amount is crucial to treatment e f f i c a ~ y . ~ , ~ ~ , ’ ~

muscles and can be valuable in assisting with osseous manipulation once the muscles are more relaxed.

Scoliosis Peat bath followed by traction of the spine can be very helpful in patients with scoliosis who have back pain. Also applying a peat pack over the area of spinal pain can be useful.

Arthritis Peat treatments have shown efficacy for both osteoarthritis and rheumatoid arthritis. One needs to be careful with acute rheumatoid arthritis because treatment may initially stir up symptoms. Generally in osteoarthritis these treatments have been shown in both the literature and my experience to be very beneficial. I have observed significant decreases in swelling and pain with one treatment multiple times in osteoarthritis of the knee and other areas. Generally a series of either combination bath and pack or single bath or packs is given. Treatments are done every day or two.

Headache Chronic headaches can respond to peat bath or to peat packs especially on the neck or over the cervical spine. One must be careful not to overheat the medulla with the cervical pack treatment; thus, mud applications are usually applied below the second cervical vertebra.

CLINICAL APPLICATIONS

Hamstring Strain

Care must be exercised in the selection of patients for any type of thermal therapy. It is important to allow each patient time to adapt by starting with lower-temperature and shorter-duration treatments first. Patients with neurodegenerative diseases like multiple sclerosis (MS) and conditions such as diabetes are not good candidates for WBH. In MS, the excitatory effect on nerves from heat leads to muscle cramping and in diabetes, heat may lead to an ultimate drop in blood sugar and lightheadedness or loss of consciousness. Peat has many beneficial applications, however, as described here.

One of the best applications of bath followed by mud pack is in a hamstring muscle strain. In my experience, athletes even of professional stature have been able to ”get back into the game” faster and with more function than they would have with any other type of treatment.

Discopathy A series of treatments using first peat bath followed by manual traction and then a peat pack over the affected area of the spine has worked marvelously for many of my patients with discopathy. The first thing that is helped is the pain; then there is an improvement in structural integrity and function over time. It is necessary to perform these combination treatments three times a week for 3 to 12 weeks if there is sigruficant discopathy.

Myopathy Muscle pain is easily treated with a thermal peat bath or peat pack. The increase in circulation is very helpful to

Ankle Sprain Partial peat bath immersion of the foot and leg for ankle sprain is very effective. One can see in older sprains the immediate reduction of ecchymosis after the treatment. Patients can perform home treatments in a plastic wastepaper basket on a daily basis for three to six treatments. This approach is inexpensive and wonderfully effective.

Molluscum Contagiosum A small amount of peat material applied to the molluscum twice a day can produce a reaction in about 2 weeks, when treated lesions flare and then fall off. This is a very inexpensive treatment and does not have the same danger of drug reaction as the new pharmaceuticals for this application. In one patient who had a full-body, itchy drug rash from a topical application for molluscum, I used a neutral-temperature peat bath that took the itch away and turned the full-blown red, raised,

rash to slightly raised, nonred, and nonitchy rash within 30 minutes. Within 12 hours the symptoms were almost entirely resolved.

Hypertension Ambulatory blood pressure has been shown to be affected positively by balneotherapy. After a series of treatments blood pressure at rest and during standardized levels of ergonomic exercise tend to decrease as does nocturnal blood pressure. The effect is sustained sometimes permanently.48I do not necessarily recommend this treatment for people with hypertension, except that the bath can have a major homeostatic effect on biorhythms, which can often affect hypertension positively with or without other treatments. People with hypertension have more cardiovascular problems that must be considered before they undergo thermal therapy. Generally people with mild hypertension tolerate the bath better than people with mild hypotension.

Dermatologic Problems Psoriasis and atopic dermatitis are the dermatologic conditions more commonly treated with peat bath. I, however, have had very good success in eczema and dermatitis with both peat bath and cream application. There are multiple possibilities with dermal applications.

Scleroderma Peat bath weekly for 6 to 12 treatments is often a good method of treating scleroderma. Treatment should start with a tolerable temperature and increase slowly over the series of baths so that the patient can adapt.

Human Papillomavirus Antiviral effects of topical peat application have been demonstrated on several viruses, including the human papillomavirus. Remission and prevention of implantation of the virus has been described. This is a measure that prevents cancer. The antiviral and antineoplastic effects are thought to be associated with the ability of peat constituents such as humate to bind on lectinbinding junctions, thereby blocking viral entry into ceUs.2'5'

Herpes Virus Topical treatment of herpes virus skin disease with humic and fulvic fractions of peat has been effective. I have had significant success with zoster outbreaks. Most important, the topical application of specific peat formulation creams that include humic acids has been very helpful to some of my patients.

therapy in comparison with pharmacotherapy. In the peat therapy group, the rate of pregnancy was very good, along with a practically nonexistent spontaneous abortion rate, whereas in the pharmacotherapy group the rate of spontaneous abortions was very high.&

Ankylosing Spondylitis In the treatment of ankylosing spondylitis, peat therapy has shown a decrease in the level of C-reactive protein and an elevation of hemoglobin with a series of treatments. This coincided with a significant reduction in pain and an improvement in f u n ~ t i o n .Peat ~ ~ ,bath ~ ~ and pack and just the bath are options. If a patient is not a candidate for thermal bath, the packs over the spine can be very useful.

Hematoma Organic peat with its intense vasodilating, antiinflammatory effects, interactions of ions and mineral properties, enhances reduction of hematomas. Hematomas treated with thermal peat application have been reported to resolve 50% faster, with no hemosiderin residue, than those treated with only heat applications, which often left residues.71 One can see bruising decrease with pack application immediately after the treatment and an enhancement in the absorption of the hematoma in significantly less time with bath and pack.

Immune Stimulation Peat bath in combination with hyperthermia demonstrates leukocyte elevation. The immune-stimulating effects of peat bath seen clinically correspond to hematologic changes after baths.70 Some effects on immune function are due to heat and others are due to the constituents in peat. A favorable effect is seen on peripheral blood lymphocytes in atherosclerotic disease after hydrogen-sulfide bath independent of heat.70Oxihumate has shown antiviral activity plus immuno-stimulatory effect on mononuclear lymphocytes while also having very low or no toxicity, showing promise for treatment of immunocompromised patients.35Immune stimulation or regulation may also be due to increases or changes in immunocyte numbers and function and the balancing of chronobiologic rhythms. Oral oxihumate, a potassium salt of oxihumic acid, may show some activity in blocking human immunodeficiency virus type 1 infection of MT-2 cells and may be helpful in the topical treatment of herpes virus-induced skin diseases.35 There are also internal uses for constituents of peat. Interestingly electrophoresis of peat mud showed benefits

Infertility A study on infertility due to immature follicle maturation syndrome demonstrated good results with peat

'References 44,49.67,69,70,72,73,76,79.

Peat Therapeutics and Balneotherapy in patients with duodenal ulcer, secondary to hormone shifts and normalization of collagen metabolism in the duodenal m ~ c o s aAlso, . ~ ~the internal use of peat fractions such as humic acid increase the proliferation of some T cells.49

CLINICAL PROCEDURES The following procedures should be applied with care and forethought as to diagnosis and the skillful administration of the treatment. These procedures are stimulations to the body, and the thermal effects should not be taken lightly. Patients must be thoroughly screened for contraindications to treatment before undergoing fullbody immersion hyperthermia. The very young and very old should, in general, have very gentle hot or cold stimulation if any at all. Generally, up to three thermal baths are given per week if they are hot. Thermal therapy can be depleting for some patients so consideration to the patient's vitality is primary.

Hyperthermic Medicinal Peat Bath The indications for and contraindications to hyperthermic medicinal peat bath are given in Box 45-1.

Muscle tension Neurological disorders Obesity Orthopedic disorders Osteoarthritis Postoperative rehabilitation Premenstrual syndrome Prostatitis Psoriasis Rashes Rheumatoid arthritis Sciatica Scleroderrna Skin care Sprains Strains Stress relief Trauma Viral infections

Contraindications Acute hypertension Breastfeeding Cardiac deficiency Diabetes Multiple sclerosis Neurodegenerative disease

Peat bath material-I use Healing Botanical's professional use peat bath formula containing peat extract, sulfur, wintergreen, and pine oil. Tub with water thermometer and safety features like handrails and nonslip floor mats Room with table for perspiration time Gown or loose-fitting bathing suit Two sheets Two wool blankets Two large towels (one for patient to dry off after treatment and one for head wrap) Basin with iced water and a hand towel for cooling patient's face Digital thermometer or otothermometer for patient monitoring (no glass mercury thermometers).A microcomputer-based data acquisition device that records electrocardiogram (ECG) and body and ambient temperatures during bathing can be used; this is preferred over individual readings of pulse and oral temperature during the bath because the ECG shows heart function and the clinician is freed from the task of doing the monitoring. This device can be a real-time recorder for the bath.75 Exhaust fan or room air filter Footstool for entering and leaving tub The design of the bath area should take into consideration getting patients in and out of the tub and then as directly as possible to a treatment table.

Indications Acne Arthritis pain Back pain Benign prostatic hypertrophy Bursitis Carpal tunnel syndrome Dermatitis Eczema Fibromyalgia Flu Fractures Acute gouty toe Chronic gout Gynecologic disorders Headaches Hematomas Hives Insomnia Lumbalgia Metabolic disorders

Materials

Open wounds Preexisting high fever Pregnancy Pulmonary deficiency Respiratory insufficiency Systemic lupus erythematosus

Procedure 1. Before a patient begins treatment, cardiovascular risk and any other conditions that do not respond to or are aggravated by thermal therapy should be ruled out. Once the patient has been classified as to risk factors for thermal therapy, the clinician should ask about previous experience with heat in sauna or steam baths or other types of infrared heating of the tissues. Much depends on the patient's positive health perspective of the self and of the pain or disease process, and the patient's expectations of the therapeutic bath or application. 2. Make sure the tub is clean without a ring. Check log book on last treatment and cleaning. If any evidence of an unclean tank is seen, it must be cleaned and disinfected before use: Wearing rubber gloves, use a soft scouring sponge to scrub the tank with disinfectant soap, followed by a rinse of hot water. Then spray the surface with 10%bleach solution, and wait 10 minutes before rinsing with very hot water. Alternatively, a nonbleach product that is antimicrobial can be used; there are many choices for practitioners to choose from on the market. 3. Fill the tub to 10 inches from the top with water at a temperature of 105" to 113" F (41"to 45" C).

Therapeutic Modalities 4. The starting temperature and possible duration of treatment are determined by the condition. 5. Straight water bath should not exceed 110" F. With peat additive, the temperature should not exceed 113" F. 6. Add peat to the bath. 7. Close monitoring during treatment, by means of periodic recording of the patient's pulse, oral temperature, duration of treatment, and tank temperature, is necessary. A quick spike in pulse above initial pulse within the first minute or minutes is a contraindication to treatment. Any adverse reaction, such as tingling of fingers and toes, nausea, headache, lightheadedness, or vertigo, should be evaluated closely, and treatment terminated. Some patients may be able to tolerate only a low temperature and short duration for the first treatment. For a patient having a series of treatments, the first treatment is of shorter duration and lower temperature to see how the patient responds. The ability to tolerate treatments should improve as patients acclimate through their series of treatments. 8. The patient should enter extremely still water slowly. It will not feel as hot if the water is still. 9. Have the patient remain still as he or she becomes fully immersed, to help decrease the sensation of intense heat. 10. To treat the pelvis, utilize a sitz bath rather than a full bath to concentrate the effects of the treatment. A full bath after the sitz bath may be useful. 11. The water will cool as time passes, although the peat material will help maintain the temperature. If the starting temperature was 105" F, hot water may have to be added. 12. Bath duration is 8 to 20 minutes and should not exceed 20 minutes owing to the additive pharmacologic effects and the tendency for hyperthermia to produce increased metabolism and mobilization of chemicals within the body. 13.If the patient becomes fatigued or distressed, he should exit the bath to be wrapped in the waiting sheet and wool blankets; do not wait longer to have the patient leave the bath. 14. The patient must have help exiting the tub, from two people who provide lifting support from under the arms on either side. This is a time to be very careful. The clinician should assist the patient by placing an arm under the patient's arm but having the patient use his or her own ability to walk and get out of the tub. If the clinician tries to lift the patient rather than provide necessary support, the patient's tendency is to put all his or her weight on the clinician, which is not the goal. After thermal therapy, patients are usually fine to walk, but there is a chance of

lightheadedness and, in rare cases, vertigo. Patients may need assistance. 15. Encourage the patient to concentrate on walking on his or her own. 16. Have the patient lie down on a fresh sheet and wrap the patient in both sheets and two or three wool blankets. Cover the head with a towel. 17. Continue to monitor pulse and oral temperature for the duration of the 20-minute perspiration time. 18. Rinse a face cloth in cold water and apply for 10 seconds or long to the patient's face every 1or 2 minutes during both bath and perspiration times. This is extremely important during the bath. 19. Encourage the patient to relax and help the patient to focus on pleasant matters during the bath. The psychological component of the bath is huge. Having patients think and talk about whatever excites and pleases them about their lives or their future during the difficult part of the bath and the treatment will help them tolerate the heat and reframe their disease processes. 20. After the patient has been wrapped from head to foot in sheet and wool blankets (it is not necessary to have blankets under the patient, as the table is a good insulator that prevents the blankets from getting wet), allow the patient to go through the hydrotherapy reaction of rise and fall in temperature, pulse, and diaphoresis three times. Then remove the patient from the sheets and allow him or her to return to normal activities. This cyclic reaction is seen with peat bath. With water bath, the patient may or may not sweat after the bath. With peat bath, perspiration is helpful, as there is increased absorption or skin effect if perspiration is allowed to continue after the bath. 21. Have the patient rest and replace electrolytes after treatment. The patient should not do a lot of exercise for 12 to 24 hours after a full bath especially the patient with back problems. The patient should promote good posture in the treated area during this time. 22. During the perspiration time, manual traction can be applied to the spine. This is done by grasping the ankles of the 'supine patient and pulling for 30 to 45 seconds with enough traction that the patient almost slides on the table. Indications for manual traction are disc problems, scoliosis, and impingement; it is a nice addition to any peat bath for any condition because it feels good to the patient. 23. Advise the patient not to shower with soap for up to 12 hours after the peat bath, as absorption rates continue after the bath if peat additives have been used. 24. Patients should dry thoroughly and remain covered, warm, and out of draft for 3 hours after treatment. This precaution can easily be overlooked and cause

Peat Therapeutics and Balneotherapy aggravation if cold stimulation is allowed to happen. More than one reminder to the patient is necessary, as after thermal bath people naturally are ready to cool down. 25. Clean the tank and room thoroughly after use. Log out times of bath and tank cleaning.

Medicinal Peat Peloid The indications for and contraindications to this procedure are given in Box 45-2. Care should be taken when performing this application to avoid bums. It is important for the patient to have a strong feeling of warmth without a hot burning sensation. For a typical application, this heat sensation should last for 20 to 30 minutes and may take a few minutes to start once the mud has been applied. Start timing from the point that the patient first feels warmth. The practitioner should use his or her own touch and sense of heat during the application.

Materials Peat poultice material-I use Healing Botanical’s professional use poultice formula containing peat pulp, peat extract, sulfur, wintergreen, and pine oil. Hot water should be added to this dry material 3 minutes before application, and the solution should be mixed so it becomes very slightly supersaturated. The point at which it just becomes shiny and has the consistency of mixed cake batter is perfect. In 1 to 3 minutes it will be time to apply it to the area being treated.

Indications Acne Arthritis pain Back pain Bursitis Carpal tunnel syndrome Eczema Fibromyalgia Fractures Acute gouty toe Chronic gout Headaches Hematomas Hives Lumbalgia Muscle tension

Molluscum contagiosum Orthopedic disorders Osteoarthritis Postoperative rehabilitation Premenstrual syndrome Prostatitis Psoriasis Rashes Rheumatoid arthritis Sciatica Skin care Sprains Strains Stress relief Trauma

Contraindications Open wounds Pregnancy Very thin, fragile skin

Heat-insensitive skin Allergies to any of the peloid materials

It will still be warm for application because hot water was used. Three large towels Small towel Face cloth Small blanket to cover hydrocollator Two small stainless steel basins One small paper cup Hydrocollator (alternativelyhot water bottle can be used)

Procedure This is a thermal peat pack meant to be applied for 30 minutes. The procedure is as follows: 1. Make a square layer of peat material about 0.25 inches thick, 2 inches bilaterally over the spine and 6 to 8 inches long over the spine. If the spinal area is not being treated, area to be treated is covered. The area of application should be as flat and level as possible. 2. Cover the peat directly with a single-layer warm wet facecloth. So as to remember the borders of peloid exactly, ridge the facecloth around the margins of the peat. 3. Border the wet face cloth-covered peloid with a rolled bath towel, making a quarter turn at the comers while folding the towel to match the margin of the peat. 4.Apply one layer of towel over the facecloth and peat material. Depending on the size and mass of the hydrocollator and its temperature, this layer may not be necessary. 5.Put a fresh hydrocollator pack directly over the towel. The hydrocollator should be heated at a gentle boil for 1hour before use. Do not allow any exposed skin to come in contact with the hydrocollator. 6. Cover the hydrocollator pack with a towel or small blanket to insulate it and prevent heat loss. 7. Have a cup of cold water ready to pour on the wet face cloth-covered peloid if it gets too hot. In a good treatment, the peloid pack should get hot enough to require two to three dousings of water or more. 8. As soon as the patient says that the pack is getting too hot, lift up the hydrocollator pack and towel and pour the water directly over the face cloth-covered peloid until cool. Then replace the hydrocollator and coverings. 9. Never leave the patient unattended with the hydrocollator on the mud! 10. Treatment time is approximately 25 to 30 minutes. 11. To remove the peat from the skin after treatment, slide a small basin along the skin under the peat, scraping the peat into the bowl. Wipe the area with a full facecloth wetted with warm water in a gentle twisting motion back and forth to remove peat residue from the skin.

Therapeutic Modalities

12.Cover the treated area after treatment to maintain warmth for 3 hours. The patient's clothing is fine but a wool blanket would do a better job.

Combination Full Bath and Peat Pack Materials

Partial-Immersion Medicinal Peat Bath

The same materials as described for the two preceding applications.

The indications for and contraindications to this procedure are given in Box 45-3.

Procedure

Materials Deep-well basin-the tall plastic wastebasket size works well for the leg Medicinal peat bath Water thermometer Small towel

Procedure 1. Fill basin to three-quarters fullwith 108"to 114" F water. 2. Add peat to the bath. 3. Have the patient immerse the wrist, ankle, or elbow slowly into the water. Try to immerse the forearm and leg if treating the hand or foot. 4. Keep the body part immersed for 25 minutes. 5. After the treatment, cover the area with a wool sock or clothing, and keep covered for 3 hours after treatment. 6. Often peat material is sent home with the patient to do home treatments. 7.Clean up the basin by washing with antimicrobial soap. Then disinfect with 10% bleach solution, and rinse after 10 minutes.

Indications Arthritis pain Bursitis Carpal tunnel syndrome Eczema Fibromyalgia Fractures Acute gouty toe Chronic gout Hematomas Orthopedic disorders Osteoarthritis

Plantar fascitis Postoperative rehabilitation Psoriasis Rashes Rheumatoid arthritis Skin care Sprains Strains Tendinitis Tenosynovitis Trauma

Contraindications Open wounds Pregnancy

Heat-insensitive area

This treatment is used for many conditions. I particularly like it for treatment of vertebral disc injury or degenerative joint conditions. This procedure is also very good for injuries such as hamstring strain. It focuses the balneologic effects in the area to which the peloid pack is applied. Performing the peat bath first and then applying the peat pack is the ultimate treatment for those who can tolerate the bath. After the patient steps out of the bath, he or she walks to the table and lies face up for the regular traction sequence. After three tractions, it is appropriate to turn the patient face down and apply the peat pack over the spine or area being treated.

CONCLUSION As a physician using balneotherapy for 10 years, I have achieved excellent results in a large percentage of patients who undergo peat therapy. This therapy often helps other therapies to work better. Balneotherapy can be primary or adjunctive. The potential effect on the body should not be taken lightly. I have observed excellent results for the following conditions: Arthritis Tenosynovitis Strains and sprains Discopathy Plantar fascitis Low back pain, including sciatica Scoliosis Fractures Gout Muscle pain Dermatologic conditions such as eczema The combination of medical sophistication in diagnosis and application of various balneologic methods provides an excellent tool for physicians to treat in a natural way to the great benefit of their patients.

Peat Therapeutics and Balneotherapy

1. Sukenik S, Flusser D, Abu-Shakra M. The role of spa therapy in various rheumatic diseases. Rheum Dis Clin North Am 1999;25:883-897. 2. Matz H, Orion E, Wolf R. Balneotherapy in dermatology. Dermatol Ther 2003;16:132-140. 3. Braverman DL, Ericksen JJ, Shah RV, et al. Interventions in chronic pain management. 3. New frontiers in pain management: complementary techniques. Arch Phys Med Rehabil2003;84:1. 4. Dietrich J. Endocrinological changes after peat therapy. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 5. Tishler M, Yaron M, Brostovski Y.Effect of spa therapy in Tiberias on patients with ankylosing spondylitis. Clin Rheumatol 1995;1421-25. 6. Guillemin F, Constant F, Collin JF, Boulange M. Short and long-term effect of spa therapy in chronic low back pain. Br J Rheumatol 1994;3:2. 7. Ponikowska I, Przemyslaw A, Nowobilski KV, Nowobilski R. The clinical principals of balneology and physical medicine. Massage Ther J 2003;Winter:90-103. 8.Storojenko N, Tupikova V, Kibzun V, Tsopikov V. Treatment of patients affected by bums with hydrosulphur mineral water irrigation at health resorts of Sochi (Russia). Presented at 2nd Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1994. 9. Faizullin ZZ. Rehabilitation of patient with chronic persistent hepatitis by means of sulphide-chloride-sodium-bathsat the sanatorium stage. Presented at 2nd Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1994. 10. Sukenik S, Buskila D, Neumann L, et al. Sulphur bath and mud pack treatment for rheumatoid arthritis at the Dead Sea area. BeerSheva, Israel: Ben-Gurion University of the Negev, 1989. 11. Agishi Y, Ohtsuka Y. Recent progress in medical balneology. Hokkaido University Medical Library Series 1995;34. 12. Callies R, Kaiser G. Leukocyte evaluation of RA for efficacy of a peat cure. Physiotherapy 1978;30:19-26. 13.Bellometti S, Cecchettin M, Galzigna L. Mud pack therapy in osteoarthrosis: changes in serum levels of chondrocyte markers. Clin Chim Acta 1997;268101-106. 14. Agishi Y, Ohtsuka Y, Watanabe I, et al. Effects of therapeutic elements on physiological functions in man and balneotherapy recent progress in medical balneology and climatology. Hokkaido University Medical Library Series 1995;34. 15. Korepanov AM, Zhukova MA, Chernysheva NG, et al. [SMC-electrophoresis of peat mud in the treatment of patients with duodenal ulcer in outpatient care unit]. Vopr Kurotol Fizioter Lech Fiz Kult 2003;5:22-25. 16. Konrad K, Tatrai T Hunka A, et al. Controlled trial of balneotherapy in treatment of low back pain. Ann Rheum Dis 1992;51:820-822. 17. Praetzel HG, Aigner UM, Wemert D, et al. Therapeutic effects of sulfur-peat baths on patients with rheumatic muscle pain. Phys Rehab Kur Med 1992;2:92-97. 18.Scheffel KZ, Praetzel HG. Analgesic effects of humic acid bath. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 19. Bender T, Karagulle Z, B a h t P, et al. Hydrotherapy, balneotherapy, and spa treatment in pain management. Rheumatology International Clinical and Experimental Investigations July 15, 2004. Available online at http:~springerlink.metupress.com/mediu/ H82CAPLNZKWW4UP J4P1Contributionsf7/3. 20. Given PH, Spackman W, Imbalzano JR, et al. Physiochemical characteristics and levels of microbial activity in some Florida peat swamps. Int J Coal Geol 1983;3:77-99.

21.Goecke C. Efficacy of peat therapy: health resort medicine. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 22. Elkayam 0, Wigler I, Tishler M, et al. Effect of spa therapy in Tiberias on patients with rheumatoid arthritis and osteoarthritis. J Rheumatol1991;18:1799-1803. 23. Bellometti S, Cecchettin M, Lalli L, Galzigna L. Mud pack treatment increases serum antioxidant defenses in osteoarthrosic patients. Biomed Pharmacother 1996;50:37. 24. Weislaw 0, Turowski G, Tmwski ZM. The influence of balneotherapy on T-cell populations and direct lymphocytotoxicity in patients with vascular disorders of lower limbs. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 25.Praetzel HG, Aigner UM, Weinert D, Limbach B. The analgesic effects of sulfur peat baths for non-articular rheumatic afflictions. Presented at 2nd Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1994. 26. Magyarosy KL, Resch KH, Krause W, et al. Electromyographic research for the efficacy of function of peat packs on musculature of the back. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology),Bad Worishofen, Germany, April 1994. 27. Falch 8. Balneophototherapy for atopic dermatitis new scientific findings in dermatology. Schweiz Z Ganzheits Medizin 2002;146@63. 28. Pizzoferrato A, Garzia I, Cenni E, et al. Beta-endorphin and stress hormones in patients affected by osteoarthritis undergoing thermal mud therapy. h4inerva Med 2000;91:239-245. 29.Praetzel HG. Preface. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 30. Kasianova IM.Hydrotherapy in the treatment of obesity. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Munich: April 1994131-133. 31. Praetzel HG. Forty years of medical balneology and climatology: Director Medical Institute of Balneology and Climatology. Munich: Ludwig Maxmillions University, 1990. 32. Gyarmati. Heviz Hungary heilbad (curebath). Presented at Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1990. 33.Dafinova I, Boncheva DV. The effect of mud applications and helium-neon laser irradiation on osteoarthrosis patients with changes in knee joints. In Health resort medicine: 32nd World Congress of the International Society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 34. Grigor’eva VD, Mamiliaeva DR. The use of low-temperature peloids in treating patients with rheumatoid arthritis (I). Vopr Kurortol Fizioter Lech Fiz Kult 1994;Sept/Oct:17-21. 35. Grigor’eva VD, Mamiliaeva DR. The use of low-temperature peloids in treating patients with rheumatoid arthritis (11). Vopr Kurortol Fizioter Lech Fiz Kult 1995;Jan/Feb:20-23. 36. Praetzel HG, Schnizer W. Handbook of medical bath. Heidelberg, Karl F Haug, 1992. 37. Schmidt KL. Sulfur water. In Compendium of balneology and cure medicine. Darmstadt: Steinkopff, 1989. 38. Solovieva VP, Sotnikova EP, Naumova GV, Kosobokova RV. Biologicallyactive peat preparations and their possible applications in medicine. In International Peat Society: Proceedings of the 6th International Peat Congress, Duluth, Minnesota, Aug 17-23, 1980.

39. Artmann C, Pratzel HG. Influence on the immune system by sulfur water bath. Presented at Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1990. 40.Cutolo M, Seriolo B, Craviotto C, et al. Circadian rhythms in RA. Ann Rheum Dis 2003;62:593-596. 41.Pollmann L, Hildebrandt G. Temperature changes of the oral mucosa induced by footbaths: preventive effect against common cold infections.Marburg, Germany, Institute fur Arbeitsphysiologie und Rehabilitationsforschung der Universitat Marburg, 1993. 42. Gauthier A, Davenne D, Martin A, et al. lime of day effects on isometric and isokinetic torque developed during elbow flexion in humans. Eur J Appl Physiol2001;84:249-252. 43. When taking medications, timing is everything. Tufts University Health and Nutrition Letter 2003;21:2. 44.Peter A, Flach R. Changes in immunoglobulin G and acute phase proteins in bath cures. Physiotherapy 1974;26357-364. 45. Agishi Y, Ohtsuka Y. Chronobiological aspects of cure treatment. In New frontiers in health resort medicine, No. 059-04. Hokkaido, Japan: Noboribetsu Branch Hospital, Hokkaido University School of Medicine, 1996. 46.Bellometti S, Galzigna L. Function of the hypothalamic adrenal axis in patients with fibromyalgia syndrome undergoing mud-pack treatment. Int J Clin Pharm Res 1999;24:27-33. 47. Hamilos DL, Nutter D, Gershtenson J, et al. Circadian rhythm of core body temperain subjects with chronic fatigue syndrome. Clin Physiol2001;21:184-195. 48. Ekmekcioglu C, Strauss-Blasche G, Feyertag J, et al. The effect of balneotherapy on ambulatory blood pressure. Altem Ther Health Med 2000;6:46. 49. Joone GK, Dekker J, Jansen van Rensburg CE. Investigation of the immunostimulatory properties of oxihumate. Z Naturforsch [C] 2003;58:263-267. 50. Beer AM, Luttig G, Lukanov J. Moortherapie 2000: Vortrage des Internationalen Moortherapie-Symposions, Bad Kissingen, Oktober 1999. 51. Beer M. Indications for gynecological balneotherapy. In Health resort medicine: 32nd World Congress of the International society of Medical Hydrology (and Climatology), Bad Worishofen, Germany, April 1994. 52.Kuhn G, Rohwer J, Buhring M. Balneotherapy for progressive systemic sclerosis Presented at 2nd Symposium, Sulfur in Health Resort Medicine, Bad Nenndorf, Germany, May 1994. 53. Sukenik S, Neumann L, Buskila D, et al. Dead Sea bath salts for the treatment of rheumatoid arthritis. Clin Exp Rheumatol 1990;8 353-357. 54. Kotwica S, Split W, et al. Spa treatment of sciatic pains at Swieradow. Neurol Neurochir Pol 1976;10715-722. 55. Levitskii EF, Abdoulkina NG, Zaitsev AA, et al. The optimization of the duration of the sanitarium-health resort treatment of patients with neurological manifestations of spinal osteochondrosis (I). Vopr Kurortol Fizioter Lech Fiz Kult 1996;Sep/Oct:26-28. 56. Siderov W,Mamiliaeva DR. The current aspects of pelotherapy of patientswith rheumatoid arthritis.ArthritisRheum 199437 1132-1137. 57. Konrad K, Tatrai T, Hunka A, et al. Controlled trial of balneotherapy in treatment of low back pain. Now and Then Nov 1991. 58.Bellometti S, Galzigna L. Serum levels of a prostaglandin and leukotriene after thermal mud pack therapy. J Invest Med 1998; 46:140-145. 59.Beer AM, Grozeva A, Sagorchev P, Lukanov J. Comparative study of the thermal properties of mud and peat solutions applied in clinical practice. Biomed Tech (Berl) 2003;48:301-305.

60.Praetzel HG. Balneologically activated skin functions and their clinical evidence. J Jpn Assoc Phys Med Balneol Climatol1993;5711-13. 61. A l l Beer A, Junginger HE, Lukanov J, et al. Evaluation of the permeation of peat substances through human skin in vitro. Int J Pharm 2003;253169-175. 62. Beer AM, Sagorchev P, Lukanov J. Isolation of biologically active fractions from the water soluble components of fulvic and ulmic acids from peat. Phytomedicine 2002;9:659-666. 63.Kubota K, Kurabayashi H, Tamura K, et al. A transient rise in plasma &endorphin after a traditional 47°C hot-spring bath in Kusatsu-Spa, Japan. Life Sci 1992;51:1877-1880. 64.Tolomio C, Ceschi-Berrini C, Moschin E, Galzigna L. Colonization by diatoms and antirheumatic activity of thermal mud. Cell Biochem Funct 1999;17:29-33. 65. Maglara AA, Vasilaki A, Jackson MJ, McArdle A. Damage to developing mouse skeletal muscle myotubes in culture: protective effect of heat shock proteins. J Physiol2003;253:837-846. 66. Zellner M, Hergovics N, Roth E, et al. Human monocyte stimulation by experimental whole body hyperthermia. Wien Klin Wochenschr 2002;114:102-107. 67. Rhind SG,Gannon GA, Shek PN, et al. Contribution of exertional hyperthermia to sympathoadrenal-mediated lymphocyte subset redistribution. J Appl Physiol 1999;87:1178-1185. 68.Atanackovic D, Pollock K, Corovic A, et al. Effects of 41.8"C whole body hyperthermia (WBH) on T cell homing molecules in patients with advanced malignancies (abstract 3475). Proc Am SOCClin Oncol2003;22:864. 69. Carroll NM, Elaraj DM, Puhlmann M, et al. Alterations in tumor necrosis factor-induced endothelial cell procoagulant activity by hyperthermia. Int J Cancer 2004;111:457-462. 70. Haveman J, Van Der Zee J, Wondergem J, et al. Effects of hyperthermia on the peripheral nervous system: a review. Int J Hyperthennia Jun 2004;20:371-391. 71. Olivera AP, Schirmer MH, Olivera VM. Treatment of hematomas with peat used in balneotherapy. J Med Esthetics 1997;31-3. 72. Peter A. CR Proteins of rheumatic afflictions. Physiotherapy 1987;39: 331-335. 73. Ohtsuka Y, Yabunaka N, Watanabe I, et al. Platelet antioxidative defense system is modified by balneotherapy and bathing temperature. In:New frontiers in health resort medicine, No. 059-04. Hokkaido, Japan: Noboribetsu Branch Hospital, Hokkaido University School of Medicine, 1996. 74. Bellometti S, Poletto M, Gregotti C, et al. Mud bath therapy influences nitric oxide, myeloperoxidase and glutathione peroxidase serum levels in arthritic patients. Int J Clin Pharmacol Res 2000;20:69-80. 75. Yoshhiro U, Yoshiharu Y, Caldwell WM, Hahn AW. A microcomputer-based data acquisition system for ECG, body and ambient temperatures measurement during bathing. International ISA Biomedical Sciences Instrumentation Symposium 36,2000373-eoa. 76. Ortyl W, Turowski G, Zubel M. The influence of balneotherapy on T-cell populations and direct lymphocytotoxicity in patient with vascular disorders of lower limbs. Mater Med Pol 1991;3:79. 77.Poensin D, Carpenter PH, Fechoz C, Gasparini S. Effects of mud pack treatment on skin microcirculation. Joint Bone Spine 2003; 70:367-370. 78. Basili S, Martini F, Ferroni P, et al. Effects of mud-pack treatment on plasma cytokine and soluble adhesion molecule levels in healthy volunteers. C l i Chim Acta 2001;314:209-214.

Preventive Genomics, Nutrigenomics, and the Promise of Personalized Medicine T. Michael Culp, MA, ND Patrick Hanaway, MD CHAPTER CONTENTS Introduction 487

The Clinical Application of Nutrigenomics-the Example of Cardiovascular Disease 491 Electrolytes and Hypertension 493 Homocysteine and Micronutrients 493 Summary 494

Genes and Environment-Nature and Nurture 488 The Clinical Utility of Genomics

489

From Early Detection to Preventive Genomic Testing 489 Why Do Polymorphisms Exist?

490

Nutritional Genomics (Nutrigenomics) 490

INTRODUCTION Medicine is the practice of restoring sick individuals to health. Since the days of Hippocrates, medical practice has struggled to achieve two elusive ideals. The first is to treat sick individuals truly as individuals, with the understanding that the patient at hand is unique in potential, experience, environmental influences, and disease processes and, as such, forms a n integrated being who can genuinely be understood only as a unique whole, a gestalt. The second ideal of medicine strives for its own annihilation: It is always better to prevent disease than to cure it. The reality of medical practice, however, often falls short of its ideals. All too often medical practice adopts assembly line tactics whereby ”one size fits all,” and prevention is largely confined to pronouncements based on epidemiologic studies about what appears to be healthy for the population as a whole, with little information available to assist the individual in his or her particular struggle to attain optimal health. In truth, although medicine has long had the desire for personalization and prevention, it has not had the tools to make these values a reality. The genomic revolution is beginning to offer practitioners and patients new and exciting tools that may extend the promise of personalized medicine as well as personalized prevention to every individual.

Clinical Challenges for Preventive and Nutritional Genomic Testing 494 Bioethical Considerations: Opportunities and Potential for Discrimination 494 Summary

495

Until recently, the use of genetic information in medicine was limited to identifying single-gene disorders with high penetrance, often called Mendelian disorders, f i e cystic fibrosis, Tay-Sachsdisease, Huntington’s disease, hemophilia, and sickle cell anemia, or to screen for metabolic disorders in newborns, like phenylketonuria. With the mapping of the human genome, our paradigm for understanding medical genetics is shifting away from the idea of single-gene defects causing specific diseases and toward the concept that genetic variability plays a significant role in the pathophysiology of nearly all diseases.’ Indeed, genomics as an emerging field of study is based on the premise that health and disease depend on the totality of all our genes as a dynamic system, influencing and being influenced by our biochemistry, our physiology, and our environment. Within the human genome are literally millions of subtle variations of the genetic code, known as polymorp h i s m ~(literally, ”many shapes”). It is these polymorphisms that are largely responsible for our biochemical individuality. In other words, our polymorphisms make us unique individuals. There are many types of polymorphisms, but by far the most common is singlenucleotide polymorphisms (SNPs, pronounced “snips”), in which a single nucleotide of the DNA is altered and may in turn alter the amino acid sequence coded for by 487

Therapeutic Modalities

that section of the DNA or may affect transcription in some other way, or, what is most often the case, may have no specific physiologic effect at all. Still, the sum total of all of an individual’s polymorphisms significantly affects physiologic function, rendering that individual biologically unique. The Centers for DiseaseControl and Prevention (CDC)* published a Gene-Environment Interaction Fact Sheet in August 2000 that outlines the basic principles of a broad understanding of the causal interaction of genes and environment in human disease. In it the CDC makes the following four main points: 1. Virtually all human diseases result from the interaction of genetic susceptibility and modifiable environmental factors. 2. Variations in genetic makeup are associated with almost all disease. 3. Genetic variations do not cause disease but rather influence a person’s susceptibility to environmental factors. 4. Genetic information can be used to target interventions.

In this brief paper, the CDC has essentially outlined the chief tenets of preventive genomics (or predictive genomics) as a new field of medical inquiry and practice. These ideas are not exactly new. Indeed, in 1909, Archibald Garrod3published lnborn Errors of Metabolism, in which, after idenhfymg the first human disease that behaved as a Mendelian recessive trait (alkaptonuria), he went further to make the sweeping hypothesis that altered heredity was in fact ”the seat of chemical individuality.” ”Inborn errors of metabolism,” he wrote, “are due to a failure of a step in the metabolic sequence due to loss or malfunction of an enzyme.” By examining the subtle end products of metabolism, he continued, we should be able to identify the differences that altered heredity produces in each individual. This is a remarkable insight, given that the words gene and genetic did not exist in 1909, and it would be roughly 50 years before the structure and true function of DNA were confirmed. Garrod’s book was published 3 years before the first vitamin was discovered. He concludes his nearly prophetic work by envisioning the complex interaction between our unique genetic constitution and environmental factors in the simple statement “These idiosyncrasies may be summed up in the proverbial saying that one man’s meat is another man’s poison.”3 It is only by virtue of understanding these idiosyncrasies, or polymorphisms, that medicine can advance to the point at which it may be able to treat patients as unique, whole, and particular individuals. This is the promise and the potential of preventive genomics. In this chapter, we discuss the current state of preventive

genomics in terms of both theoretical understanding and clinical practice. As a concrete clinical example, we focus on cardiovascular disease and the gene-environment interactions that affect its prevention, treatment, and clinical outcomes.

GENES AND ENVIRONMENT-NATURE AND NURTURE Environrnent is broadly understood in genomics to involve everything that is not the genome, including physical agents, exogenous chemicals, and infectious agents and also diet, lifestyle, and behavioral factors. The complex interactions between genes and environment are only beginning to be fully understood. Scientists once believed that genes were immutable archives of information digitally coding for proteins, but it is now clear that gene expression is substantially affected by and sensitive to environmental changes. Genes literally respond to the environment, and by extension, it is possible to alter gene expression by proactively modlfylng our environment, broadly under~tood.~ Herein lies the rationale for individual prevention and treatment strategies: The expression of our genes is modified by the environment we subject them to. The cures for complex diseases and syndromes are not to be found exclusively in nature or in nurture but in the interactive symphony between the two. Nature (our genes) provides a plastic template that is largely adaptable to a wide range of environments (“survival of the most adaptable”). By contrast, nurture (our environment) switches genes on and off, largely controlling genetic expression (the molecular process by which adaptation occurs). When this concept is seen in light of polymorphic differences between individuals, the environment we choose can multiply the physiologic effects of our subtle genetic differences. To illustrate this idea of gene-environment interaction, we consider the research of Caspi et a1.5 They studied variations in the promoter sequence for the gene coding for monoamine oxidase-A (MAO-A) and found that a promoter polymorphism caused some people to have high-activity MAO-A genes and others to have lowactivity genes. They then examined whether these genes played a role in antisocial and violent behavior in men who had been abused as children. Remarkably, they found that men with the high-activity MAO-A gene were virtually immune to the effects of maltreatment as children, seldom if ever becoming violent offenders, whereas men with the low-activity MAO-A gene were much more antisocial and violent, but only if they were themselves abused as chldren. In other words, for violent behavior to manifest in adulthood, both the low-activity gene (nature) and childhood maltreatment

Preventive Genomics, Nutrigenomics, and the Promise of Personalized Medicine

(nurture) needed to be present. If either was missing from the equation, the adult was very likely to be well socialized and nonviolent.

THE CLINICAL UTILITY OF GENOMICS The ability of environmental changes to affect gene expression is the cornerstone for developing a strategy of clinical intervention through understanding and manipulating the molecular pathophysiology of complex diseases. Preventive genomics is that branch of medicine that identifies polymorphisms in the individual in order to predict the likelihood of development of a particular disease or functional imbalance in that individual when he or she is exposed to a particular "environment." From this understanding we are able not only to give an increasingly precise estimate of disease risk but also, in susceptible individuals, to develop comprehensive preventive strategies and, in already affected individuals, to determine a more optimal treatment regimen. Unfortunately for this process, there are literally millions of polymorphisms in the human genome, most of which have little or no effect on physiology, health, or disease. In order for preventive genomics to be clinically useful, polymorphisms must meet four criteria. Clinically useful polymorphisms must be relevant, prevalent, modifiable, and measurable. First, the only polymorphisms in the genome of medical interest are those that exert a significant effect on specific aspects of our biochemistry and physiology (relevant). Second, given our current knowledge of the human genome, only polymorphisms that exist in a substantial portion of a population are likely to be able to be demonstrated in epidemiologic and case-controlled studies to be clinically relevant-in essence, we compare polymorphisms that occur in substantial numbers in both groups (prevalent). Third, only polymorphisms whose genetic expression is modz@bZe via reasonable clinical intervention are clinically useful. Such an intervention may be any modification of environment, including diet, lifestyle, and targeted nutriceuticals or pharmaceuticals. Although genes themselves are not modifiable, the phenotype they generate is modifiable via these environmental changes. Finally, because our genes do not themselves change, we must be able to measure changes in our functional physiology in order to determine that the environmental changes have in fact been effective in modifymg the phenotypic expression of our unique genes. For this purpose, functional laboratory testing must be available: The effects of our therapeutic interventions must be measurable. To illustrate this model of clinical utility, let us consider the example of the antioxidant protection afforded by the hepatic enzyme glutathione-Stransferase (GSTM1).

High levels of oxidative stress are associated with numerous degenerative diseases and with the aging process itself. So an enzyme like GSTMl that protects against such oxidative damage is clearly relevant. Indeed, the GSTMl null genotype has been associated with numerous cancers in epidemiologic and casecontrol studies.6 Although there a several isoforms of GST, the p isoform (GSTM1) is the most common in the liver. Up to 50%of the population does not have the gene for GSTM1, so the mutation is highly prevalent. Because other forms of GST and other antioxidant pathways exist, it is possible to improve antioxidant protection by maintaining a high reduction potential through exogenous avenues, including supplemental dietary antioxidants. Thus the increased oxidative stress is modifiable. Finally, we can validate the clinical efficacy of our intervention strategy by measuring functional levels of oxidative stress through any number of simple laboratory tests, such as urinary lipid peroxide and serum glutathione measurements.

FROM EARLY DETECTION TO PREVENTIVE GENOMIC TESTING A susceptibility gene is one that may render us more susceptible to development of a chronic disease when we are exposed to an adverse environment. Most susceptibility genes have a low positive predictive value (the probability that a disease will develop in a person with a positive test result) and a low attributable risk (the proportion of cases of a disease that can be attributed to a susceptibility gene).7 Therefore, some researchers have questioned the clinical utility of susceptibility genetic testing? but such arguments, by applying a single-gene/single-disease model to susceptibility genes, miss the potential clinical relevance. Susceptibilitygenes, much like taking a family history, must be seen as important but incomplete contributors in what is invariably a multifactorial risk assessment. In terms of health outcomes, preventive genomic polymorphisms raise disease risk modestly and are additive in their effects (genegene interactions), and their actual phenotypic expression is strongly affected by diet, lifestyle, and environment (gene-environment interactions). Rather than negate their clinical utility because of a low positive predictive value and a low attributable risk, these polymorphisms begin to offer a molecular basis for understanding the pathophysiology of complex multifactorial diseases; an understanding of the environmental factors that affect gene expression begins to evoke effective preventive therapeutic strategies. Because environment is broadly understood to refer to anything outside the genome itself, therapeutic regimens may be constructed to include any portion of the

Therapeutic Modalities environment that has been shown to affect gene expression and phenotype. This is tmly a holistic approach because effective therapeutic strategies may involve diet, nutritional, and targeted pharmaceutical supplementation, lifestyle and behavioral modification, and avoidance or elimination of toxins, xenobiotics, and microbes. Intervention at any level of our "environment" may prove clinically beneficial. Functional medicine is the clinical discipline designed to promote health, to anticipate and prevent disease, or to correct an existing disease by improving physiologic function. The underlying assumption is that health and disease lie on the same continuum and the connecting thread of the continuum is physiologic function. Prior to the manifestation of any frank disease, a progressive loss of homeostasis and increasing dysfunction occur. Clinical intervention in this strategy may begin at the earliest signs of imbalan~e.~ The promise of preventive genomics is that the point of effective intervention may begin even earlier, before the beginnings of physiologic dysfunction.

WHY DO POLYMORPHISMS EXIST? The theory of natural selection has two central tenets, as follows (1) all organisms compete for limited resources and (2) organisms with some advantage in acquiring those resources are more likely to survive, to thrive, and to pass on that advantage to their offspring. Polymorphic variations are the ultimate source of these advantages. Indeed, all polymorphisms that are prevalent in a species likely afford some adaptive advantage in some particular environment. Genetic polymorphisms have been preserved in populations when they endow a better chance of survival or of reproduction. The cumulative weight of slight genetic variations over time is the means by which variability within a species arises and by which new species also emerge. However, what may be good for a species and its evolution may not be good for a specific individual, because the environmental pressures exerted on a species over millions of years may be very different from the environment encountered in the present. In individuals, altered polymorphic genes (the legacy of evolution) produce altered proteins, and altered proteins exhibit altered functions. For the individual, altered protein function may be beneficial, neutral, or harmful. More precisely, given the pressures of natural selection, polymorphisms and the proteins they code for are likely to be beneficial in some environments but harmful in others. Because we cannot change our genes, the goal of preventive genomics is to alter an individual's environment in order to maximize his or her genetic potential. Genes cannot be modified, but gene expression can be. One of the common misconceptions of polymorphisms

is that they reveal only limitations, but in reality, they reveal an individual's potential.

NUTRITIONAL GENOMICS JNUTRIGENOMICS) The links between diet and health and between poor diet and chronic disease were well established over the previous century, but the advent of genomic testing has generated renewed interest in the molecular links between genes and diet and how those links affect both health and disease. Using our molecular understanding of the effects of polymorphisms on nutritional biochemistry, nutritional genomics (or nutrigenomics) promises to promote a new understanding of optimal nutrition for individuals, including macronutrient balance as well as unique vitamin and mineral requirements based on their genotypes.'O Nutrigenomics promises to be clinically applicable both reactively, in the treatment of physiologic dysfunction and disease, and proactively, in the promotion of optimal health. Both macronutrients and micronutrients function as dietary signals that influence gene and protein expression and hence alter the metabolic activity and homeostatic balance of cells." With high-throughput genomic tools that can measure subtle alterations in messenger RNA and cellular protein production, nutritional researchers are able to elucidate the molecular actions of specific nutrients, including the variations in effects of nutrients in the presence of various genetic polymorphisms.'* The ultimate goal of such investigations would be the ability to personalize dietary, nutrient, and supplement recommendations. However, the thorough investigation of the genetic and metabolic effects of hundreds of foods and nutrients on people of varying genotypes will take years or decades to complete. Currently, most of the clinically relevant nutrigenomic information available relates to the relationship between polymorphisms with increased chronic disease risk and the dietary therapies and supplements that have been demonstrated to treat the physiologic imbalance effectively. This is particularly true of SNPs; in as many as one third of gene mutations, the corresponding enzyme has a decreased binding affinity for a vitamin or mineral coenzyme, resulting in a lower rate of reaction and altered enzyme function. In a review article, Ames et all3provide evidence of more than 50 human diseases involving defective enzymes that can be remedied or ameliorated by the administration of high doses of vitamins, which at least partially restore enzymatic activity. Thus the clinical validity of high-dose nutrient therapy is established, but only in genetically susceptible individuals. From the novel perspective of nutrigenomics, nutrients may be viewed as dietary signals that are detected by the cellular sensor systems that influence gene and protein

Preventive Genomics, Nutrigenomics, and the Promise of Personalized Medicine

expression and, consequently, metabolite production and cellular Such alterations may affect any functional biochemical pathway, including cell-cell signaling, oxidative stress, inflammation, hormone response, nutrient absorption, energy homeostasis, and waste product detoxification and excretion. Theoretically,this approach allows two complementary strategies for molecular nutrigenomics research and eventually for clinical intervention. First, the nutrients that affect specific gene expression must be identified, along with the alterations in gene-nutrient interactions caused by the presence of specific polymorphisms. Second, by using high-throughput computer chip assays, researchers may be able to idenhfy protein and metabolite “signatures” associated with nutrient changes. Monitoring these molecular signatures may provide ”early warnings” of nutrient-induced changes to homeostasis, effectively screening for impending disease. Although a complete review of all known nutrient interventions to correct for the metabolic imbalances associated with polymorphisms is well beyond the scope of this chapter, we propose to illustrate the potential effect of genomic testing on the nutritional amelioration of physiologic imbalances, morbidity, and mortality associated with cardiovascular disease.

THE CLINICAL APPLICATION OF NUTRIGENOMICS-THE EXAMPLE OF CARDIOVASCULAR DISEASE Cardiovascular disease accounts for approximately 40% of all deaths in most industrialized countries and is also responsible for signhcant morbidity and diminished quality of life. Furthermore, using data from more than 84,000 women who were monitored for 14 years, epidemiology researchers at Harvard University estimated that about 83% of cardiovascular disease could be prevented if everyone ate a reasonably healthy diet, exercised daily, did not smoke, maintained a normal weight, and drank 1 to 2 alcoholic beverages per day.14 Even though these five diet and lifestyle changes seem simple, only about 3% of the women in the study actually performed them. Not only is compliance an issue, but epidemiologic studies raise deeper philosophical questions, because such studies assume that all participants are essentially similar to one another. Are the same therapies equally effective for all individuals? Do all individuals need the same quantities of these diet and lifestyle modifications? Can preventive genomic testing help us individualize our therapeutic protocols? Let us begin by asking what proportions of carbohydrate, protein, and fat in the diet are the most effective in maintaining normal serum cholesterol levels? Is it a low-fat, low-cholesterol diet as touted by Nathan Pritikin and Dean Ornish? Or perhaps a 40-30-30

(40% carbohydrate, 30% protein, 30% fat), low-calorie ”Zone” diet as proposed by Barry Sears? Or a low-carbohydrate, high-protein, high-fat diet such as that made popular by Robert Atkins? Logically they cannot all be the best diet for everyone, yet some people swear by each of them as THE answer for optimal diet. There is mounting evidence that optimal macronutrient proportions in the diet may be a function of certain polymorphisms. Apolipoprotein E (APOE)is a molecule that mediates the interaction of chylomicron remnants and intermediate-density lipoprotein particles with lipoprotein receptors, including the low-density lipoprotein (LDL) receptor and the chylomicron remnant or APOE receptor. There are three variations of the APOE gene, known as APO ~ 2 ~ , 3 and , ~ 4 and , these polymorphic variants are important genetic modifiers of serum lipid responses and consequently may significantly affect an individual’s risk for development of coronary artery disease. The ~ 3 / &genotype is the most common in all populations and serves as the benchmark genotype for comparison with any other possible genotype. The ~4 allele is associated with a moderately increased risk of atherosclerosis and coronary artery disease (odds ra ti0 [OR] = 1.53 for men and 1.99 for women in one study).15 The ~2 allele is associated with lower LDL cholesterol levels. LDL cholesterol levels declined with each A P O E ~ allele by 8.8 mg/dL in Hispanics, by 25.6 in nonHispanic white persons, and by 18.1 mg/dL in AfricanAmericans.l6 Given that each person inherits two alleles, there are six possible genotypes: ~ 2 / ~~22, / ~~33, / ~&2/&4, 3 , &3/~4, and &4/~4. In patients with elevated serum total and LDL cholesterol, the cholesterol-lowering response to a low-fat, low-cholesterol diet increased as the sum of the allele numbers increased (in other words, response improved in the order that the genotypes are listed in the first sentence in this paragraph).”J8 Conversely, individuals carrying an ~4 allele who ate a high-fat diet were much more likely to have elevated serum ch~lesterol.’~ By contrast, serum triglyceride levels were found to be significantly higher in men who carried an ~2 allele. ~ 3 / individuals ~ 3 were found to have the lowest triglyceride levels, and ~4carriers to have intermediate 1e~els.l~ In another multiethnic study, plasma triglyceride levels were inversely correlated with the number of A P O E ~ alleles (175,159, and 143 mg/dL with 0, 1, and 2 alleles, respectively).16Still another study found ~4 carriers to have elevations in triglycerides, but only those who consumed alcohol regularlyz0A study of Turkish men who did not consume alcohol found no elevated triglyceride values in ~4carriers2*The most effective dietary therapy to lower triglycerides is restricting carbohydrate, especially sugar, consumption. Because A P O E ~men are prone to significant triglyceride elevations and their cholesterol levels are less sensitive to dietary fat intake,

Therapeutic Modalities a lower-carbohydrate, higher-protein, higher-fat diet may be therapeutically desirable for them. Individuals with the &/& genotype are moderately affected by dietary fat intake but tend to have lower triglyceride levels than the other genotypes. In one study, individuals with high cholesterol and triglyceride values were treated with a short-term (7-day) very-low-calorie juice fast ( ~ 2 0 8calories/day), and their responses were stratified by APOE genotype.= Only E3/& individuals experienced significant improvement in all parameters, experiencing reductions in LDL cholesterol by =lo% and in triglyceride values by ~ 1 8 %In. these individuals, it is tempting to speculate, the low-calorie, moderate 40-30-30 carbohydrate-pmtein-fat ratio diet (”TheZone” diet) might be more effective in treating both hypercholesterolemia and hypertriglyceridemia, although no clinical trials to validate this hypothesis have yet been published. Also in this trial, E2 carriers experienced a -31% drop in LDL levels but a ~ 1 5 %increase in triglyceride levels, lending some additional support for the carbohydrate-sensitive triglyceride hypothesis. ~4 carriers had an opposite response, consisting of a reduction of triglyceride levels by 4 9 % but a rise in LDL levels by ~ 1 3 % . Other dietary interventions that affected cholesterol levels were fiber and alcohol. High intake of soluble fiber (>5.7 g/MJ) reduced LDL cholesterol by 6.6% and 5.6%, respectively in ~3 and ~4 allele carriers but had little effect on 122carriers.” Similarly, a study of Korean patients with coronary artery disease found that replacing white rice with whole grains produced the greatest benefit in E 3 / ~ 3individuals (12% reduction in triglyceride, 8% reduction in LDL cholesterol, and 8% increase in high-density lipoprotein [HDL] cholesterol levels), moderate benefit in ~4 carriers (including a 15% increase in HDL cholesterol values), and no effect in ~2 carriers.24 Thus, a high-fiber diet may be clinically most useful for E 3 / ~ 3individuals, modestly useful for 124carriers, but not particularly useful for ~2carriers. The modest consumption (1-2 drinks) of alcohol daily has been shown epidemiologically to be very protective against coronary artery disease in the general population. However, APOE genotyping reveals that the benefits are not the same for everyone. In a comparison of nondrinkers with drinkers of alcohol, women who were drinkers had lower cholesterol (total and LDL) than nondrinkers, regardless of APOE genotype. In men, however, A P O E carriers ~ who were drinkers had lower cholesterol but APO ~4 carriers had higher cholesterol, and alcohol consumption had no significant effect for APOE3/E3 individuakE It is worth noting that moderate exercise, although not dietary therapy, was found to be effective in improving serum lipids in ~2 and ~3 genotypes but not in ~4 carriers.26In another study, however, high-intensity

physical exercise was most effective in ~4 carriers?’ Thus, ~2 and ~3 carriers may benefit from modest daily exercise, but for an individual with an 124 allele to benefit from exercise, it must be high-intensity. Similarly, knowledge of APOE genotype may allow for a more discriminating and more effective use of targeted pharmaceuticals for patients with lipid abnormalities. Statin drugs exhibited a greater cholesterol-lowering effect in A P O E ~carriers, followed by APOE3/&3,with less effectiveness for AP0124carriers. A P O Ecarriers ~ also showed better response to gemfibrozil and cholestyramine than the other genotypes. The greatest cholesterol~ came from probucol, lowering effects for A P O Ecarriers a potent antioxidant.26However, even though statins had a weaker cholesterol-lowering effect in A P O Ecarri~ ers, statins were most protective in preventing a second heart attack in men with an ~4 allele. Statin use reduced the risk of a second heart attack in ~4 carriers by 64%, compared with only 33%for other genotypes.28 To be sure, more prospective clinical trials are needed to fully elucidate the optimal therapeutic dietary interventions to protect against coronary artery disease in individuals based on their APOE genotype status. However, distinct patterns are beginning to emerge in terms of dietary and lifestyle management for the prevention and treatment of coronary artery disease; they are summarized in Table 46-1. Apolipoprotein E polymorphisms are the best studied in terms of their association with atherosclerosis and coronary artery disease, but other polymorphisms exert similar effects. Cholesteryl ester transfer protein (CETP) is responsible for the transfer of insoluble cholesteryl esters from HDL to other lipoprotein^.^^ The TaqlB polymorphisms of the CETP gene result in increased CETP levels, with impaired ability to remove cholesterol from the cells and the blood stream. The TaqlB polymorphism is associated with lower HDL cholesterol levels and with an increased risk of development of atherosclerosis and coronary artery disea~e.3~,~* In one study, individuals who were homozygous for the TaqlB polymorphism had larger reductions in LDL and VLDL levels through eating a low-fat diet with a high ratio of polyunsaturated to saturated dietary fat.32Furthermore, daily moderate alcohol consumption raised HDL levels substantially, but only in individuals with the CETP p ~ l y r n o r p h i s r n . ~ ~ , ~ E-selectin (SELE) is a glycoprotein molecule that modulates the adhesion of circulating neutrophils to the endothelial lining of blood vessels. E-selectin is expressed on the surface of endothelial cells after stimulation by dammatory mediators (mediated by nuclear factorkappaB [NFKB]). Several polymorphisms in the SELE gene increase adhesion activity of E-selectin, dramatically increasing the risk of atherosclerosisand premature coronary artery d i ~ e a s e . ~ ~ , ~ ~

Preventive Genornics, Nutrigenornics, and the Promise of Personalized Medicine

Genotype* TheraDv

~2Jdor E2/~3

€31~3

€41~3or €41~4

Diet

Lower-carbohydrate

Low-calorie, moderate-fat Soluble fiber

Low-fat, no-cholesterol Soluble fiber

Alcohol intake

Daily (women and men)

Daily (women) (little effect for men)

Daily (women) None (men)

Exercise

Moderate

Moderate

High-intensity

Pharmaceutical/nutriceutical

Bile sequestrants Statins

Statins

Probucol Statins

*The EUE~ genotype is extremely rare and therefore lacks statistical power in both association studies and prospective trials.

The primary therapeutic aim for carriers of an SELE polymorphism is to decrease NFKBstimulation, in turn reducing SELE expression. Maintaining high antioxidant potential has been shown to decrease NFkB activation.37,38 Thus higher levels of dietary antioxidants and possibly supplemental antioxidants may be beneficial. The proinflammatory cytokines tumor necrosis factoralpha (TNF-a) and interleukin-1 (IL-1) also increase and milk thistle NFKBactivation. Antioxidants, fish (silymarin) supplementation have each been shown to suppress IL-1 and TNF-a production directly and would therefore lower NFKBactivation.

Electrolytes and Hypertension Hypertension is an independent risk factor for coronary artery disease and for stroke. Therapeutic response to sodium restriction in hypertensive individuals is highly variable. A SNP in the angiotensinogen gene (AGT) allows an amino acid substitution in which threonine (T) replaces methionine (M) at amino acid 235. The T allele is associated with increased production of angiotensin, with a tendency for higher blood pressure. There is a stepwise increase of serum AGT from MM to MT to TT genotypes among pesons with hypertension40and those with normal blood pressure.4l Although there have been some discrepancies between studies, a metaanalysis of all studies published between 1992 and 1996 showed the 235T allele to have consistent, mild associations with hypertension (OR = 1.20), a positive family history of hypertension (OR = 1.42),and more severe hypertension (OR = 1.34).42 The 235T allele of the angiotensinogen gene is associated with greater blood pressure decreases than the 235M allele after an intervention to reduce sodium intake (’and retinal vascular occlusion (Box 55-1).% formation. However, as homocysteine levels increase, this It has been known for more than 25 years that inborn protective mechanism can become overloaded, allowing errors of homocysteine metabolism result in high levels damage to endothelial cells to Because of the of homocysteine in the blood and severe atherosclerotic role of sulfate compounds in the formation of amino disease. It is now known that, even within the range sugars needed to form the basement membrane of blood considered normal (4 to 16 pnol/L), there is a graded vessels, high levels of homocysteine are likely to conincrease in risk for CAD. In a study of 304 patients with tribute to the formation of blood vessels that are more CAD versus controls, the odds ratio for CAD increased susceptible to oxidative s t r e s ~The . ~ end result of the as plasma homocysteine increased, even within the combination of oxidative damage and endothelid collagen normal range. A 5 pmol/L increase in plasma homocysinstability can be the formation of atheroscleroticplaques. teine was correlated with an increase in the odds ratio of Decreased plasma folate levels are correlated with increased levels of homocysteine, as well as a subsequent 2.4 (p < 0.001), with no ”threshold effect.1148 increased incidence of CAD. In a 15-year Canadian study A review of numerous studies found that mild hyperof CAD mortality in 5056 men and women age 35 to homocysteinemia after a methionine load test o c a m in 21%,24%, and 32%of patients with CAD, cerebrovascular 79 years, lower serum folate levels were correlated with a disease, and peripheral vascular disease, respectively.43 sigruficantly increased risk of fatal CAD.65In a cohort from the Framingham Heart Study, concentrations of Another group of researchers found the incidence of hyperhomocysteinemia (>14 pnol/L by their definition) folate and P5P were inversely correlated with homocysin a group of 1160 elderly (ages 67 to 96) individuals in teine levels and the risk of extracranial carotid-artery stenosisMLow P5P and low vitamin BI2 have also been the Framingham Heart Study, to be 29.3%. The study also indicated that plasma homocysteine levels increase linked with hyperhomocysteinemia and a sigruficantly increased risk of CAD.48Anotherstudy of 160 cardiac with age.54 transplant patients followed for an average of 28 days A number of interrelated atherogenic mechanisms are thought to be involved with hyperhomocyteinemia. found that the high homocysteine levels seen in 99 of these patients surprisingly demonstrated no causal role These include advanced thickening and smooth muscle in the atherothrombotic vascular complications of transcell proliferation of endothelial vessel wall intima, plantation. Vitamin B6 deficiency was seen in 21% of enhanced lipid deposition in the vessel wall, forced detachment of endothelial cells, activation of leukocytes recipients with, and in 9% without, cardiovascular comand thrombocytes, increased LDL oxidation, initiation plications or death, or both. Compared with patients of platelet thromboxane synthesis, enhanced oxidative with normal B6 levels, there was a 2.7-fold increase in untoward cardiac events for those patients with B6 levels stress induced by peroxide formation during homocysless than or equal to 20 nm01/L.~ teine oxidation, and prothrombotic coagulation interRemethylation of homocysteine and the subsequent feren~e.5~@ One way homocysteine assists this process formation of SAMe is critical for biosynthesis of L-camiis by the generation of hydrogen peroxide.6l By creating tine, CoQlo, and creatine. Similarly, the transsulfuration pathway must be functioning properly for optimal biosynthesis of cysteine, GSH, pantethine, and taurine. All of these nutrients are used clinically to reduce oxidative stress, improve risk factor markers, or treat heart Generate superoxide and hydrogen peroxide, which have been disease. linked to damage to arterial endothelium

Heart Disease

Change coagulation factor levels so as to encourage clot formation Prevent small arteries from dilating, so they are more vulnerable to obstruction Cause smooth muscle cells in the arterial wall to multiply Interact with low-density lipoproteins, causing them to precipitate and damage endothelial tissue Cause platelets to aggregate

Peripheral Vascular Disease Elevated homocysteine levels have been established as an independent risk factor for intermittent claudication (IC) and deep vein thrombosis. Elevated homocysteine levels corresponded with an increased incidence of intermittent claudication and decreased serum folate

Syndromes and Special Topics levels in a study of 78 patients with IC.67A fourfold increase in risk of peripheral vascular disease was noted in individuals with hyperhomocysteinemia compared with those with normal homocysteine levels.68A group of researchers in the Netherlands found high homocysteine levels to be a significant risk factor for deep vein thrombosis, with a stronger relationship among women than me11.6~ An increased risk of peripheral vascular occlusion has been noted in women taking oral contraceptives, which might be linked to the significantly increased homocysteine levels in women so affected. It is already known that oral contraceptives can cause declines or deficiencies in vitamins B6, B1= and folate, nutrients integral to the processing of homocysteine. Laboratory assessment of plasma homocysteine levels may be helpful to detect women who may be predisposed to peripheral vascular occlusion while on oral contraceptive^.^^

Stroke Stroke patients have significantlyelevated homocysteine levels compared with age-matched with a linear relationship between risk of stroke and homocysteine levelsn and a sigruficant decrease in blood folate concentrations in those with elevated homocysteine." One investigation revealed that people with a dietary intake of at least 300 mcg per day of folic acid reduced their risk of stroke and heart disease by 20% and 13%, respectively, compared with those who consumed less than 136 mcg of folic acid per day.74

Pregnancy Biochemical enzyme defects and nutritional deficiencies are receiving increasing attention for their role in causing neural tube defects (NTDs),as well as other negative pregnancy outcomes including spontaneous abortion, placental abruption (infarct), preterm delivery, and low infant birth weight. Evidence has suggested that derangement of methionine-homocysteine metabolism could be the underlying mechanism of pathogenesis of neural tube defects and might be the mechanism of prevention observed with supplementation of folic It has been firmly established that a low dietary intake of folic acid increases the risk for delivery of a child with an NTD and that periconceptional folic acid supplementation reduces the occurrence of NTD.77-83 Research also indicates that supplemental folic acid intake results in increased infant birth weight and improved Apgar scores, along with a concomitant decreased incidence of fetal growth retardation and maternal A derangement in methionine-homocysteine metabolism has also been correlated with recurrent miscarriage and placental infarcts (abruption).@ The amino acid homocysteine, when elevated, might be a teratogenic agent contributing to congenital defects

of the heart and neural tube. Evidence from experimental animals lends support to this belief. When avian embryos were fed homocysteine to raise serum homocysteine to over 150 nmol/ml, dysmorphogenesis of the heart and neural tube, as well as of the ventral wall, was observed.89 Because homocysteine metabolism, through the remethylation and transsulfuration pathways, affects several biochemical pathways involving the production of nutrients that are essential to the optimal functioning of the cardiovascular, skeletal, and nervous systems, it is not surprising that these other nutrients have been linked to complications of pregnancy in animal models and humans. Low plasma vitamin B12levels have been shown to be an independent risk factor for NTD.90,91 Methionine has been shown to reduce the incidence of NTD by 41% in an animal model when administered This evidence indicates on days 8 and 9 of pregnancy.9293 that a disturbance in the remethylation pathway with a subsequent decrease in SAMe may be a contributing factor to these complications of pregnancy. Phosphatidylcholine, due to its role as a precursor to acetylcholineand choline, is acknowledged as a critical nutrient for brain and nerve developmentand functionP4-% Since the metabolic pathways of choline (via betaine), methionine, methylcobalamin, and 5-methylTHF are interrelated, intersecting at the regeneration of methionine from homocysteine, a disturbance in the metabolism of either of these two methyl-donor pathways, due to limited availability of key nutrients or decreased enzyme activity, directly affects the body's ability to optimize levels of SAMe. Evidence suggests that women with a history of NTDaffected pregnancies have altered folic acid metabol i ~ m . 9 ~Patients - ' ~ with a severe congenital deficiency of the enzyme MTHFR, which is needed for the formation of 5-methylTHF, have reduced levels of both methionine and adenosylmethionine in their cerebrospinal fluid and show demyelination in the brain and degeneration of the spinal cord.2J01Because of its direct impact in the activation of folic acid to its methyl derivative, a milder version of this enzyme defect is also strongly suspected to increase the incidence of NTD.lo2 It is established that high vitamin A intake during the first 2 months of pregnancy is associated with a severalfold higher incidence of birth defects.lo3JM Although the mechanism of action remains to be elicited, in an animal model the activity of hepatic MTHFR is suppressed with high vitamin A levels, suggesting that its teratogenic effect during early pregnancy may be associated with a subsequent derangement in the remethylation of homo~ysteine.'~~ Because a more significant correlation has been found between high homocysteine levels in women experiencing placental abruption, infarction, and spontaneous

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease abortion than in control women and homocysteine and CoQlosynthesis depend on the methionine-SAMehomocysteine pathway, it is possible that low CoQloand elevated homocysteine independently found in complicated pregnancy may also, in fact, be found to be related condition~.'~~J~~ Nutritional intervention with the cofactors required for optimal metabolism of the methionine-homocysteine pathways offers a new integrated possibility for primary prevention of NTD and several other complications of pregnancy. Supplementation with betaine and the active forms of cobalamin and folic acid such as methylcobalamin and folinic acid, along with riboflavin-5'phosphate (because of its role as a cofactor for the MTHFR enzyme),may play a sigruficantrole in reducing or preventing these emotionally devastating outcomes.

Neurologic and Mental Disorders In addition to the known impact of homocysteine on the cardiovascular system and micronutrient biochemical pathways, numerous diseases of the nervous system are correlated with high homocysteine levels and alterations in B1> folate, or B6 metabolism including depression, schizophrenia, multiple sclerosis, Parkinson's disease, Alzheimer's disease (AD), and cognitive decline in the elderly. Methylation reactions via SAMe, including methylation of DNA and myelin, are vitally important in the CNS. The neurologic complications of vitamin B12 deficiency are likely due to a reduction of activity of the Blz-dependent enzyme methionine synthase and the subsequent reduction of SAMe production. The CNS lacks the alternate betaine pathway of homocysteine remethylation; therefore if methionine synthase is inactivated, the CNS has a greatly reduced methylation capacity.l@Other causes of reduced methionine synthase activity include folic acid deficiency and nitrous oxide anesthesia exposure.lB Homocysteine has also been found to be a neurotoxin, especially in conditions in which glycine levels are elevated, including head trauma, stroke, and BIZ deficiency."O Homocysteine interacts with the N-methyl-Daspartate receptor, causing excessive calcium influx and free radical production, resulting in neurotoxicity?l The neurotoxic effects of homocysteine or reduced methylation reactions, or both, in the CNS contribute to the mental symptomatology seen in B12 and folate deficiency. Increased homocysteine levels can also be seen in schizophrenics."' Sigruficant deficiencies in B12 and folate are common in the elderly population and can contribute to a decline in cognitive f u n ~ t i ~ n .An ~ ~investigation ~ - ~ ~ * of cognitive ability in older men (54 to 81 years old) found poorer spatial copying skills in those with higher homocysteine levels. Better memory performance was correlated with higher vitamin B6 levels.115

BIZ deficiency and increasing severity of cognitive impairment have been seen in AD patients compared with controls and patients with other dementias.lI6In a study of 52 AD patients, 50 hospitalized nondemented controls, and 49 elderly subjects living at home, patients with AD were found to have the highest homocysteine levels and the highest methylmalonic acid (an indicator of B12deficiency) levels.117 In another Framingham study cohort with an average of 8 years' follow-up, dementia developed in 111of 1092 nondementia subjects, including 83 who were diagnosed with AD. The adjusted relative risk of dementia was 1.4 for each increase of 1 standard deviation in the logarithmically adjusted homocysteine value. The relative risk of AD was 1.8 per increase of 1 standard deviation at base line and 1.6 per increase of 1 standard deviation 8 years before base line. Additionally, in those with a plasma homocysteine level that was greater than 14 pmol/liter, the risk of AD nearly doubled.11s In a study of 741 psychogeriatric patients, high plasma homocysteinelevels were found in demented and nondemented patients; however, only demented patients also had lower blood folate concentrations compared with controls. Patients with concomitant vascular disease had sigruficantly higher plasma homocysteine than those without diagnosed vascular disease. Sigruficantly higher homocysteine levels, compared with controls, have also been found in Parkinson disease patient^."^ Homocysteine's effects on neurotransmitter metabolism, along with its potential reduction of methylation reactions, could be a contributing factor to the etiology of depression. Folate and BIZ deficiency can cause neuropsychiatric symptoms including dementia and depression. Although no studies have been performed to date investigating depression, folate and B12 deficiency, and homocysteine levels, with what is known about these deficiencies and methionine synthase inhibition, it is suggestive that this connection will be revealed in the future. SAMe is used therapeutically as an antidepressant in Europe and is the third most popular antidepressant treatment in Italy in 1995.120~'21 As yet, SAMe is not available as a supplement in the United States. Methylation of myelin basic protein is vital to the maintenance of the myelin sheath. The worst-case scenario of folate and B,, deficiency includes demyelination of the posterior and lateral columns of the spinal cord, a disease process called subacute combined degeneration of the spinal cord (SCD).'O8 SCD can also be precipitated by nitrous oxide anesthesia, which causes an irreversible oxidation of the cobalt moiety of the B12 molecule and the subsequent inhibition of methionine synthase activity, a decrease in homocysteine remethylation, and decreased SAMe production?@ This has been treated using supplemental methionine, which further supports the theory of a nitrous oxide-induced biochemical block

Syndromes and Special Topics at methionine synthase.'22 Particularly at risk for this condition are B12-deficientindividuals who visit their dentist and receive nitrous oxide.109,123 Abnormal methylcobalamin metabolism is one of the proposed mechanisms for the pathophysiology of the demyelinating disease multiple sclerosis (MS). Deficiency of vitamin B12 has been linked to some cases of MS, and it is suggested that dietary deficiency, or more likely, a defect in R-protein-mediated absorption or methylation of BI2 might be a sigruficant contributor to the pathogenesis of MS.124

Diabetes Mellitus Homocysteine levels appear to be lower in individuals with type 1 diabetes mellitus. Forty-one type 1 diabetic subjects (age 34.8 f 12 years, duration of illness: 10.7 It 11.1 years) were compared with 40 age-matched control subjects (age 34.2 f 9.1 years). Following an overnight fast, homocysteine was sigruficantly lower (p = 0.0001) in the diabetic group (6.8 It 2.2) than in the controls (9.5 f 2.9). This difference was apparent in male and female subgroups.125However, increased levels of homocysteine have been reported in type 1 diabetics with proliferative retinopathylX and n e p h r ~ p a t h y . ' ~ ~ , ' ~ ~ Evidence to date suggeststhat metabolism of homocysteine is impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM). Following a methionine load, hyperhomocysteinemia occurred with significantly greater frequency in patients with NIDDM (39%) as comp a d with age-matched controls (7%).The area under the curve over 24 hours, reflecting the total period of exposure to increased homocysteine, was also elevated with greater frequency in patients with NIDDM and macrovascular disease (33%)as compared with controls (0'3'0). The authors concluded that hyperhomocysteinemia is associated with macrovascular disease in a sigruficant proportion of patients with NIDDM.lB Other researchers have reported a correlation between increased homocysteine levels and the occurrence of macroangiopathy in patients with NIDDM. Intramuscular injection of lo00 pg methylcobalamin daily for 3 weeks reduced the elevated plasma levels of homocysteine in these individual^.'^^ Elevated homocysteine levels appear to be a risk factor for diabetic retinopathy in individuals with NIDDM. This might be due to a point mutation on the gene for the enzyme MTHFR.130J31 A sigruficantlyhigher percentage of diabetics with retinopathy exhibit this m ~ t a t i 0 n . IElevated ~~ homocysteine levels cause cell injury to the small vessels, which may contribute to the development of retinopathy, as well as macroangiopathy in the cardiovascular system.13

Rheumatoid Arthritis Elevated total homocysteine levels have been reported in patients with rheumatoid arthritis (RA) and psoriasis.

Twenty-eight patients with RA and 20 healthy agematched control subjects were assessed for homocysteine levels while fasting and in response to a methionine challenge. Fasting levels were 33%higher in RA patients than in controls. Four hours following the methionine challenge, the increase in plasma homocysteine concentration was also higher in patients with RA.132 Another study found statistically sigruficant increases in homocysteine in RA patients (p = 0.003), with 20% of the patients having homocysteine levels above the reference range.'" A mechanism for this increased homocysteine in RA patients has not been elucidated. Penicillamine, a common sulfhydryl-containing arthritis treatment, has been found to lower elevated homocysteine levels in vivo.134

Psoriasis One study of 30 psoriasis patients and their matched controls were evaluated for blood concentrations of lipids, lipoproteins, acute phase reactants, homocysteine, and atherothrombotic markers. This study observed that more than 50% of the psoriasis patients had homocysteine levels that were higher than 15p o l / L , while only 20% of the control individuals were above this cutoff point. It was concluded that the mean levels of serum homocysteine, fibrinogen, fibronectin, intercellular adhesion molecules, plasminogen activator inhibitor, and autoantibodies against oxidized low-density lipoprotein were increased in psoriatic patients, whereas tissue plasminogen factor, vitamin B12, and folate levels were decreased ~ignificantly.5~ Further investigation into both the prevalence of hyperhomocysteinemia and the mechanism of action affecting RA and psoriasis is necessary.

Kidney Failure Because homocysteine is cleared by the kidneys, chronic renal failure, as well as absolute or relative deficiencies of 5-methylTHF, methylcobalamin, P5P, or betaine results in increased homocysteine levels. In 176 patients with end-stage renal disease on peritoneal or hemodialysis, homocysteine concentrations averaged 26.6 f 1.5 pmol/L in patients with renal failure as compared with 10.1 f 1.7 pmol/L in normals. Abnormal values exceeded the 95th percentile for normal controls in 149 of the patients with renal failre.'^^ Data also indicate that plasma homocysteine values represent an independent risk factor for vascular events in patients on peritoneal and hemodialysis. Patients with a homocysteine concentration in the upper two quintiles (>27.8 pmol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; p = 0.007) of vascular complications. Vitamin B levels were also lower in patients with vascular complications than in those with0~t.l~~

Homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease

Alcoholism and Ethanol Ingestion Chronic alcoholism is known to interfere with onecarbon metabolism. Because of this, it is not surprising to find that mean serum homocysteine levels are two times higher in chronic alcoholics than in nondrinkers (p < 0.001). Beer consumers have lower concentrationsof homocysteine compared with drinkers of wine or spirits (p = 0.05). In chronic alcoholics, serum P5P and red blood cell folate concentrations have been shown to be significantly lower than in control subjects.13Plasma homocysteine was sigruficantly higher, compared with controls, in 42 active alcoholics hospitalized for detoxication. In another group of 16 alcoholicswho were abstaining from ethanol ingestion, plasma homocysteine did not deviate from that of contr01s.’~ Feeding ethanol to rats produces prompt inhibition of methionine synthase, as well as a subsequent increase in activity of betaine homocysteine methyltransferase. Despite the inhibition of methionine synthase, the enhanced betaine homocysteine methyltransferase pathway uses hepatic betaine pools to maintain levels of SAMe.13’ Results indicate that ethanol feeding produces a sigzuficantloss in SAMe in the first week, with a return to normal SAMe levels in the second week. Betaine feeding enhances hepatic betaine pools in control animals, as well as ethanol-fed animals; attenuates the early loss of SAMe in ethanol-fed animals; produces an early increase in betaine homocysteine methyltransferase activity; and generates increased levels of SAMe in both control and ethanol-fed group^.'^ It has been shown that minimal supplemental dietary betaine at the 0.5% level increases SAMe twofold in control animals and fivefold in ethanolfed rats. Concomitant with the betaine-generated SAMe, ethanol-induced hepatic fatty infiltration was ameliorated.137Betaine supplementation also reduces the accumulation of hepatic triglyceride produced after ethanol inge~ti0n.I~~

Gout Although homocysteine levels have been positively correlated with increased uric acid l e ~ e l s , ” no ~ ~studies ~J~ have investigated homocysteine levels in gout patients. It is possible the increased uric acid levels in gout are due to decreased SAMe production because of the reduction in homocysteine recycling. The excess adenosine, which would have reacted with methionine to form SAMe, is degraded to form uric acid as its end product. Niacin is contraindicated in gout, a5 it competes with uric acid for e~creti0n.l~~ Animal studies have shown that increased levels of Sadenosylhomocysteine and thus homocysteine cause significant reductions in SAMe-dependent methylation reactions.I6 Therefore because degradation of the niacin-containing coenzyme nicotinamide adenine dinucleotide (NAD) is dependent on methylation by SAMe, and SAMe activity is severely

reduced in hyperhomocysteinemia, niacin levels might be higher in these people, resulting in less uric acid excretion, higher uric acid levels, and increased gout symptoms in susceptible individuals. This possibility and its mechanism need further investigation.

Osteoporosis Homocystinuria due to cystathionine synthase deficiency is an autosomal recessive error of sulfur amino acid metabolism characterized clinically by lens dislocation, mental retardation, skeletal abnormalities, and thromboembolic ~ h e n 0 m e n a . lIndividuals ~~ with this enzyme deficiency have decreased concentrations of cysteine and its disulfide form, cystine. In children with homocystinuria, osteoporosis is a common presenting symptom.143Because of the role of sulfur compounds in the formation of sulfated amino sugars, disturbed crosslinking of collagen has been proposed as a possible mechanism of action. One group of researchers studying 10 patients with homocystinuria found normal synthesis of collagen but a signhcant reduction of cross-links.lM Because of the correlation between homocystinuria and osteoporosis in children with this amino acidopathy and the increase in homocysteine concentrations in postmenopausal women, several authors have implied that elevated homocysteine levels contribute to postmenopausal osteoporosis. The Framingham study of 825 men and 1174 women, ranging from59 to 91 years old, affirmed this suspicion by evaluating plasma homocysteine levels and relative incident of hip fracture over a period of 16 to 19 years. The mean plasma total homocysteine concentrationwas 13.4 f 9.1 pmol/L with 41 hip fractures among men and 12.1 k 5.3 pmol/L and 146 hip fractures in the women’s subgroup. It was shown that both men and women in the highest quartile of plasma homocysteine indeed had a greater risk of hip fracture than those in the lowest quartile, where the risk was almost four times as high for men and 1.9 times as high for women.145Since physical activity is well known to lower homocysteine, as well as prevent falls, it may therefore influence the association between homocysteine levels and the risk of fracture.15Therefore it seems prudent to prescribe exercise, as well as appropriate supplemental therapies for women and men with high homocysteine and osteopenia/porosis.

Drug-Induced Hyperhomocysteinemia Since fibrate drugs are known to increase homocysteine levels (see ”Pharmaceutic Effects on Homocysteine” earlier), one randomized, double-blind crossover study investigated the effect using fenofibrate adjunctively with 650 pg of folic acid, 5 mg of vitamin B6, and 50 pg of B12 or just fenofibrate in hyperlipidemic men. Subjects who received the fenofibrate plus placebo had an average increase in homocysteine concentration of

Syndromes and Special Topics 44%. Subsequent to the fenofibrate plus vitamin treatment, it was 13%. In this study vitamins significantly prevented most of the homocysteine increase seen after fenofibrate plus placebo. The authors of this study suggest that routine use of these nutrients may be beneficial with this pharmaceutic therapy.32

DIAGNOSTIC CONSIDERATIONS Many studies cited herein have used a reference range, with 12 to 16 pmol/L being the upper limit of normal. This level will probably drop, as it did cholesterol testing, because researchers have found a highly sigruficant increase in relative risk of atherosclerotic cardiovascular disease and other disease processes as homocysteine levels increase, even within the "normal" range. A number of clinical laboratories currently perform plasma homocysteine determinations, by themselves or within a cardiovascular panel.

THERAPEUTIC CONSIDERATIONS Although folic acid supplementation (400 pg daily) alone can reduce homocysteine levels in many subjects, given the importance of vitamin BI2 and B6 to proper homocysteine metabolism, all three should be used together. In one study, the prevalence of suboptimal levels of these nutrients in men with elevated homocysteine levels were 56.8%, 59.1%,and 25% for folic acid, vitamin B1= and B6, respectively, indicating that folic acid supplementation alone would not lower homocysteine levels in many cases.146In other words, folic acid supplementation will only lower homocysteine levels if there are adequate levels of vitamin B12 and $. This fact could reduce the effect of folic acid fortification of food. In 1998 the FDA mandated the fortification of food products with folic acid. Although homocysteine levels have decreased modestly after the fortification of food with folic acid, the effect on mortality has been minor at best.19 This indicates the importance of more aggressive supplementary measures to reduce homocysteine-associated cardiovascular risk. In one study of 100 men with hyperhomocysteinemia, oral therapy with 650 pg folic acid, 400 pg vitamin Biz, 10 mg vitamin B6, or a combination of the three nutrients was given daily for 6 weeks. Plasma homocysteine was reduced 41.7% during folate therapy and 14.8% during B12 therapy, while 10 mg B6 did not reduce plasma

1. Tucker KL, Selhub J, Wilson PW, et al. Dietary intake pattern relates to plasma folate and homocysteineconcentrations in the Framingham Heart Study. J Nutr 1996;126:3025-3031. 2. LussierCacanS, Xhignesse M, Piolot A, et al. Plasma total homocysteine in healthy subjects: sex-specific relation with biological traits. Am J Clin Nutr 1996;61:587-593.

homocysteine significantly. The combination worked synergistically to reduce homocysteine levels by 49.80/o. 147 Several studies using folic acid, B6 B1= and betaine, either alone or in combination, have demonstrated the ability of these nutrients to normalize homocysteine levels.*Other studies confirm that oral folate supplementation alone will almost always lower high homocysteine, while B6 and B12 will lower homocysteine only in those with a genetic metabolic defect or dietary deficiency in those nutrients, or both.148J50Some studies have used high-dosage oral folate therapy (2.5 to 5 mg) to effectively reduce hyperhomocysteinemia in patients with peripheral atherosclerotic vascular disease, 50% of whom had abnormally high fasting plasma homocysteine levels, while 100% had abnormal plasma homocysteine after a methionine load. If a dietary deficiency or an increased demand resulting from genetic biochemical individuality exists for 5-methylTHF, methylcobalamin, P5P, or betaine, treatment with these active forms of mifronutrients should reduce homocysteine levels better than the nonactive forms (e.g., folic acid, cyanocobalamin, pyridoxine, betaine hydrochloride). In addition, betaine is important when there is a deficiency of the P5P-dependent enzyme cystathionine synthase-the most common genetic abnormality affecting the transsulfuration pathway of homocysteine breakdown. Betaine supplementation in combination with vitamin B6 corrects the hyperhomocysteinemia in these individuals.25J48

Therapeutic Approach Supplements Folic acid: 800 pg daily Vitamin B12:800 pg Pyridoxine: 25 to 50 mg daily If unresponsive to the previous dosages, patients may take the following: Folinic acid: 800 pg daily Methylcobalamin: 800 pg daily Pyndoxal 5'-phosphate: 20 mg daily Betaine (trimethylglycine):1200 mg daily NAC: 500 mg daily

'References 26, 29,55, 57, 148, 149.

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118. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 2002; 346:476-483. 119. Main P, Le B o d A, Cordillet E, et al. Sulfate and cysteine levels in the plasma of patients with Parkinson’s disease. Neurotoxicology 1995;16527-529. 120. Reynolds EH, Carney M W , Toone BK. Methylation and mood. Lancet 1984;2196-198. 121. Arpino C, Da Cas R, Donini G, et al. Use and misuse of antidepressant drugs in a random sample of the population of Rome, Italy. Acta Psychiatr %and 1995;927-9. 122. Stacy CB, Di Rocco A, Gould RJ. Methionine in the treatment of nitrous-oxide-induced neuropathy and myeloneuropathy. J Neurol1992;239:401403. 123. Schilling RF. Is nitrous oxide a dangerous anesthetic for vitamin B1Z-deficient subjects? JAMA 1986;28;255:1605-1606. 124. Reynolds EH, Bottiglieri T, Laundy M, et al. Vitamin 812 metabolism in multiple sclerosis. Arch Neurol1992;49:649-652. 125. Robillon JF,Canivet B, Candito M, et al. Type 1 diabetes mellitus and homocysteine. Diabetes Metab 1994;20:494-496. 126. Hultberg B, Agardh E, Anderson A, et al. Increased levels of plasma homocysteine are associated with nephropathy, but not severe retinopathy in type 1 diabetes mellitus. Scand J Clin Lab Invest 1991;51:277-282. 127. Agardh CD, Agardh E, Anderson A, et al. Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus. Scand J Clin Lab Invest 1994;54: 637-641. 128. Munshi MN, Stone A, Fink L, et al. Hyperhomocysteinemia following a methionine load in patients with non-insulin-dependent diabetes mellitus and macrovascular disease. Metabolism 1996; 45:133-135. 129. Araki A, Sako Y, Ito H. Plasma homocysteine concentrations in Japanese patients with non-insulin-dependent diabetes mellitus: effect of parenteral methylcobalamin treatment. Atherosclerosis 1993;103149-157. 130. Vaccaro 0, Ingrosso D, Rivellese A, et al. Moderate hyperhomocysteinaemia and retinopathy in insulin-dependent diabetes. Lancet 1997;3491102-1103. 131. Neugebauer S, Baba T, Kurokawa K, et al. Defective homocysteine metabolism as a risk factor for diabetic retinopathy. Lancet 1997;349:473-474. 132. Roubenoff R, Dellaripa P, Nadeau MR, et al. Abnormal homocysteine metabolism in rheumatoid arthritis. Arthritis Rheum 1997;40718-722. 133. Krogh Jensen M, Ekelund S, et al. Folate and homocysteine status and haemolysis in patients treated with sulphasalazine for arthritis. Scand J Clin Lab Invest 1996;56:421-429. 134. Kang SS, Wong PW, Glickman PB, et al. Protein-bound homocyst(e)ine in patients with rheumatoid arthritis undergoing D-penicillamine treatment. J Clin Pharmacol1986;26:712-715. 135. Dennis VW, Robinson K. Homocysteinemia and vascular disease in end-stage renal disease. Kidney Int Suppl 1996;57: Sll-S17. 136. Robinson K, Gupta A, Dennis V, et al. Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in endstage renal disease and is closely linked to plasma folate and pyridoxine concentrations. Circulation 1996;942743-2748. 137. Barak AJ, Beckenhauer HC, Tuma DJ. Betaine, ethanol, and the liver: a review. Alcohol 1996;13395-398. 138. Barak AJ, Beckenhauer HC, Tuma DJ. Betaine effects on hepatic methionine metabolism elicited by short-term ethanol feeding. Alcohol 1996;13:483486. 139. Malinow MR, Levenson J, Giral P, et al. Role of blood pressure, uric acid, and hemorheological parameters on plasma homocysteine concentration. Atherosclerosis 1995;114:175-183.

Syndromes and Special Topics 140.C o d BM, Malinow MR, Beamer N, et al. Elevated plasma homocysteine concentration as a possible independent risk factor for stroke. Stroke 1990;21:572-576. 141. Gershon SL, Fox M.Pharmacologic effects of nicotinic acid on human purine metabolism. J Lab Clin Med 1974;84:179-186. 142. Tamburrini 0, Bartolomeo-De Iuri A, Andria G, et al. [Bone changes in homocystinuria in childhood.] Radio1 Med (Torino) 1984;70937-942. 143. Kaur M, Kabra M, Das GP, et al. Clinical and biochemical studies in homocystinuria. Indian Pediatr 1995;32:1067-1075. 144. Lubec B, Fang-Kircher S, Lubec T, et al. Evidence for McKusick's hypothesis of deficient collagen cross-linking in patients with homocystinuria. Biochim Biophys Acta 1996;1315159-162. 145. McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 2004;350:2042-2049.

146. Ubbink JB, Vermaak WJ, van der Menve A, et al. Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr 1993;5747-53. 147. Ubbink J, Vermaak W, van der Merwe A, et al. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927-1933. 148. Dudman N, Wdcken D, Wang J, et al. Disordered methionhe/ homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy, and enzymology. ArteriosclerThromb 1993;13:1253-1260. 149. Wilcken DE, Wilcken B, Dudman NP,et al. Homocystinuria-the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983;309:448-453. 150. Mason JB, Miller JW. The effects of vitamins B12, B6, and folate on blood homocysteine levels. Ann N Y Acad Sci 1992;669:197-203.

Hyperventilation Syndrome/Breathing Pattern Disorders Leon Chaitow, ND, DO CHAPTER CONTENTS DIAGNOSTIC SUMMARY 629 Introduction 629 HyperventilationSyndrome/Breathing Pattern Disorders Defined 629 Gender 630 Diagnostic Overview 630 General Considerations 630 Benefits of Normal Respiratory Function 630 The Carbon Dioxide-Oxygen Balancing Act 631 Pathophysiology 631 Diagnostic Considerations 635 Symptoms and Signs of Hyperventilation Syndrome/Breathing Pattern Disorders 635 Acute Hyperventilation Progression 635 Chronic Hyperventilation 636 Laboratory and Off ice Tests for Hyperventilation Syndrome/Breathing Pattern Disorders 637 The Nijmegan Questionnaire 637

Biomechanical(Structural) Considerations 638 The Structure-FunctionContinuum 638 The Muscles of Breathing 638 Structure-FunctionSummary 639 Neural Regulation of Breathing 639 Chemical Control of Breathing 639 Voluntary Control of Breathing 639 Therapeutic Considerationsand Therapeutic Approach 640 Treatment and Rehabilitation of Hyperventilation SyndromeBreathing Pattern Disorders 640 An Osteopathic/Naturopathic Protocol for Care of Hyperventilation Syndrome/Breathing Pattern Disorders 641 Breathing Rehabilitation Exercises 641 Is Breathing Retraining Effective? 641 Osteopathic Treatment of Chronic Asthma 641 Summary 642

Hyperventilation syndrome/breathing pattern disorders (HVS/BPDs) are described as follows:

which are tuned to maintain arterial carbon dioxide (PaCOz)levels within a narrow range. Although at any given time the body's carbon dioxide (CO,) production is set at a certain level, the exaggerated breathing depth and rate associated with H V S / BPDs eliminates COzat a faster pace, resulting in a fall in PaCOzand arterial hypocapnia. The arterial hydrogen ion (pH) (acid/alkaline balance) rises into the alkaline region, thus inducing respiratory alkalosis.

Hyperventilation is a pattern of overbreathing in which the depth and rate exceed the metabolic needs of the body at that time. Breathlessness usually OCCUIS at rest or with only mild exercise. Physical, environmental, or psychologic stimuli override the automatic activity of the respiratory centers,

As a direct result of HVS/BPDs, many patients present with multiple symptoms, some of which mimic serious disease. However, blood tests, electrocardiograms (ECGs), and thorough physical examinations may reveal nothing out of the ordinary. Up to 10% of patients in general internal medicine practice reportedly suffer from HVS/BPDs as their primary diagnosis.] One study

INTRODUCTION Hyperventilation Syndrome/Breathing Pattern Disorders Defined

629

Syndromes and Special Topics reported a series of 45 patients with chest pain who had normal coronary arteries on angiography and were ultimately diagnosed with HVS/BPDs. Over a 3.5-year average follow-up, 67% had made subsequent emergency visits for chest pain and 40% had been readmitted to rule out myocardial infarction.2The implications are that many individuals with HVS/BPDs experience severe and genuinely distressing symptoms, and considerable medical expenses are incurred in excluding more serious pathology.

Gender More females than males have HVS/BPDs, ranging from a ratio of 2 1 to 71. The peak age of incidence is 15 to 55 years, althoughother ages can be affected.Women may be more at risk because of hormonal influences, since progesterone stimulates respiratory rate, and in the luted (postovulation/premenstrual)phase, COz levels drop on average 25%.Additional stress can then "increase ventilation at a time when CO, levels are already Acute hyperventilation represents approximately 1% of all cases of hyperventilation, well outnumbered by chronic hyperventilation: Bradley5 stated: Unfortunately breathing pattern abnormalities and their sequelae . . . are commonly missed by doctors and health care professionals or dismissed as "over anxiousness," so that no treatment options are offered.

Diagnostic Overview

and the diaphragm ascends back to its original domed position, aided by the elastic recoil of the lung. A relaxed pause at the end of exhalation releases the diaphragm briefly from the negative and positive pressures exerted across it during breathing. *Under normal circumstances individuals are quite unaware of their breathing. Breathing rates and volumes increase or fluctuate in msponse to physical or emotional demands, but in normal subjects they return to relaxed low chest patterns after the stimuli ceases. Patients, especially those whose symptom presentation includes chronic fatigue or anxiety, or both, and who display or report a number of the following signs or symptoms, might be considered suitable candidates for respiratory treatment. The following symptoms are indications of possible breathing pattern dysfunction: A feeling of constriction in the chest Shortness of breath Accelerated or deepened breathing Inability to breathe deeply Feeling tense (the Nijmegen questionnaire avoids the use of the word anxiety) lightness around the mouth Stiffness in the fingers or arms Cold hands or feet Tigling fingers . Bloated abdominal sensation Dizzy spells Blurred vision Feeling of confusion or losing touch with environment

Presenting symptoms and observation during case taking should offer the alert clinician an opportunity to consider BPD as a factor/feature of the individual's condition. Unless it is considered, it is unlikely to be diagnosed. Various tools are available to assist in such a diagnosis, ranging from laboratory tests to simple but effective questionnaires and palpation procedures (see "Diagnostic Considerations" later). In order to recognize HVS/BPDs, one must be aware of the characteristics of a normal breathing pattern.

Details of diagnostic methods are outlined later in this chapter.

Normal Breathing Pattern

The exchange of gases involving acquisition of oxygen (0,)and elimination of CO, leads to enhanced cellular function and facilitates the following:

The breathing rate should be 10 to 14 breaths/minute, moving 3 to 5 L of */minute through the airways of the chest. During the active inhalation phase, air flows in through the nose where it is warmed filtered and humidified before being drawn in to the lungs by the downward movement of the diaphragm and outward movement of the abdominal wall and lower thoracic structures. *The upper chest and accessory breathing muscles should remain relaxed. The expiratory phase is ideally effortless as the abdominal wall and lower intercostals relax downward

GENERAL CONSIDERATIONS Benefits of Normal Respiratory Function

Normal performance of the brain, organs, and tissues of the body Normal speech and human nonverbal expression (e.g., sighing) Fluid movement (lymph, blood) Spinal mobility through regular, mobilizing, thoracic cage movement Digestive function via rhythrmc positive and.negative pl.essure fluctuations,via normal diaphragmaticfunction Any chronic alteration in breathing function automatically modifies these functions negatively.

Hyperventilation Syndrorne/Breathing Pattern Disorders

The impact of habitual BPDs such as hyperventilation on an individual’s physiology can be profound, potentially resulting in, or exacerbating, a wide range of health problems, sometimes severely, ranging from anxiety and panic attacks to fatigue and chronic pain.

The Carbon Dioxide-Oxygen Balancing Act Gilbert6 offers a reminder as to common perceptions about, and the balancing act that is manifested below the surface of, breathing function: Simply put, the body extracts oxygen from the inhaled air and excretes carbon dioxide to be exhaled. That formulation suggests that all we need to remember is that oxygen is good and carbon dioxide is bad. Yet if one considers that life-giving oxygen can also be corrosive and toxic, and that a deficiency of the waste gas carbon dioxide (COJ can cause fainting, seizures, or death, then the “good/bad” distinction must be restated as “good within certain limits” and ”bad within certain limits.” Maintaining these two gases within those limits is a complex task for the body, even more so because the supply

Breathing in excess of metabolic requirements

of each gas fluctuates with each breath. This tidal oscillation must be smoothed out so that the brain and bodily tissues and also so that C 0 2in the body receive a steady supply of 02, remains at a stable level. This need for COzstability may be less familiar than the need for stability of 0, but with respect to both of these gases, we live in a narrow zone of homeostasis bordered on both sides by physiological disaster. Much of what goes wrong with breathing involves attempts to avoid this disaster.

Figure 56-1 shows H V S symptoms.

Pathophysiology Physiologic and Pathophysiologic Causes of Altered Patterns of Breathing7 Hyperventilation can be an appropriate physiologic response to the body’s metabolic needs; for example, tachypnea (rapid breathing) or hyperpnea (increase in respiratory rate proportional to increase in metabolism) may result as the respiratory centers respond automatically and appropriately to rising COzproduction due to exercise or organic disease that may be creating acidosis.

w 1. Upper fixator overactivity shortening of accessory breathing muscles Reduced PCO, 2. Painful nodules in nape of = respiratory alkalosis neck, anterior chest and shoulder girdle 3. Temporal headaches 4. Painful legs 5. Whole body expresses *Increased neuronal tension-cannot relax in activity speeding spinal any position reflexes as well (initially) as heightened pain perception + photophobia, + hyperacusis

1

J

Increased neuronal irritability. Reduced blood flow to tachycardia

I

I

I

I

I

I

*all these symptoms are increased during progesterone phase of menstrual cycle

\ \

I

Increased circulating histamines make allergic reaction more Dizziness, lightheadedness, ”foggy brain“ Cold extremities Chest pain Anxiety, apprehension (sense of mild panic) Depressed cortical activity Vasomotor instability, blurring of consciousness and vision Loss of cortical inhibition results in emotional lability Figure 56-1 Negative health influences of a dysfunctional breathing pattern such as hyperventilation. (From Chaitow L, Bradley D, Gilbert C. Multidisciplinary approaches to breathing pattern disorders. London: Churchill Livingstone. 2002:90.)

It is therefore important to exclude organic causes that diminish arterial oxygen saturation (Pa03 or elevate PaC02 levels. Organic causes of HVS/BPDs that should be excluded/ identified before breathing rehabilitation is initiated include the following:

Respiratory: asthma, chronic obstructive respiratory disease, pneumonia, pulmonary embolus, pneumothorax, and pleural effusion Cardiovascular: acute and chronic left heart failure, right heart failure, tachyarrhythmias Hemepoeitic:anemia Renal: nephrotic syndrome, acute and chronic kidney failure Endocrine: Diabetes with ketoacidosis, pregnancy, progesterone therapy Metabolic: liver failure Pharmaceutic:aspirin, caffeine, amphetamine, nicotine Gilbert6 summarizes causes of HVS/BPDs as follows: In considering aberrations in the breathing pattern, it is helpful to keep in mind:

Adequate and inadequate compensations for pathology elsewhere (e.g., acidosis from diabetes or kidney problems) Responses to extrinsic factors (such as allergy or drugs) Responses to intrinsic factors such as progesterone Truly pathologic disorders of the breathing system itself Psychogenic or functional breathing problems

Gilbert also noted that the following factors can lead to altered breathing patterns: Ketoacidosis promotes deeper, faster breathing because the breathing centers are responding to the higher C02content. Diarrhea results in the loss of alkaline plasma bicarbonate ions, which if prolonged leads to acidosis. This stimulates corrective overbreathing in order to remove C02 (as carbonic acid) and normalize the pH. Excessive vomiting causes loss of hydrochloric acid, shifting the body toward alkalosis, slowing breathing to allow C02to build up and restore pH. Hypoventilation is the result. Use of steroids and diuretics can lead to alkalosis.

Categorization of Causes It is possible to place the common etiologic features of HVS/BPD into biomechanical, biochemical, psychologic, environmental, pathologic, and habitual categories. The reasons for an individualbreathing inappropriately can derive diredly from structural, biomechanical causes such as a restricted thoracic spine, rib immobility, or

shortness of key primary and accessory respiratory muscles. Causes of breathing dysfunction can also have a more biochemical etiology, possibly involving allergy or infection, which triggers narrowing of breathing passages, and subsequent asthmatic-type responses. Acidosis, resulting from conditions such as kidney failure, also directly alter breathing function as the body attempts to reduce acid levels via elimination of C02 through hyperventilation. The link between psychologic distress and breathing makes this another primary cause of many manifestations of dysfunctional respiration. Examining a person suffering from anxiety or depression without breathing dysfunction being noted is difficult to imagine. Other catalysts that may affect breathing function include environmental factors (e.g., altitude, humidity).8 BPDs may also emerge from a background of established pathology (e.g., asthma, cardiovascular disease, kidney failure, chronic pain). Where this is the case, the aim of this chapter is not to explore these states, as they are discussed elsewhere in this textbook. The etiology of HVS/BPD may involve combinations of the factors listed earlier; however, in most instances, altered breathing patterns, whatever their origins, seem to be maintained by nothing more sinister than pure habit.7

The Hydrogen Ion Factor Gilbert6 stated the following: The story [of HVS/BPD] might best begin with pH, because this factor influences every organ of the body. . . . The variable of relative acidity facilitates many metabolic exchanges and it must be kept in careful balance. Since pH describes proportion of hydrogen ions available for combination, and the pH is on a log scale, a small change in pH, such as 7.4to 7.2,means doubling the number of hydrogen ions present. The binding of hydrogen to negative sites helps to regulate enzymatic action, endocrine secretion, integrity of protein molecules, and cellular metabolism, including oxygen absorption and release, A pH of 7.2would seriously compromise many physiological functions. The physiological normal pH in the arterial blood is around 7.4,with an acceptable range from 7.35to 7.45.Outside these limits lie ill effects of many kinds. The body will sacrifice many other things in order to maintain proper pH.

The Carbon Dioxide-Hydrogen Ion Connection The acidity of the blood is determined mainly by C02. COz is the end-product of aerobic metabolism, deriving mainly from the mitochondria. C 0 2 is odorless; heavier than air; and, if inhaled in its pure form, causes suffocation. COz is present in the atmosphere at a concentration of around two-hundredths of 1%,harmless to humans but adequate to sustain plant life.

Hyperventilation Syndrome/Breathing Pattern Disorders

Transportation of C 0 2 occurs from the tissues into the blood and then to the lungs for exhalation. The body converts C02to carbonic acid (H2C03),of which there is a perpetual surplus. The lungs exhale around 12,000 mEq of carbonic acid per day, compared with less than 100 mEq of fixed acids excreted by the kidneys. Any increase in bodily activity produces C02, acidifying the blood, unless more C02 is excreted/ exhaled. It is therefore obvious that changes in breathing volume relative to C 0 2production regulate the momentto-moment concentration of pH of the bloodstream (longer-term regulation of pH is shared with the kidneys). It is the concentration of C02in the blood, not oxygen, that is the major regulator of breathing drive. Higher C 0 2level immediately stimulates more breathing, apparently on the assumption that abundance of C02 means oxygen-poor air is being breathed, breathing has stopped, or something else is happening that is an antecedent to suffocation.

Respiratory Homeostasis Jennett9describes the delicate homeostatic balancing act in which pH and C02are key features: When there are not other overriding drives affecting breathing, the neural control system acts to maintain a constant arterial K O 2 . This must mean that the volume of Cot expired continually balances the volume produced by tissue metabolism. Measurements show that alveolar and arterial concentrations of C02stay constant, which means that the volume of gas breathed out from the functional (alveolar)volume of the lungs must vary precisely with the rate of metabolic C02production. In rest and activity, when the system is left to itself, it is so efficient that the matching OCCUTS virtually breath-by-breath, even when metabolic activity is continually changing.

The Bicarbonate Buffer Gilbert6 explained the following: There exists a further balancing mechanism, the bicarbonate buffer. The bicarbonate ion (HCOc) is derived from C02during its ride in the bloodstream; C02 dissociates into hydrogen ions (H+)and (HC03-). This bicarbonate reserve is adjustable as needed, up to a point, and constitutes a major alkaline buffer system which opposes rises in acidity. The kidneys regulate the regulators by adjusting amount of bicarbonate returned to the bloodstream. If the kidneys detect excess acidity (a surplus of positively-charged hydrogen ions) they will try to retain more bicarbonate to balance the acid, but this is not a fast process; adjusting their filtration characteristics takes hours to days. In the short run, meanwhile, if bicarbonate buffering of excess acid is not sufficient, or if the bicarbonate is depleted, a faster back-up buffering system is available: hyperventilation. Excessive breathing exhales more C02 (acid), thereby bringing pH closer to normal.

Oxygen Delivery and Smooth Muscle Constriction The blood carries oxygen mainly in molecules of hemoglobin, which are contained in red blood cells. In an appropriate environment, hemoglobin combines readily with oxygen (to the form of oxyhemoglobin). This process varies according to local pH, as well as PO2. This ability to combine is important for both absorbing oxygen through the alveoli and also for releasing oxygen through the capillary walls, where oxygen diffuses into the tissues. These two properties are largely determined by local conditions, so that when pH is low (i.e., the blood is more acidic), hemoglobin in that area is stimulated to release additional oxygen. This is true of metabolically active tissues in general but especially of muscles. An exercising muscle needs all the oxygen it can get, and this is assisted by its chemical nature, explained by West as follows: An exercising muscle is acid, hypercarbic, and hot, and it benefits from increased unloading of O2 from its capillaries!

The effect of pH on oxyhemoglobin dissociation is called the Bohr effect. In the lungs the need is to bind oxygen to hemoglobin, not release it. Not surprisingly, the lungs have a more alkaline environment. The fact that a shift of the blood toward acidity promotes dissociation and release of oxygen from the hemoglobin is particularly important when considering hyperventilation because the resulting alkalinity causes the hemoglobin molecule to retain more oxygen than usual. With increased alkalinity encouraging smooth muscle contraction and therefore diminished diameter of blood vessels, as well as the reluctance of hemoglobin to release its oxygen, a relative oxygen deficit is likely in tissues and the brain, leading to symptoms such as fatigue, aching, cramping, and cognitive problems.

Hypoglycemia as an Exacerbating Factor Fluctuating blood glucose levels may trigger HVS/BPD symptoms in patients with high carbohydrate diets, which produce rapid rises followed by sharp falls to fasting levels or bei~w.~JO Patients are recommended to eat breakfast including protein and to avoid going without food for more than 3 hours." This fits in with a midmorning and afternoon protein snack, as well as the usual three meals a day. This is particularly relevant to patients who experience panic attacks or seizures, which have been shown more likely to strike when blood glucose levels are Referral to a nutritionist may be warranted.

Syndromes and Special Topics

Psychology and Hyperventilation SyndrornerSreathing Problem Disorders Gilbert6 described aspects of the influence of emotion on breathing: Hyperventilation as a chronic syndrome or behavioral tendency is squarely in the category of disorders often called "functional," "psychophysiological," or "psychosomatic." But it is not always so clearly delineated; disruption of the optimal breathing pattern can happen in subtler ways. Increased variability from breath to breath is known to correlate with anxiety ~tates.lZ*~ Low PCOz and increased frequency of sighing are typical of those with panic disorder even when not panicking.**These generalizations miss individuals who do not have a chronic breathing pattern disorder, but who do experience disrupted breathing under particular conditions.These "conditions" can provoke either an amygdala "alarm" discharge or some specific, learned breathing response, as well as occasional panic.

Conway and colleagues15used hypnosis to investigate the sources of hyperventilation episodes and concluded that people who hyperventilate fall into at least two groups, the chronic and the episodic, explained as follows: It has been considered that emotional events, particularly involving loss, separation and impotent anger, are the precipitating factors that may initiate a trend to hyperventilation. . . . On some occasions the important initiating event, psychological strain or life event was evident from the history, but in others questioning under hypnosis revealed psychological triggers, not elucidated previously, which provoked marked falls in PetCOz. Since it is a feature of many psychosomatic illnesses that the initiating factors are repressed and only the somatic symptoms remain, this technique may be of considerable help in some patients in whom therapy may not be progressing as well as might have been expected.

INPUT

Freeman and associates16also showed that individuals who reported several symptoms indicating hyperventilation (including chest pain/palpitations and dizzinessnot exclusively respiratory symptoms) displayed rather strong hyperventilation in response to recalling emotionally disturbing events, whereas the control subjects did not. Bereavement, loss of control, grief, and anger were common topics associated with the symptoms. Gilbert6 concludes: Aside from medical problems, there are still many factors in the psychological and behavioral realms competing for control of breathing [Figure 56-21. Successful regulation must take all factors into account, with special consideration for priorities of survival. The human brain adds a layer of complication with its power to imagine, project, and recall, often stimulating breathing reflexes without apparent reason.

Somatic Changes Due to Hyperventilation SyndromerSreathing Problem Disorders Garland" suggested that "psychology overwhelms physiology" when he described the following somatic changes that flow from a pattern of upper chest breathing, which, at its extreme, becomes hyperventilation: When faced with persistent upper chest breathing patterns, physicians should be able to identrfy reduced diaphragmatic efficiency and commensurate restriction of the lower rib cage, as these evolve into a series of changes with accessory breathing muscles being inappropriately and excessively used. A degree of visceral stasis and pelvic floor weakness will develop, as will an imbalance between increasingly weak abdominal muscles and increasingly tight erector spinae muscles.

OUTPUT

Figure 56-2 Final modulation of the breathing act includes input from many possible sources: the need for vocalization (a cry for help, a shouted warning, perhaps a growl); preparation for exertion;the need to freeze and become less noticeable;the need to maximize sensory acuity by keeping the body still; and the need to either remain calm or return to a baseline state of calmness.These inputs often conflict with each other, but if there is a hint of a threat to survival. they seem to have priority over all other considerations. (From Chaitow L. Bradley D, Gilbert C. Multidisciplinaryapproaches to breathing pattern disorders. London: Churchill Livingstone. 2002:122.)

Hyperventilation Syndrorne/Breathing

Fascia1restriction from the central tendon via the pericardial fascia, all the way up to the basi-occiput, will be noted. The upper ribs will be elevated and there will be sensitive costal cartilage tension. The thoracic spine will be disturbed by virtue of the lack of normal motion of the articulation with the ribs, and sympatheticoutflow from this area may be affected. Accessory muscle hypertonia, notably affecting the scalenes, upper trapezius, and levator scapulae will be palpable and observable. Fibrosis will develop in these muscles, as will myofascial trigger points. The cervical spine will become progressively rigid with a fixed lordosis being a common feature in the lower cervical spine. A reduction in the mobility of the second cervical segment and disturbance of vagal outflow from this region is likely. Garland concluded his listing of somatic changes associated with hyperventilationby saying that: Physically and physiologically [all of] this runs against a biologically sustainable pattern, and in a vicious cycle, abnormal function (use) alters normal structure, which disallows return to normal function.

Garland also points to the likelihood of counseling (for associated anxiety or depression) and breathing retraining, being far more likely to be successfully initiated if patients appropriately deal with the structural components, as listed.

DIAGNOSTIC CONSIDERATIONS Symptoms and Signs of Hyperventilation Syndrome/Breathing Pattern Disorders Bradley stated the following: The symptoms and signs of hyperventilation [are] diverse. None is absolutely diagnostic. Consequently clinicians rely on a suggestive group of symptoms. Each patient has a characteristic set of symptoms which can be amplified during an acute episode, or when hyperventilation is exaggerated. The intermittent nature and variable intensity of the symptoms adds to the difficulty of diagnosis. In addition, many patients will not mention some of their symptoms, either because they think they are unrelated or they are ashamed to mention them. Examples are hallucinations, phobias, sexual problems, fear of impending death or madness, and nightmares. Careful interrogation about the relationship of breathlessness to exercise usually reveals a variation in severity from day to day.

Symptoms Table 56-1 is not fully comprehensive but represents the commonest symptoms and signs of HVS/BPD.

For greater depth see T m o n s and Ley7 Gardner,18 Nix0n,19and Chaitow and colleagues?

Metabolic Disturbances and Hyperventilation Syndrome Two tests of nerve hyper excitability produced by hypocapnia-inducedhypocalcaemia are Trousseau's and Chvostek's signs. The Trousseau sign consists of occluding the brachial artery into the arm by pumping the blood pressure cuff above the systolic pressure for 2l/2 minutes. A positive sign is where paresthesia is felt severely within the period and the wrist and fingers arch in carpopedal spasm, termed main d'accoucheur or obstetrician's hand. The Chvostek sign occurs if, when tapping the facial nerve as it emerges through the parotid salivary gland, a contraction of the facial muscle twitches the side of the mouth. This is also a test for magnesium deficiency.2O Acute hypophosphatemia also contributes to weakness and tingling.

Cardiac Signs Chest pain associated with HVS/BPDs requires that heart disease is excluded as a diagnosis. Adrenalineinduced ECG changes can occur in hyperventilation, uncomplicated by coronary heart disease. One study suggests up to 90% of noncardiac chest pain is thought to be induced by WS/BPDs?* In older patients, established coronary artery disease can be exacerbated by vasoconstriction arising from hypocapnia, which puts them at risk of coronary occlusion and myocardial damage. Alternatively, hyperventilation can trigger spasms of normal caliber coronary arteries. Syndrome X refers to patients who have a history of angina, a positive exercise test (chest pain within 16 minutes), and yet a normal angiography. Thought to be a functional abnormality of coronary microcirculation, it is much more common in women than men.22

Gastrointestinal Signs Rapid breathing or mouth breathing instigates aerophagia from air gulping causing bloating, burping, and extreme epigastric discomfort. Irritable bowel syndrome is listed as a common symptom of chronic overbreathing. Fear and anxiety may induce abdominalcramps and diarrhea.] The median swallowing rate in healthy, nondyspeptic controls is 3 or 4/15 min. In the absence of food, up to 5 ml of air accompanies saliva into the gastrointestinal tract with each s w a l l ~ w . ~

Acute Hyperventilation Progression The patient presenting with an acute hyperventilation episode appears distressed.

Most common symptoms and signs of hyperventilationsyndromebreathing pattern disorders System

Symptoms

Suggested causes

Cardiovascular

Chest pain and angina, palpitation and arrhythmias, tachycardia, lightheadedness and syncope, altered ECG features

Reduced coronary blood flow, altered excitability of SA and AV nodes of cardiac muscle, reduced cardiac output, peripheralvasodilatation

Gastrointestinal

Discomfort in lower chest and epigastric area, esophageal reflux and heartburn, Moatin@distension,exacerbation of hiatal hernia symptoms, dry mouth, air swallowing and belching

Aerophagia, increased swallowing rate, mouth breathing

Neurologic

Headache, numbness and tingling (mainly involving extremities and perioral), positive Trousseau’s and Chvostek’s signs, dizzinesdgiddiness, ataxia and tremor, blurred and tunnel vision, anxiety and panic, phobias, irritability, depersonalization, detachment from reality, impaired concentration, cognition, performance, easy fatigue, insomnia, hallucinations

Cerebrovascular constriction (seenotes on smooth muscle contraction below); vasoconstrictionof vertebral or carotid arteries, or both; reduced O2 delivery, neuronal excitability resulting from alkalosis; hypocalcaemia

Respiratory

Breathlessness; restricted sensation around thorax; sighinwyawning; obvious use of upper chest, accessory breathing muscles (e.9.. scalenes) on inhalation; chest tenderness

Overuse of accessory breathing muscles and fatigue of primary respiratory muscles

Muscular

Stiffness and aching, weakness in limbs, cramping, carpopedal spasm, tetany

Hyper excitability of motor nerves, muscle fatigue, calcium/magnesium imbalance

AV; Atrioventricular; ECG, electrocardiogram: SA, sinoatrial.

The pattern of respiration is of deep, rapid breaths, using the accessory muscles visible in the neck and the upper chest. Wheezing may be heard as a result of bronchospasm triggered by hypocapnia. A stressful precipitating event is usually reported. Hypocapnia reduces blood flow to the brain (2% decrease in flow per 1mmHg reduction in arterial C q ) , causing frightening central nervous system symptoms. The reduced oxygenation of brain and tissues of the body results from contraction of smooth muscle surrounding blood vessels and a reluctance of the hemoglobin carrier molecule to release oxygen in the increasingly alkaline environmentcaused by excessive loss of COP Poor concentration and memory lapses may occur as a result, with tunnel vision and onset in those susceptible of migraine-type headaches or tinnitus. Sympathetic dominance brings on tremors, sweating, clammy hands, palpitations, and autonomic instability of blood vessels causing labile blood pressures.24 Bilateral perioral and upper extremity paresthesia and numbness may be reported. Unilateral tingling is most often confined to the left side. Dizziness, weakness, visual disturbances, tremor and confusion-sometimes fainting or even seizures-are typical symptoms.

Spinal reflexes become exaggerated through increased neuronal activity caused by loss of C02ions from the neurons. Tetany and cramping may occur in severe bouts.= On a psychologic level, Bradley5 described a ”cascade of symptoms” (see Figure 56-1) in which an original cause (emotionalor physical) leads to tension and anxiety that results in hyperventilation, possibly an acute hyperventilation attack, which (with repetition), over time, results in anticipation anxiety and avoidance behaviors or phobias, or both.

Chronic Hyperventilation The diagnosis of chronic and intermittent hyperventilation is more difficult than acute hyperventilation. A careful history and systemic inquiry, checking all other symptoms in the other body systems, usually highlights a suspicious pattern, particularly to the experienced clinician who can think beyond his or her own specialist area. Careful inquiries as to the precipitating causes of attacks helps both with the diagnosis and focusing on choice of treatment. Nixon19 suggested that there are often attacks where there is no preceding stressful event. For example, in chronic hyperventilatorsthe respiratory

Hyperventilation SyndromeBreathing Pattern Disorders

center may have been reset to tolerate a lower than normal partial pressure of PaCOz levels in the blood. In such patients, a single sigh or one deep breath may reduce the PaC02 enough to trigger symptoms. Examination must exclude organic diseases of the brain and nervous system; the heart, particularly angina and heart failure; respiratory disease; and gastrointestinal conditions, especially if there are suspicious symptoms in these systems.

Laboratory and Office Tests for Hyperventilation Syndrome/Breathing Pattern Disorderss Many possible tests for respiratory function exist, some of which require bulky or sophisticated equipment (e.g., forced expiratory volume, forced vital capacity, flowvolume curves, lung volume, gas transfer, cardiorespiratory). Some are difficult to perform (e.g., airway resistance), and some are invasive (e.g., blood gases). A selection of tests are listed as follows: Preliminary tests to exclude respiratory and cardiac disease include peak expiratory flow rate (PEFR), chest radiograph, and ECG. A PEFR measurement, compared with age, sex, and height tables, provides a simply done, quick exclusion of significant respiratory restriction in the clinic room. Where chest pain is a presenting symptom, an exercise ECG should be done. If a hyperventilation provocation test (HVPT) is performed (during which the patient is asked to voluntarily overbreathe to bring on symptoms), ECG should be monitored (see “Caution” later). Arterial blood gas determination is invasive and painful, (arterial puncture) appropriate in the emergency department, where the diagnosis of acute hyperventilation is required. For patients in whom chronic hyperventilation is suspected, the end-tidal carbon dioxide (PET C02) can be measured noninvasively from a continuous sampling through nasal prongs with the mouth occluded, or the tube can be sited in an oral airway for those with nasal obstruction to monitor C02deficits. PET C 0 2 can be evaluated following a 4-minute quiet breathing rest period, followed by exercise and recovery, or a hyperventilation provocation test can be conducted in the recovery period. Most patients with chronic hyperventilation have a PET COz at or below 30 mmHg and a markedly delayed recovery from hypocapnia after overbreathing.26 The think test2’ may be initiated 3 to 4 minutes into the recovery period. The patient is asked to recall a painful emotional experience during which symptoms developed. If the PETC02drops 10mmHg, the test supports hyperventilation. Bradley5 noted: “In some patients

with hyperventilationthe PaC02and the PET C02may be in the normal range. In those who are asymptomatic at the time of testing, this finding could be accepted. However, a normal level while experiencing symptoms negates hypocapnia as the cause of symptoms. It prompts a search for a n alternative explanation.” Palpation and observation can demonstrate a paradoxical breathing pattern in which the abdomen retracts and the upper chest expands on inhalation (as opposed to normal abdominal protrusion and lower thorax expansion). The breath-holding-time test does not require additional measurements or equipment. The time a hyperventilating patient can hold his or her breath is usually greatly reduced, often not beyond 10 to 12 seconds. Thirty seconds has been used as the approximate dividing line between hyperventilators and normals by some clinicians. It is worth noting that breathless patients without hyperventilation may have equal difficulty in breath holding.18 Buteyko performed comparative studies with a simple breath-holding technique to test C02levels and found that a simple technique of breath holding after expiration could predict the percent of alveolar C02 and therefore the degree of hyperventilation to a high degree of accuracy. According to his calculations, optimal levels of alveolar PC02 correlate to postexpiratory breath holding time of 40 to 60 seconds. Many asthmatics and hyperventilators are found to be able to hold the breath out for less than 10 seconds.2830

Caution Bradley cautioned the following: The hypervendation provocation test is best done before explanations of symptoms, to prevent suggestion and bias. Patients need to be warned only of a dry mouth. The patient is asked to concentrate on how they feel during the 1-2 minute period when they are over breathing at the rate of 30-40 per minute. The rate is set by the examiner’s hand movements. The operator must stress the importance of the test and the need to continue for as long as they can. An arterial blood gas determination at the end of the test can be of use to establish the depth of hypocapnia. Some clinicians rely on as little as 12 deep breaths which the patient can recover from easily, and subjective symptoms produced are recorded. In both the breath holding and voluntary over-breathing tests, the skills of the clinician are importantfor maintaining the trust and co-operation of patients.

The Nijmegan Questionnaire Bradley5 pointed out that: As yet there is no “gold standard” laboratory test to clinch the diagnosis of CHVS. However the questionnaire provides a non-invasive test of high sensitivity (up to 91%) and specificity up to 95%.31This easily administered internationally validated3*diagnostic questionnaireis the simplest, kindest and to

Syndromes and Special Topics

I

I I

Chest pain Feeling tense Blurred vision

Never 0

I I

I

Rare 1

I

I I I

Sometimes

2

I

Often

3

I I

I

Veryoften 4

1

I

I

I

Dizzy spells Feeling confused Faster or deeper breathing Short of breath Tight feelings in chest Bloated feeling in stomach Tingling fingers Unable to breathe deeply Stiff fingers or arms Tight feelings round mouth Cold hands or feet

'Nijmegen. Patients mark with a tick how often they suffer from the symptoms listed. A score above 23/64is diagnostic of hyperventilation syndrome.

Figure 56-3 Nijmegenquestionnaire. (From Chaitow L. Bradley D. Gilbert C. Multidisciplinaryapproachesto breathing pattern disorders, London: Churchill Livingstone. 2002: 176.)

date most accurate indicator of acute/chronic hyperventilation. It also has great educative value as patients often for the first time appreciate the widespread nature of their symptoms. Re-testing at a later date is helpful in showing patients their progress as their symptoms decrease or vanish.

Bradley noted that the results of this simple test also help indicate whether the initiating trigger causing the HVS/BPDs has been resolved, suggesting that the patient has only to deal with the '%ad breathing" habit and musculoskeletal and motor pattern changes, or whether the initiating triggers are ongoing or unresolved and may need further cognitive help (Figure 56-3).

BIOMECHANICAL (STRUCTURAL) CONSIDERATIONS The Structure-Function Continuum Nowhere in the body is the axiom of structure governing function more apparent than in its relation to respiration. Just as prolonged changes in patterns of use, such as an inappropriate [hyperventilation]breathing pattern, induce structuralchanges, involving the muscles and joints (e.g., rib) of respiration, so do these changes ultimately prevent normal function. Ultimately, the self-perpetuating cycle of functional change creating structural modification, leading to

reinforced functional tendencies, can become complete, from whichever direction dysfunction derives. Examples follow: Structural adaptations can prevent normal breathing function. Abnormal breathing function ensures continued structural adaptational stresses.17 Restoration of normal function demands restoration of adequate structural mobility, while maintenance of restored biomechanical flexibility requires that function (how the individual breathes) should be normalized through reeducation and training. Individually, neither approach is as useful as a combination of restoration of structural integrity, combined with functional improvement. It should be obvious that other underlying etiologic features, whether these relate to psychosocial, biochemical, or biomechanical factors, should be addressed as far as possible as a prerequisite of rehabilitation.

The Muscles of Breathing The muscles associated with breathing function can be grouped as either inspiratory or expiratory. They are either primary in that capacity or provide accessory support.

Hyperventilation Syndrome/

Because expiration is primarily an elastic response of the lungs, pleura, and "torsion rod" elements of the ribs, all muscles of expiration could be considered to be accessory muscles, as they are recruited only during increased demand. They include internal intercostals, abdominal muscles, transverse thoracis, and subcostales. With increased demand, iliocostalis lumborum, quadratus lumborum, serratus posterior inferior, and latissimus dorsi may support expiration, including during the high demands of speech, coughing, sneezing, singing, and other special functions associated with breathing. Space does not permit in-depth discussion of the muscles of respiration, further details of which can be found in Chaitow and colleagues.6

Structure-Function Summary Respiratory function-breathing-depends on the efficiency with which the structures constituting the pump mechanisms operate. At its simplest, the thoracic spine and the attaching ribs, together with their anterior sternal connections, along with all the soft tissues, muscles, ligaments, tendons, and fascia, need to be structurally intact, with an uncompromised neural supply, in order to function optimally. Without an efficient pump mechanism, all other respiratory functions are suboptimal. Clearly a host of dysfunctional patterns can result from altered airway characteristics, abnormal status of the lungs, or from emotional and other influences. Even if allergy or infection is causal in altering the breathing pattern, the process of breathing can usually be enhanced by relatively unglamorous nuts and bolts features such as normalization of rib restrictions or shortened upper fixator muscles.

Neural Regulation of Breathing6 Respiratory centers in the brainstem unconsciously influence and adjust alveolar ventilation to maintain arterial blood oxygen and carbon dioxide pressures at relatively constant levels, to sustain life under varying conditions and requirements. The three main groups are as follows: The dorsal respiratory group, located in the distal portion of the medulla, receives input from peripheral chemoreceptors and other types of receptors via the vagus and glossopharyngeal nerves. These impulses generate inspiratory movements and are responsible for the basic rhythm of breathing. The pneumotaxic center in the superior part of the pons transmits inhibitory signals to the dorsal respiratory center, controlling the filling phase of breathing. The ventral respiratory group, located in the medulla, causes either inspiration or expiration. It is inactive in quiet breathing but is important in stimulating

abdominal expiratory muscles during levels of high respiratory demand. The Hering-Breuer reflex prevents overinflation of the lungs and is initiated by nerve receptors in the walls of the bronchi and bronchioles sending messages to the dorsal respiratory centre, via the vagus nerve. The reflex "switches off" excessive inflation during inspiration, as well as excessive deflation during exhalation. The autonomic nervous system enables the automatic unconscious maintenance of the internal environment of the body in ideal efficiency and adjusts to the various demands of the external environment, be it sleep with repair and growth, quiet or extreme physical activity, or stress (Figure 56-4). A "third" nervous system regulating the airways has been recognized, called the nonadrenergic noncholinergic (NANC) system. Containing inhibitory and stimulatory fibers, nitric oxide (NO) has been identified as the NANC neur~transmitter?~ NANC inhibitory nerves cause calcium ions to enter the neuron, mediating smooth muscle relaxation and bronchodilation. NANC stimulatory fibers-also called C-fibers-are found in the lung supporting tissue, airways, and pulmonary blood vessels and appear to be involved in bron&wonstriction following exercise-induced asthma.32

Chemical Control of Breathing The central role of respiration is to maintain balanced concentrations of oxygen (9) and carbon dioxide (C02) in the tissues. Increased levels of C 0 2 act on the central chemo-sensitive areas of the respiratory centers themselves, increasing inspiratory and expiratory signals to the respiratory muscles. O2 on the other hand, acts on peripheral chemoreceptors located in the carotid body (in the bifurcation of the common carotid arteries) via the glossopharyngeal nerves and the aortic body (on the aortic arch), which sends the appropriate messages via the vagus nerves to the dorsal respiratory center.

Voluntary Control of Breathing Automatic breathing can be overridden by higher cortical conscious input (directly via the spinal neurones, which drive the respiratory muscles) in response to, for instance, fear or sudden surprise. Speaking requires voluntary control to interrupt the normal rhythmicity of breathing, as does singing and wind instrument playing. Evidence indicates that the cerebral cortex and thalamus also supply part of the drive for normal respiratory rhythm during wakefulness. (Cerebral influences on the medullary centers are withdrawn during sleep.) Habitual BPDs and HVS probably originatefrom some of these higher

center^.^

Syndromes and Special Topics

-........_..Parasympathetic Sympathetic

-----

Motor (to skeletal muscle)

Figure 56-4 Schema of the autonomic innervation (motor and sensory) of the lung and the somatic (motor) nerve supply to the intercostal muscles and diaphragm. (From Scanlan C, Wilkins R, Stoller J. Egan’s fundamentals of respiratory care, ed 7. St. Louis: Mosby, 1999.)

THERAPEUTIC CONSIDERATIONS AND THERAPEUTIC APPROACH Treatment and Rehabilitation of Hyperventilation SyndromeBreathing Pattern Disorders Different models of care in managing HVS/BPDs are available. It is assumed that all organic causes of breathing pattern changes have been excluded and that coexisting problems such as asthma, chronic obstructive airway disease, chronic pain, and hormonal imbalances receive appropriate specialized attention. It is also assumed that manual therapy approaches would be incorporated as an essential element of rehabilitation. Bradley described a physical therapy model of rehabilitation for HVS/BPDs as follows535: Management includes assessment and treatment involving detailed explanations of breathing pattern disorders and building an individual integrated recovery programme based on: breathing retraining tension release through talk and relaxation stress perception and management

enjoyable graduated exercise prescriptions rest/sleep guides

Apart from the essential manual therapy elements of rehabilitation (see later), Bradley noted that: As many new patients present in a state of hyper-arousal the initial assessment and treatment programmes [should] highlight this. Emphasis on de-sensitising through breathing retraining and relaxation is . . . one starting point.

B r a d l e y ’ ~ physical ~,~~ therapy rehabilitation follows stages that are summarized in the acronym BETTER Breathing retraining, Esteem/self-image, Total body relaxation, Talk/breath control, Exercise prescription, Rest /sleep. Breathing retraining incorporates a number of elements: Awareness of faulty breathing patterns Relaxation of the upper chest, shoulders, and accessory muscles Abdominal/low chest breathing pattern retraining Awareness of normal breathing rates and rhythms both at rest and during activity

Hyperventilation Syndrome/Breathing Pattern Disorders

The elements of the physical therapy protocol involving relaxation, exercise, talk/breath control, and sleep are all individualized and are not described here.

Breathing Rehabilitation Exercises Box 56-1 describesthreebreathing rehabilitation exercises.

Is Breathing Retraining Effective?

An Osteopathichlaturopathic Protocol for Care of Hyperventilation SyndromeBreathing Pattern Disorders Initial (and continual/periodic) assessment of breathing function based on functional evidence and palpation determines what needs to be done to improve breathing function. Education and information are vital for creating motivation and awareness as to why homework is essential in normalizing BPDs. The patient must understand clearly that the practitioner/therapist can do no more than create an environment, a possibility, for restoration of more normal function, but the breathing work itself is up to the patient. Treatment of muscles and joints alone, no matter how appropriate, can never restore normal breathing patterns without cooperative effort. Conversely,breathing retraining without the freeing of restricted structures is far more difficult to achieve. Psychotherapy and counseling are also unlikely to be successful unless retraining is introduced, and structural factors are dealt with. Manual attention to the upper fixators/accessory breathing muscles (upper trapezii, levator scapulae, scalenes, sternocleidomastoid, pectorals, and latissimus dorsi) is usually required. The diaphragm area also requires direct attention as a rule (lower anterior intercostals, sternum, costal margin, beneath costal margin, abdominal attachments, quadratus lumborum and psoas). Active trigger points in these muscles may need deactivating manually or via acupuncture. The thoracic spine and ribs may require mobilization (osteopathicor chiropractic adjustments). Osteopathic lymphatic pump methods may be required if there is evidence of stasis. Retraining: Various breathing exercises should be introduced, individualized to the specific needs of the patient commonly on the basis of pursed lip breathing and pranayama yoga methods (see Box 56-1 later).36-38 Relaxation methods including autogenic training or progressive muscular relaxation, or both, might usefully be introduced. Sleep pattern disturbances might require attention. Exercise of aerobic nature should be carefully introduced. Dietary advice and counseling should be introduced as appropriate.

Chronic HVS/BPDs are commonly successfully treated; however, a timeframe of 12 to 26 weeks may be required, with active patient participation throughout to break well-established habits. Lum41 discussed the reasons for people becoming hyperventilators: Neurological considerations can leave little doubt that the

habitually unstable breathing is the prime cause of symptoms. Why they breathe in thisway must be a matter for speculation, but manifestly the salient characteristics are pure habit. Lum' reported that more than 1000 anxious and phobic patients were treated using breathing retraining, physical therapy, and relaxation. Results indicated the following:

Symptoms were usually abolished in 1 to 6 months with some younger patients requiring only a few weeks. At 12 months 75%were free of all symptoms, 20%had only mild symptoms, and about 1 in 20 patients had intractable symptoms. Breathing rehabilitation therapy was evaluated in patients with HVS, the diagnosis based on the presence of several stress-related complaints, reproduced by voluntary hyperventilation." Patients with organic diseases were excluded, and most patients met the criteria for an anxiety disorder. Therapy was conducted in the following sequence: Brief, voluntary hyperventilation to reproduce the reported complaints Reattribution of the cause of the symptoms to hyperventilation Explaining the rationale of therapy involving reduction of hyperventilation by acquiring an abdominal breathing pattern, with slowing down of expiration Breathing retraining for 2 to 3 months working with a physiotherapist After breathing therapy, the sum scores of the Nijmegen Questionnaire were markedly reduced. A canonical correlation analysis relating the changes of the various complaints to the modifications of breathing variables showed that the improvement of the complaints was correlated mainly with the slowing down of breathing frequency.

Osteopathic Treatment of Chronic Asthma In a pretest/posttest crossover study using four osteopathic manipulative procedures, compared with sham

Syndromes and Special Topics

1. Pursed lip breathing3'.=

Pursed lip breathing, combined with diaphragmatic breathing, enhances pulmonary efficiency. The patient is seated or supine with the dominant hand on the abdomen and the other hand on the chest. The patient is asked to breathe in through the nose and out through the mouth, with pursed lips, ensuring diaphragmatic involvement by means of movement of the abdomen against the hand on inhalation. Exhalation through the pursed lips is performed slowly and has been shown to relieve dyspnea, slow the respiratory rate, increase tidal volume, and help restore diaphragmatic function. Author's Note: Essentially blowing firmly and slowly, through a narrow aperture such as pursed lips, effectively tones the diaphragm via eccentric isotonic activity. 2. Antiarousal breathingSas

The patient is asked to sit or recline comfortably and exhale slowly and fully through pursed lips, and the following guidance is given: Imagine a candle flame about 6 inches from your mouth, and blow a thin stream of air at it (pursed lip breathing). As you exhale, count silently to establish the length of the "out breath." When you have exhaled fully, without strain, pause for a count of '1 ," then inhale through the nose. Full exhalation creates a =coiledspring," making inhalation easier. Count to yourself to establish how long your "in breath" lasts.

procedures, involving 10 individuals diagnosed with chronic asthma, researchers demonstrated signrficant increases in both upper and lower thoracic forced respiratory excursion. Subjective evaluation of asthma symptoms ("ease of breathing") improved after treatment, but not sham treatment. However, the symptoms did not improve to a statistically sigruhcant The four procedures used were as follows: Introduction of balanced ligamentous tension at the atlantooccipital and cervicothoracicjunctions Still's method for treatment of elevated first rib Release of lower rib exhalation restriction (depressed rib status) Diaphragmatic release

Without pausing to hold the breath, exhale slowly and fully, through pursed lips, blowing the air in a thin stream, and then pause for a count of 1. Repeat the inhalation and exhalation for 230 cycles twice daily. After some weeks of daily practice you should achieve an inhalation phase that lasts 2 to 3 seconds and an exhalation phase of 6 to 7 seconds, without strain. Exhalation should always be slow and continuous; there is little value in breathing the air out in 2 seconds and then simply waiting until the count reaches 8 before inhaling again! Feelings of anxiety should reduce with this exercise. Practice twice daily, and repeat the exercise for a few minutes (6 cycles takes about 1 minute) every hour if anxious or when stress increases. Practice on waking; before bedtime; and, if possible, before meals. 3. Recitation of mantra or prayer

The respiratory (and cardiovascular) effects of rosary prayer ("Ave Maria" in Latin) and recitation of a yoga mantra were assessed.40 Results were similar, showing a slowing of respiration to approximately 6 counts per minute and synchronization of all cardiovascular rhythms (Traube-Hering-Meyer [THM] oscillations), representing blood pressure, heart rate, cardiac contractility, pulmonary blood flow, cerebral blood flow, and movement of cerebrospinalfluid. This influence on autonomic activity, represented by the THM oscillations, is clearly health enhancing, since it slows respiratory rate to the level considered optimal in breathing rehabilitati~n.'-~*~I

manipulation), as well as education combined with rehabilitation via specific home application of breathing exercises, can achieve marked benefit in HVS/BPDs, as well as breathing dysfunction with a pathologic background.

SUMMARY HVS/BPDs is a common disorder affecting up to 10% of patients in a general internal medicine practice. However, it is rarely recognized or appropriately treated. Breathing retraining is effective clinically and economically, as long as enough patience is exercised to actively engage the patient in a program requiring weeks to months of behavioral change.

The implication is that a combination of biomechanical facilitation of breathing (osseous and soft tissue

1. Lum LC.Hyperventilationsyndromes in medicine and psychiatry: a review. J R Soc Med 1987;80.229-331. 2. Newton E.Hyperventilationsyndrome. The emergency department. Available online at www.emedicine.com/EMERG/topic270.htm [accessed June29,20011. 3. Damas-Mora J,Davies L, Taylor W, JennerFA. Menstrual respiratory changes and symptoms. Br J Pyschiatry 1980;136:492497.

4. Lum LC. Hyperventilation:the tip and the iceberg. J Psychosom Res 1975;19:375-383. 5. Bradley D. Physiotherapy breathing rehabilitation strategies. In Chaitow L, Bradley D, Gilbert C, eds. Multidisciplinaryapproaches to breathing pattern disorders. Edinburgh: Churchill Livingstone, 2002. 6. Chaitow L, Bradley D, Gilbert D. Multidisciplinary approaches to breathing pattern disorders. Edinburgh: C h M Livingstone, 2002.

Hyperventilation SyndromeBreathing Pattern Disorders 7. T i o n s BH, Ley R, eds. Behavioral and psychological approaches to breathing disorders. New York Plenum Press, 1994115. 8. West J. Respiratory physiology. Philadelphia: Lippincott Williams & wilkins, 2000. 9. Jennett S. Control of breathing and its disorders. In T m o n s BH, Ley R, eds. Behavioral and psychological approaches to breathing disorders. New York Plenum Press, 1994. 10. Brostoff J. Complete guide to food allergy. London: Bloomsbury, 1993. 11. Hough A. Physiotherapy in respiratory care. London: Stanley Thornes, 1996. 12. Han JN, Stegen K, Simkens K, et al. Unsteadiness of breathing in patients with hyperventilation syndrome and anxiety disorders. Eur Respir J 1997;10167-176. 13. Beck JG, Shipherd JC, Ohtake I? Do panic symptom profiles influence response to a hypoxic challenge in patients with panic disorder? A preliminary report. Psychosom Med 2000;6267&683. 14. Wilhelm FH, Trabert W, Roth WT. Characteristics of sighing in panic disorder. Biol Psychiatry 2001;49606-614. 15. Conway AV, Freeman LJ, Nixon PG. Hypnotic examination of trigger factors in the hyperventilation syndrome. Am J Clin Hypn 1988;30296-304. 16. Freeman LJ, Conway A, Nixon PG. Physiological responses to psychological challenge under hypnosis in patients considered to have the hyperventilation syndrome: implications for diagnosis and therapy. J R Soc Med 1986;7976-83. 17. Garland W. Somatic changes in hyperventilating subject. Presentation at International Society for the Advancement of Respiratory Psychophysiology Congress, France, 1994. 18. Gardner WN. The pathophysiology of hyperventilation disorders. Chest 1996;109:516-534. 19. Nixon PG. The grey area of effort syndrome and hyperventilation: from Thomas Lewis to today. J R CONPhysicians Lond 1993;27:377-383. 20. Werbach M. Adult attention deficit disorder: a nutritional perspective. J Bodywork Mov "her 2000;4182-183. 21. De Guire S, Gervitz R, Kawahara Y, Maguire W. Hyperventilation syndrome and the assessment and treatment for functional cardiac symptoms. Am J Cardiol1992;70673-677. 22. Kumar P,Clark M. Clinical medicine, ed 4. Edinburgh: WB Saunders, 1998:687-688. 23. Calloway SP, Fonagy P. Aerophagia and irritable bowel syndrome. Lancet 1985;2:1368. 24. Magarian GJ. Hyperventilation syndromes: infrequently recognized common expressions of anxiety and stress. Medicine 1982;61:219-236. 25. Fried R, Grimaldi J. The psychology and physiology of breathing. New York Plenum Press, 1993:186-187. 26. Chambers JB, Kiff PJ, Gardner WN, et al. The value of measuring end tidal partial pressure of carbon dioxide as an adjunct to treadmill exercise testing. BMJ 1988;2961281-1285.

27. Nixon PG, Freeman LJ. The 'thinktest': a further technique to elicit hyperventilation.J R Soc Med 1988;81:277-279. 28. Courteney R. The Buteyko Method-an osteopathic approach to asthma? Osteopathy Today August 200216-19. 29. Bowler SD, Green A, Mitchell CA. Buteyko breathing techniques in asthma: a blinded randomised controlled trial. Med J Aust 1998;169575-578. 30. Buteyko K. Buteyko method; experience of application in medical practice. Moscow: Patriot, 1990. 31. Van Dixhoom J, Duivenvoorden HJ. Efficacy of Nijmegen questionnaire in recognition of the hyperventilationsyndrome.J Psychosom Res 1985;29199-206. 32. Vansteenkiste J, Rochette F, Demedts M. Diagnostic tests of hyperventilation syndrome. Eur Respir J 1991;4393-399. 33. Snyder SH. Nitric oxide: first in a new class of neurotransmitters? Science 1992;257494-496. 34.Beachey W. Respiratory care anatomy & physiology. St Louis: Mosby, 1998. 35. Bradley D. Hyperventilation syndrome/breathing pattern disorders. Auckland, N Z Tandem Press, 1998. 36. Cappo BM, Holmes DS.The utility of prolonged respiratory exhalation for reducing physiological and psychological arousal in non-threatening and threatening situations. J Psychosom Res 1984;28:265-273. 37. Faling L. Controlled breathing techniques and chest physical therapy in chronic obstructive pulmonary disease. In Casaburi R, ed. Principles and practices of pulmonary therapy. Philadelphia: WB Saunders, 1993. 38. Tiep BL, B u n s M, Kao D, Madison R, Herrera J. Pursed lip breathing using ear oximetry. Chest 1986;90:21&221. 39. Grossman P, de Swart JC, Defares PB. A controlled study of a breathing therapy for treatment of hyperventilation syndrome. J Psychosom Res 1985;2949-58. 40. Bemardi L, Sleight P, Bandinelli G, et al: Effect of rosary prayer and yoga mantras on autonomiccardiovascular rhythms: a comparative study. BMJ 2001;323:1446-1449. 41. Lum LC. Hyperventilation and anxiety state. J R Soc Med 1981; 741-4. 42. Han JN, Stegen K, De Valck C, et al.Influence of breathing therapy on complaints, anxiety and breathing pattern in patients with hyperventilationsyndrome and anxiety disorders.J Psychosom Res 1996;41:481-493. 43. Bockenhauer S, Julliard KN, Lo KS, et al. Quantifiable effects of osteopathic manipulative techniques on patients with chronic asthma. J Am osteopath Assoc 2002;102371-375.

Immune Support

CHAPTER CONTENTS Introduction 645 Psychoneuroimmunology 645 Stress 646 Cyclic Nucleotides and Immune Function 646 Lifestyle 647 Nutritional Factors 647 Nutrient Deficiency 647 Protein 647 Sugar 647 Obesity 648 Lipids 648 Alcohol 648 Vitamins 648 Minerals 649 Trace Minerals 650

EnhancingThymus Function 650 Antioxidants 650 Nutrients 651 Botanicals 651 Echinacea spp. 651 Panax ginseng 651 Astragalus membranaceus 652 Therapeutic Approach 652 General Measures 652 Supplements 652 Botanicals 652

INTRODUCTION

PSYCHONEUROIMMUNOLOGY

The immune system is a complex integration of synergistic segments that are continuously barraged by stimulifrom both internal and external sources. Immunology has continued to be a rapidly developing field in which mechanisms are continually being conceptualized and revised. For the physician interested in assessing and maintaining a patient’s health, the development of a thorough understanding of the clinical aspects of the immune system and the many factors that enhance and/or inhibit normal function is essential. The immune system is truly “holistic,” as evidenced by the close association of psychological, neurologic, nutritional, environmental, and hormonal factors with immune function. Supporting the immune system is critical to good health. Conversely, good health is critical to supporting the immune system. The best approach to supporting immune function is a comprehensive plan involving lifestyle, stress management, exercise, diet, nutritional supplementation, glandular therapy, and the use of plant-based medicines.

Psychoneuroimmunology (PNI) is the term used to describe the interactions between the emotional state, nervous system function, and the immune system. The growing body of knowledge documenting the mind’s profound influence on physiology in health and disease necessitates a fundamental change in the way physicians perceive their patients. An important step is the study of nervous system response to environmental or intrapsychic perceptions that activate endocrine and neurotransmitter processes, which in turn influence the immune system.’ A complete and detailed account of the many facets of PNI, or behavioral immunology, is beyond the scope of this chapter. The role of attitude and emotions in immune function was also discussed in Chapter 8, and the importance of stress management to a healthy immune system is discussed in Chapter 62. We focus here on the effects of stress on the immune response. 645

Syndromes and Special Topics

Stress The term stress-induced illness is certainly not a misnomer, because many clinical and experimental studies have clearly demonstrated that stress, personality, attitude, and emotion are etiologic or contributory in suppressing the immune system as well as leading to the development of many diverse diseases.' Reaction to stressful stimuli is entirely individual, reinforcing the fact that people differ sigruficantly in their perceptions and responses to various life events. The variations in response help account for the wide diversity of stress-induced illnesses. Stress-induced increases in corticosteroid and catecholamine levels lead to an immunosuppressed state, leaving the host susceptible to infectious and carcinogenic illnesses. This immunosuppression is proportional to the level of stress, and although the effects are numerous, they appear to involve a common mechanism: an increase in glucocorticoids, proinflammatory cytokines, and catecholamines resulting in significant alterations in hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal medullary (SAM)axes, leukocyte function, thymic involution, and suppressed lymphopoiesis. More than 150 clinical studies have now shown that stress can alter immune function and contribute to the development of signhcant disease and poor Lymphocytes, monocytes or macrophages and granulocytes, have receptor sites for the many regulating hormones and neurotransmitters of the HPA and SAM axes. Alterations in these compounds lead to disruption of cellular trafficking, proliferation, cytokine secretion, antibody production, and cytolytic activity. For example, glucocorticoids inhibit the production of interleukin-12 (IL-l2), interferon-gamma (IFN-y), IFN-a, and tumor necrosis factor-alpha (TNF-a) by antigen-presenting cells and type 1 helper T (Thl) cells, but upregulate the production of IL-4, IL-10, and IL-13 by Th2 cells. This mechanism systemically causes a selective suppression of the Thl-cellular immunity axis and a shift toward Th2-mediated humoral immunity, rather than generalized immunosuppression. During an immune response and inflammation, the activation of the stress system, and thus increased levels of systemic glucocorticoids through induction of a Th2 shift, may actually protect the organism from systemic "overshooting" with Thl/ proinflammatory cytokines and other products of activated macrophages with tissue-damaging potential. However, conditions associated with significant changes of glucocorticoids, such as acute or chronic stress or cessation of chronic stress, severe exercise, pregnancy, and the postpartum state, through modulation of the Thl-Th2 balance may affect the susceptibility to or the course of infections as well as autoimmune and atopic/ allergic diseases.*5 A study in medical students taking examinations found that psychological stress produced a shift in the cytokine balance toward a Th2 profile.6 The data showed decreased synthesis of Thl cytokines,

including IFN-y, and increased produdion of Th2 cytokines, including IL-10. This study and others indicate that stressinduced decrease of Thl cytokines results in dysregulation of cell-mediated immune responses. To help demonstrate causal relations between psychosocial stressors and the development of infectious illness, investigators have inoculated subjects with several different types of vaccines to demonstrate clinically relevant alterations in an immunologic response to challenge under well-controlled conditions. For example, the chronic stress associated with caring for a spouse with Alzheimer disease or, for younger people, experiencing more stressful life events was associated with a poorer antibody response to an influenza virus vaccine than in well-matched control subjects.'~The premise is that the production of a delayed, weaker, and shorter-lived immune response to a vaccine would be analogous to an impaired immune responses to other pathogens. Consistent with this concept, subjects who show poorer responses to vaccines also experience higher rates of clinical illness as well as longer-lasting infectious episodes. Fortunately, the effects of stress on the immune system can be attenuated or even overcome with positive mood, effective stress reduction techniques, humor, laughter, and guided imagery.'~~

Cyclic Nucleotides and Immune Function In addition to glucocorticoids, the catecholamines also play a role in stress-induced immune dysfunction. In many systemsof the body, cholinergic and beta-adrenergic stimulation mediate diametrically opposed actions. On the cellular level, this antagonism is mediated via cyclic adenosine monophosphate (CAMP) and cyclic guanosine monophosphate (cGMP). Beta-adrenergic stimulation of responsive target tissues causes a rise in intracellular CAMP, whereas acetylcholine acting on muscarine receptors leads to increased levels of cGMP. The immune system is also affected by this yin-yang balance, although it appears to be much more complex than in other systems. Cyclic AMP and cGMP have shown antagonistic effects in all immune functions studied to date. The immune effects of cGMP include the fo1lowing9-l5: Enhanced lymphocyte mediated cytotoxicity Stimulation of T-cell rosette formation (a measure of thymus-derived lymphocyte activity) with inhibition of B-cell rosette formation Enhanced lymphoid cell and lymphocyte proliferation Increased lymphocyte lysosomal enzyme release Increased leukocyte chemotaxis From this information, it is apparent that cGMP usually serves to enhance immune function during infection and carcinogenesis.In contrast, CAMPappears to inhibit white blood cell (WBC) proliferation and functional response, thus possibly serving to modulate the immune system.

Immune Support There are many conditions in which enhancing cGMP activity and inhibiting CAMPactivity are contraindicated (e.g., autoimmune disease, atopy, gout, and psoriasis). In acute or chronic infection, however, the cGMP/cAMP ratio should be enhanced. Although many exogenous compounds alter the cGMP/cAMP ratio, paramount in any treatment plan are adequate rest and elimination of stressful activity. These measures promote an increase in cholinergic activity while concurrently lowering betaadrenergic activity. In addition, other CAMP-promoting factors (e.g., caffeine and its analogues) should be eliminated, and cGMP stimulators (e.g. ascorbic acid) should be in~reased.*~J~

LIFESTYLE A healthy lifestyle goes a long way in establishing a healthy immune system. This benefit is perhaps most obvious when one looks at the effects of lifestyle on natural killer cell activity.'&lsBox 57-1 lists the lifestyle practices associated with higher natural killer cell activity. One particular lifestyle factor that is absolutely critical to healthy immune function is adequate sleep. In healthy humans, sleep deprivation has consistently been demonstrated to impair different parameters of immune function and mood. Interestingly, the deterioration of immune function precedes the plummeting of subjective well-being and psychosocial performance in sleepdeprived s~bjects.'~

NUTRITIONAL FACTORS The health of the immune system gland is greatly affected by a person's nutritional status. Dietary factors that depress immune function include nutrient deficiency, excess consumption of sugar, consumption of allergenic foods, and high cholesterol levels in the blood. Dietary factors that enhance immune function include all essential nutrients, antioxidants, carotenes, and flavonoids. Consistent with good health, optimal immune function requires a healthy diet that:

Is rich in whole, natural foods, such as fruits,vegetables, grains, beans, seeds, and nuts. Is low in fats and refined sugars.

Not smoking Increased intake of green vegetables Regular meals Proper body weight More than 7 hours of sleephight Regular exercise A vegetarian diet

Contains adequate, but not excessive, amounts of protein.

In addition, individuals are encouraged to drink five or six 8-ounce glasses of water (preferably pure) per day. These dietary recommendations along with a positive mental attitude, a good high-potency multivitamin and mineral supplement, a regular exercise program, daily deep breathing and relaxation exercises (meditation, prayer, etc.), and at least 7 hours of sleep daily will go a long way in helping the immune system function at an optimum level.

Nutrient Deficiency Nutrient deficiency is the most common cause of a depressed immune system. Although research relating nutritional status to immune function has historically concerned itself with severe malnutrition states (i.e., kwashiorkor and marasmus), attention is now shifting toward marginal deficiencies of single or multiple nutrients and the effects of overnutrition. The plethora of clinical and experimental data has made inevitable the conclusion that a single nutrient deficiency can impair the immune system profoundly. Given the widespread problem of subclinical nutrient deficiency in Americans, it can be concluded that many are suffering from impaired immunity amenable to nutritional supplementation. This statement is particularly true in the elderly. Numerous studies have shown that most elderly Americans are deficient in at least one nutrient. Likewise, numerous studies show that taking a multivitamin and mineral supplement enhances immune function in elderly subjects (whether they suffer from overt nutritional deficiency or These findings have considerable fundamental, clinical, and public health sigruficance.

Protein The importance of adequate protein intake to proper immune function has been extensively studied? The most severe effects of proteincalorie malnutrition (PCM) are on cell-mediated immunity, although all facets of immune function are ultimately affected. PCM is not, however, usually due to a single-nutrient deficiency. It is normally associated with multiple nutrient deficiencies, and some immune dysfunctions attributed to PCM are most likely due to these other factors. Partial deficiencies of dietary vitamins produce a comparatively greater depression in the natural and inducible levels of cytotoxic activities than do partial protein deficiencies. Nonetheless, adequate protein is essential for optimal immune function.

Sugar The oral administration of 100-g portions of carbohydrate as glucose, fructose, sucrose, honey, or orange juice significantly reduces neutrophil phagocytosis, but starch has no effect. As can be seen in Figure 57-1, effects start

usually elevated in obese individuals, which may explain their impaired immune function (see later).

Lipids Increases of cholesterol, free fatty acids, triglycerides, and bile acids inhibit various immune functions, including the following2830: V '

0

;

2

3

4

5

Hours Figure 57-1 The effects of sugar on white cell phagocytic activity.

within 30 minutes, last for more than 5 hours, and typically show a 50% reduction in phagocytic activity at the peak of inhibition (usually 2 hours after Because polymorphonuclear leukocytes (PMNs) constitute 60% to 70% of the total WBCs and are a major portion of the defense mechanism, impairment of phagocybc activity leads to an immune-compromised state. Oral administration of increasingamounts of glucose progressively lowers neutrophil phagocytosis, with maximal inhibition corresponding to maximal blood glucose levels. In addition, oral ingestion of 75 g of glucose has been shown to depress lymphocyte response to mitogens, apparently through the elevation of insulin levels.25 Other parameters of immune function are also undoubtedly affected by sugar consumption. It has been hypothesized that the ill effects of high glucose levels are a result of elevation of insulin values and competition with vitamin C for membrane transport site^?^,^^ This hypothesis is based on evidence that vitamin C and glucose appear to have opposite effects on immunologic function and the fact that both substances require insulin for membrane transport into many tissues. Considering that the average American consumes 125 g of sucrose, plus 50 g of other refined simple sugars, each day, the conclusion that most Americans have chronically depressed immune systems is inescapable. It is clear, particularly during an infection, that the consumption of simple sugars, even in the form of fruit juice, is deleterious to the host's immune status. Short-term fasting could be encouraged, particularly during the first 24 to 48 hours of an acute infectious illness, because it results in a sigruficant (up to 50%) increase in phagocytic index.= The fast should not be continued for a long period, because eventually the leukocytes' energy sources will become depleted.

Obesity Obesity is associated with decreased immune status, as evidenced by reduced bactericidal activity of leukocytes and the higher morbidity and mortality from infections in obese individuals.28Cholesterol and lipid values are

Lymphoproliferation Response to mitogens Antibody response PMN chemotaxis Phagocytosis Optimal immune function therefore depends on control of these serum components. Interestingly, L-carnitine, even at minimal concentrations,has been shown to neutralize lipid-induced This effect is probably due to carnitine's role as a rate-limiting factor in the removal of fat emulsion from the

Alcohol Alcohol increases the susceptibility to experimental infections in animals; and alcoholics are known to be more susceptible to infections, especially pneumonia. Studies of immune function in alcoholism show a profound depression in most parameters of immunity.%

Vitamins Vitamin A Vitamin A plays an essential role in maintaining the integrity of the epithelial and mucosal surfaces and their secretions. These systems constitute a primary nonspecific host defense mechanism. Vitamin A has been shown to stimulate and/or enhance numerous immune processes, including the following: Induction of cell-mediated cytotoxicity against tumors Natural killer cell activity Lymphocyte blastogenesis Mononuclear phagocytosis Antibody response These effects are not due simply to reversal of vitamin A deficiency, because many of them are further enhanced by the administration of (supposedly) excessive levels of vitamin A.22,34In addition, vitamin A prevents and reverses stress-induced thymic involution, and additional vitamin A can actually promote thymus growth.35

Carotenes Carotenes have demonstrated a number of immuneenhancing effects. In addition to being converted into vitamin A, carotenes function as antioxidants. Because the thymus gland is so susceptible to damage by free radicals, beta-carotene may be more advantageous in

Immune Support enhancing the immune system than retinol. For more information, see Chapter 138.

Vitamin C

observed in the patients receiving 200 IU daily. No effect on autoimmune antibodies was noticed. No adverse effects were observed at any of the three dosage schedules of vitamin E. In another double-blind study in 451 elderly participants in a nursing home, vitamin E supplementation (200 IU daily) demonstrated a protective effect of vitamin E supplementation against upper respiratory tract infections, particularly the common

Vitamin C (ascorbic acid) plays an important role in the natural approach to immune enhancement.Although vitamin C has been shown to be antiviral and antibacterial, its main effect is via improvement in host resistance. Many different immunostimulatory effects have been demonstrated, including enhancing lymphoproliferaPyridoxine tive response to mitogens and lymphotrophic activity A pyridoxine deficiency results in depression of cellular and increasing interferon levels, antibody responses, and humoral immunity, lymphoid tissue a trophy, immunoglobulin levels, secretion of thymic hormones, leukopenia, reduction in quantity and quality of antibody and integrity of ground substance.",36Vitamin C also has direct biochemical effects similar to those of i n t e r f e r ~ n . ~ ~production, diminished lymphoproliferative response to mitogens, and decreased thymic hormone activity? Numerous clinical studies support the use of vitamin C Factors predisposing to deficiency are low dietary in the treatment of infectious conditions. In addition to pyridoxine intake, excess protein intake, consumption of its effects on the common cold, vitamin C has also been hydralazine (yellow) dyes, and use of alcohol and oral shown to be useful in other infectious condition^.^^ contraception. Vitamin C levels are quickly depleted during the stress of an infection as well as in chronic di~ease.3~ Folic Acid and Vitamin B,, It is useful to supplement vitamin C concurrently The megaloblasticstate induced by a deficiency of vitamin with flavonoids, which raise the concentration of vitaBI2 and/or folate results in improper WBC production min C in some tissues and potentiate its effects as well as and abnormal lymphocyte responses. Folic acid deficiency exert their own effectsM (the most common vitamin deficiency in the United Vitamin E States) has been shown to result in lymphoid atrophy and decreased lymphoproliferative response to mitogens, Vitamin E enhances both humoral immunity and cellsplenic plaque-forming colonies, and antibody producmediated immunity. A vitamin E deficiency results in lymphoid atrophy and decreases of lymphoproliferative tion. A BI2 deficiency, besides producing a deficiency in folate conversion to its active tetrahydrofolate form, response to mitogens, splenic plaque-forming colonies, leads to impairment of PMN phagocytosis and bactericiand monocyte function. Vitamin E antibody response, dal action." supplementation (30-150 IU)has been shown to4': Increase lymphoproliferative response to mitogens. Prevent free radical-induced thymus atrophy. Enhance helper T-cell activity. Increase splenic plaque-forming colonies, serum immunoglobulins, antibody response, PMN phagocytosis, and reticuloendothelialsystem activity. Elderly subjects may benefit from even higher dosages of vitamin E. A recent study sought to determine the effect of vitamin E supplementation at different dosages on immune function in 88 patients older than 65 years.22,42 To determine the effect of vitamin E on immune function, the researchers measured T-cell function by assessing delayed-type hypersensitivity (DTH) skin response; antibody response to hepatitis B, tetanus, and diphtheria, and pneumococcal vaccines; and autoantibodies to DNA and thyroglobulin. Vitamin E was given at 60, 200, or 800 IU for 235 days. Although the placebo group experienced an only 8% increase in DTH, the 60-IU group had a 20% increase, the 200-IU group a 58%increase, and the 800-IUgroup a 65%increase. With regard to antibody production, the best results were

Other B Vitamins Deficiencies of thiamin, riboflavin, and pantothenic acid lead to reduced antibody response, decreased splenic plaque-forming colonies, and lymphoid atrophy.

Minerals Iron Iron deficiency is a commonly encountered isolated nutritional deficiency that causes immune dysfunction in large numbers of patients. Marginal iron deficiency, even at levels that do not lower hemoglobin values, can influence the immune system. Lymphoid tissue atrophy, decreased lymphoproliferative response to mitogens, defective macrophage and neutrophil function, and decreased T cell/B cell ratios are common experimental and clinical findings." Iron is an important nutrient for bacteria as well as for humans. During infection, one of the body's nonspecific defense mechanisms to limit bacterial growth is to reduce plasma iron, and in vitro studies have shown that the bacteriostatic effects and some of the bactericidal effects

Syndromes and Special Topics

of serum are eliminated by the addition of iron to the serum.44As temperature rises, plasma iron levels drop, and when temperature is raised to fever levels, the growth of bacteria is inhibited, but not at high iron concentrations. These observations lead us to conclude that iron supplementation is probably contraindicated during acute infection, especially in patients with low transferrin levels. However, in patients with impaired immune function, chronic infections, and subnormal iron levels, adequate supplementation is essential.

Trace Minerals Trace minerals function primarily as activators of enzyme-metal-substrate complexes in which they are loosely bound cofactors. The role of these elements in these metalloenzymes is either structural, in which they influence the reactivity of the protein by stabilizing strained configurations of binding ligands about the metal atom, or catalytic, in which they act as centers of positive charge.

Zinc The hereditary zinc deficiency disease acrodermatitis enteropathica (AE) offers an excellent model for understanding the role of zinc in immunity. In AE, the number of T cells is reduced, lymphoproliferative response to mitogens is diminished, thymic hormone levels are lower, delayed cutaneous hypersensitivity is decreased, and PMN phagocytosis, chemotaxis, and cytotoxic activities are impaired. All of these effects are reversible upon adequate administration and absorption of zinc!5 Zinc serves a vital role in many immune system reactions; for example, it promotes the binding of complement (Clq) to immune complex, acts as a protectant against iron-catalyzed damage by free radicals, acts synergistically with vitamin A, is required for lymphocyte transformation, acts independently on lymphocytes as a mitogen, and is a necessary cofactor in activating serum thymic factor. In vitro, zinc inhibits the growth of several viruses, including rhinoviruses, picornaviruses, togaviruses, herpes simplex virus, and vaccinia virus.& Adequate zinc nutriture is particularly important in the elderly, and zinc supplementation in elderly subjects results in increased numbers of T cells and enhanced cell-mediated immune responses.46 Throat lozenges containing zinc became popular in the treatment of the common cold as a result of a doubleblind clinical trial in 1984 demonstrating that zinccontaining lozenges significantly reduced the average duration of common colds by 7 d a ~ s . 4The ~ lozenges used in this study contained 23 mg of elemental zinc, which the patients were instructed to dissolve in their mouths every 2 waking hours after an initial double dose. After 7 days, 86% of the 37 zinc-treated subjects were symptom-free, compared with 46% of the 28

placebo-treated subjects. Additional studies have confirmed these results.& Because high doses of zinc can actually impair immune function, a daily intake higher than 150 mg of zinc for longer than 1 week cannot be recommended.

Selenium Selenium, in its vital role in glutathione peroxidase, affects all components of the immune system, including the development and expression of all WBCs. Selenium deficiency results in depression of immune function, whereas selenium supplementation results in augmentation and/or restoration of immune functions. Selenium deficiency has been found to inhibit resistance to infection through impairment of WBC and thymus function, whereas selenium supplementation (100-200 pg/ day) has been shown to stimulate WBC and thymus function."-52 The ability of selenium supplementation to enhance immune function goes well beyond simply restoring selenium levels in selenium-deficient individuals. For example, in one study, selenium supplementation (200 pg/day) to individuals with normal blood selenium concentrations resulted in a 118%improvement in the ability of lymphocytes to kill tumor cells and an 82.3% rise in the activity of natural killer cells.5O These effects were apparently related to the ability of selenium to enhance the expression of the immune-enhancing compound IL-2 and, consequently, the rate of WBC proliferation and differentiation into forms capable of killing tumor cells and microorganisms. The supplementation regimen did not produce sigtuficant changes in the blood selenium levels of the participants. The results indicated that the immune-enhancingeffects of selenium in humans require supplementation above the normal dietary intake.

ENHANCING THYMUS FUNCTION Perhaps the most effective method of reestablishing a healthy immune system is employing measures to improve thymus function. Promoting optimal thymus gland activity involves the following: Prevention of thymic involution or shrinkage by ensuring adequate dietary intake of antioxidant nutrients Use of nutrients that are required in the manufacture or action of thymic hormones

Antioxidants The thymus gland shows maximum development immediately after birth. During the aging process, the thymus gland undergoes a process of shrinkage, or involution. The reason for this involution is that the thymus

Immune Support

gland is extremely susceptible to free radical and oxidative damage caused by stress, radiation, infection, and chronic illness. Many patients with impaired immune function as well as conditions associated with impaired immunity (e.g., chronic fatigue syndrome, cancer, acquired immunodeficiency syndrome) suffer from a state of oxidative imbalance characterized by a greater number of prooxidants than antioxidants in their systems. This situation is quite detrimental to thymus function. One of the primary ways in which antioxidants affect the immune system, particularly cell-mediated immunity, may be by protecting the thymus gland from damage. The antioxidant nutrients most important for protecting the thymus include the carotenes, vitamin C, vitamin E, zinc, and selenium.

Nutrients Many nutrients function as important cofactors in the manufacture, secretion, and function of thymic hormones. A deficiency of any one of these nutrients results in decreased thymic hormone action and impaired immune function. Zinc, vitamin B6, and vitamin C are perhaps the most critical. Supplementation with these nutrients has been shown to improve thymic hormone function and cell-mediated immunity. Zinc is perhaps the critical mineral involved in thymus gland function and thymus hormone action. Zinc is involved in virtually every aspect of immunity. When zinc levels are low, the number of T cells is reduced, thymic hormone levels are lower, and many WBC functions critical to the immune response are severely lacking. All of these effects are reversible with adequate administration and absorption of ~ i n c . 5 ~ 3

BOTANICALS Many herbs have been shown to have antibacterial, antiviral, and immunostimulatory effects, and a complete discussion is outside the scope of this chapter (several immune-enhancing botanicals are discussed in depth in Section 5). This chapter focuses on three of the most popular immune-enhancing botanicals, Echinuceu, Punux ginseng, and Astrugalus. These three herbs were selected on the basis of their ability to exert broadspectrum effects on immune functions and recognized popularity. They stimulate the body’s natural defense mechanisms via slightly different mechanisms and are in many ways the prototypes of the hundreds of plants with known immunological a~tivity?~

Echinacea spp. Perhaps the most widely used Western herb for enhancement of the immune system is Echinuceu. The two most widely used species are Echinucea angustifoh and

Echinuceu purpureu. Both have been shown to exert profound immune-enhancing effects. Several classes of constituents contribute to this acti0n.5~3~ One of the most important immune-stimulating components of Echinuceu are large polysaccharides, such as inulin, that activate the alternative complement pathway (one of the immune system’s nonspecific defense mechanisms) and increase the production of immune chemicals that activate macrophages. The result is increased activity of many key immune parameters: production of T cells, macrophage phagocytosis, antibody binding, natural killer cell activity, and levels of circulating neutrophils. Echinuceu strengthens the immune system even in healthy people. For example, in a study of healthy volunteers aged 25 to 40 years, the fresh-pressed juice of E. purpureu extract was found to increase the phagocytosis of Cundida ulbicuns by 30% to 40%; it also enhanced the migration of WBC cells to the scene of battle by 30% to 4O%?’ Besides immune support, Echinuceu also exerts direct antiviral activity and helps prevent the spread of bacteria by inhibiting a bacterial enzyme called hyuluronidase. This enzyme is secreted by bacteria in order to break through the body’s first line of defense, the protective membranes such as the skin or mucous membranes, so that the organism can enter the body. Echinuceu is discussed fully in Chapter 89.

Panax ginseng P. ginseng has been shown to exert immunomodulating activity as evidenced by its ability to enhance the following paramaters? Antibody plaque-forming cell response Circulatory antibody titer against sheep erythrocytes Cell-mediated immunity Natural killer cell activity Production of interferon Lymphocyte mitogenesis Reticuloendothelialsystem proliferative and phagocytic functions From a clinical perspective, the long-term ingestion of ginseng by individuals with mild immunodeficiency may reduce the risk of viral infection.Use in this manner is consistent with the historical use of ginseng by debilitated individuals. There is clinical evidence of benefit in these applications. Ginseng has been shown to prevent respiratory viral infections in a nursing home environment (89% relative risk reduction) and potentiate influenza vaccinations.~~9 It should be noted that large dosages of ginseng may be contraindicated in acute infections owing to possible inhibition of immune function (see Chapter 111for more information).

Astragalus membranaceus The root of Astrugulus is a traditional Chinese medicine used for viral infections. Clinical studies in China have shown it to be effective when used prophylactically against the common cold.60It has also been shown to reduce the duration and severity of symptoms in acute treatment of the common cold as well as to raise WBC counts in persons with chronic leukopenia. Research in animals has shown that Astrugulus apparently works by stimulating several factors of the immune system, including enhancing phagocytic activity of monocytes and macmphages, increasing interferon production and ~ t u r a killer l cell activity, improving T-cell activity, and potentiatingother antiviral mechanisms.60b1Astrugalus appears particularly useful in cases in which the immune system has been damaged by chemicals or radiation. In immunodepressed mice, AstruguZus has been found to reverse the T-cell abnormalities caused by cyclophosphamide, radiation, and aging." As with Echimea, the polysaccharides contained in the root of Astrugulus membrumceus contribute to the immune-enhancing effects.

THERAPEUTIC APPROACH A major challenge to the discerning cliniaan is to determine which of the preceding factors is the key to reactivating or supportinga patient's immune system.The regimen given here is meant as a general approach and must be tailored to the patient's specific needs in order to ITlilxiRljze the desired effects and limit unnecessary treatment.

General Measures Rest (bedrest better). Drink large amount of fluids (preferably diluted vegetable juices, soups, and herb teas). Limit simple sugar consumption (including fruit sugars) to less than 50 g/day.

1. Campeau S,Day HE, Helmreich DL, et al. Principles of psychoneuroendocrinology. Psychiatr Clin North Am 1998;21:259-276. 2.Olff M. Stress, depression and immunity: the role of defense and coping styles. PsychiaQ Res 1999;85:7-15. 3.Padgett DA, Glaser R. How stress influences the immune response. Trends Immunol2003;24444-448. 4. Mulla A, Buckingham JC. Regulation of the hypothalamepituitaryadrenal axis by cytokines. Baillieres Best Prad Res Clin Endocrinol Metab 1999;13503-521. 5.Matalka KZ. Neuroendocrine and cytokines-induced responses to minutes, hours, and days of mental stress. Neuro Endocrinol Lett 2003;24283-292. 6.Elenkov IJ. Glucocorticoidsand the Thl /Th2 balance. Ann N Y Acad Sci 2004;1024138-146. 7.KiecoltGlaserJK,Glaser R, Gravenstein S, et al. Chronic stress alters the immune response to influenza virus vaccine in older adults. Proc Natl Acad Sci U S A 1996;933043-3047.

Supplements High-potency multivitamin and mineral formula Vitamin C, 500 mg every 2 hours Bioflavonoids, 1000 mg/day Vitamin A, 5000 IU/day, or beta-carotene 25,OOO IU/day Zinc, 30 mg/day

Botanicals All dosages of botanicals should be given three timedday.

Echinacea spp. Dried root (or as tea), 0.5 to 1 g Freeze-dried plant, 325 to 650 mg Juice of aerial portion of E. putpureu stabilized in 22% ethanol, 2 to 3 ml Ticture (1:5), 2 to 4 ml Fluid extract (l:l),2 to 4 ml Solid (dry powdered) extract (6.5:l or 3.5% echinacoside), 150 to 300 mg

Panax ginseng The appropriate dose of ginseng depends on the ginsenoside content; if an extract or ginseng preparation contains high concentrations of ginsenosides (and presumably other active components), a lower dose will suffice. The standard dose for high-quality ginseng root is in the range of 4 to 6 g daily. For ginseng root extract containing 5% ginsenosides, the dose is typically 100 mg one to three times daily.

Astragalus membranaceus Dried root (or as decoction), 1to 2 g Tmcture (1:5), 2 to 4 ml Fluid extract (1:1),2 to 4 ml Solid (dry powdered) extract (0.5% 4-hydroxy-3methoxy isoflavone), 100 to 150 mg

8. Bums VE,Carroll D, Drayson M, et al. Life events, perceived stress and antibody response to influenza vaccination in young, healthy adults. J Psychosom Res 2003;55:569-572. 9.MacDonald CM. A chuckle a day keeps the doctor away: therapeutic humor and laughter. J Psychosoc Nurs Ment Health Serv 2004;42:18-25. 10.Strom TB, Carpenter CB. Cyclic nucleotides in immunosuppression-neuroendocrine pharmacologic manipulation and in vivo immunoregulation of immunity acting via second messenger systems. Transplant Proc 1980;12:304-310. 11. Femera G, Brascher H, Javierre M, et al. Rosette formation by human T and B lymphocytes in the presence of adrenergic and cholinergic drugs. Experientia 19769235941596. 12.Grieco M, Siege1 I, Goel Z. Modulation of human T lymphocyte rosette formation by autonomic agonists and cyclic nucleotides. J Allergy Clin Immunol1976;58:149-159.

Immune Support 13. Gallin J, Sandler J, Clyman R, et al. Agents that increase cyclic AMP inhibit accumulation of cGMP and depress human monocyte locomotion. J Immunol1978;120492-496. 14. Stephens C, Snyderman R. Cyclic nucleotides regulate the morphologic alterations required for chemotaxis in monocytes. J Immunol 1982;128:1192-1197. 15. Singh U. In vitro lymphopoiesis in foetal thymic organ cultures: effect of various agents. Clin Exp Immunol1980;41:150-155. 16. Kusaka Y, Kondou H, Morimoto K. Healthy lifestyles are associated with higher natural killer cell activity. Prev Med 1992;21:602-615. 17. Nakachi K, Imai K.Environmental and physiological influences on human natural killer cell activity in relation to good health practices. Jpn J Cancer Res 1992;83:789-805. 18. Morimoto K, TakeshitaT, Inoue-Sakurai C, et al. Lifestyles and mental health status are associated with natural killer cell and lymphokineactivated killer cell activities. Sci Total Environ 2001;2703-11. 19. Heiser P, Dickhaus 8, Opper C, et al. Alterations of host defence system after sleep deprivation are followed by impaired mood and psychosocial functioning. World J Biol Psychiatry 2001;289-94. 20. Marcos A, Nova E, Montero A. Changes in the immune system are conditioned by nutrition. Eur J Clin Nutr 2003;57(Suppll):S66S69. 21. Chandra RK. Nutrition and the immune system from birth to old age. Eur J Clin Nutr 2002;56(Suppl3):S73-576. 22. Chandra RK. Impact of nutritional status and nutrient supplements on immune responses and incidence of infection in older individuals. Ageing Res Rev 2004;391-104. 23. Sanchez A, Reeser J, Lau H, et al. Role of sugars in human neutrophilic phagocytosis. Am J Clin Nutr 1973;26:1180-1184. 24. Ringsdorf WM Jr, Cheraskin E, Ramsay RR Jr. Sucrose, neutrophilic phagocytosis and resistance to disease. Dent Surv 1976;5246-48. 25. Bemstein J, Alpert S, Nauss K, et al. Depression of lymphocyte transformation following oral glucose ingestion. Am J Clin Nutr 1977;30613. 26. Mann G. Hypothesis: the role of vitamin C in diabetic angiopathy. Perspect Biol Med 1974;17210-217. 27. Mann G, Newton P. The membrane transport of ascorbic acid. Ann N Y Acad Sci 1975;258243-252. 28. Palmblad J, Hallberg D, Rossner S. Obesity, plasma lipids and polymorphonuclear (PMN) granulocyte functions. Scand J Haematol 1977;19:293-303. 29. Waddell CC, Taunton OD, Twomey JJ. Inhibition of lymphoproliferation by hyperlipoproteinemic plasma. J Clin Invest 197658950-954. 30.Dianzani M, Torrielli M, Canuto R, et al. The influence of enrichment with cholesterol on the phagocytic activity of rat macrophages. J Pathol1976;118:193-199. 31. De Simone C, Ferrari M, Lozzi A, et al. Vitamins and immunity. 11. Influence of L-camitine on the immune system. Acta Vitamin01 Enzym01 1982;4135-140. 32. De Simone C, Ferrari M, Meli D, et al. Reversibility by L-camitine of immunosuppression induced by an emulsion of soya bean oil, glycerol and egg lecithin. Arzneimittelforschung 1982;32: 1485-1488. 33. Frank J, Witte K, Schrodl W, et al. Chronic alcoholism causes deleterious conditioning of innate immunity. Alcohol Alcohol 2004; 39:386-392. 34. Semba RD. Vitamin A, immunity, and infection. Clin Infect Dis 1994;19:489-499. 35. Seifter E, Rettura G, Seiter J, et al. Thymotrophic action of vitamin A. Fed Proc 1973;32947. 36.Bendich A. Vitamin C and immune responses. Food Techno1 1987;41:112-114. 37. Scott J. On the biochemical similarities of ascorbic acid and interferon. J Theor Biol1982;98:235-238. 38. Bendich A, Langseth L. The health effects of vitamin C supplementation: a review. J Am Coll Nutr 1995;14124-136. 39. Jacob RA, Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care 2002;5:66-74.

40. Di Car10 G, Mascolo N, Izzo AA, et al. Flavonoids: old and new aspects of a class of natural therapeutic drugs. Life Sci 1999;65: 337-353. 41. Kelleher J. Vitamin E and the immune response. Proc Nutr SOC 1991;5O:245-249. 42. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects: a randomized controlled trial. JAh4A 1997;2771380-1386. 43. Meydani SN, Leka LS, Fine BC, et al. Vitamin E and respiratory tract infections in elderly nursing home residents: a randomized controlled trial. JAMA 2004;292828-836. 44. StockmanJ. Infections and iron: too much of a good thing? Am J Dis Child 1981;13518-20. 45. Hadden JW. The treatment of zinc deficiency is an immunotherapy. Int J Immunopharmacol1995;17697-701. 46. Walker CF, Black RE. Zinc and the risk for infectious disease. Annu Rev Nutr 2004;24:255-275. 47.Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study. Antimicrob Agents Chemother 1984;2520-24. 48.Mossad SB, Macknin ML, Medendorp SV, et al. Zinc gluconate lozenges for treating the common cold: a randomized, doubleblind, placebo-controlled study. Ann Intern Med 1996;125: 81-88. 49. Kiremidjian-Schumacher L, Stotzky G. Selenium and immune responses. Environ Res 1987;42277-303. 50. Kiremidjian-SchumacherL, Roy M, Wishe HI, et al. Supplementation with selenium and human immune cell functions. II. Effect on cytotoxic lymphocytes and natural killer cells. Biol Trace Elem Res 1994;41:115-127. 51. Roy M, Kiremidjian-Schumacher L, Wishe HI, et al. Supplementation with selenium and human immune cell functions. I. Effect on lymphocyte proliferation and interleukin 2 receptor expression. Biol Trace Elem Res 1994;41:103-114. 52. Broome CS, McArdle F, Kyle JA, et al. An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status. Am J Clin Nutr 2004;80154-162. 53. Dardenne M, Pleau JM, Nabarra B, et al. Contribution of zinc and other metals to the biological activity of the serum thymic factor. Proc Natl Acad Sci U S A 1982;95370-5373. 54. Bogden JD, Oleske Jh4,Munves EM, et al. Zinc and immunocompetence in the elderly: baseline data on zinc nutriture and immunity in unsupplemented subjects. Am J Clin Nutr 1987;46:101-109. 55. Block IU,Mead MN. Immune system effects of echinacea, ginseng, and astragalus: a review. Integr Cancer Ther 2003;2247-267. 56. Barrett B. Medicinal properties of Echinacea: a critical review. Phytomedicine 2003;10:66-86. 57. Bauer R, Wagner H. Echinacea species as potential immunostimulatory drugs.In Wagner H, Famsworth NR,eds. Economic and medianal plant research, vol5. New York Academic Press, 1991:253-321. 58. McElhaney JE, Gravenstein S, Cole SK, et al. A placebo-controlled trial of a proprietary extract of North American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults. J Am Geriatr Soc 2004;52:13-19. 59. Scaglione F, Cattaneo G, Alessandria M, et al. Efficacy and safety of the standardised ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold. Drugs Exp Clin Res 1996;22:65-72. 60. Chang HM, But PPH, eds. Pharmacology and applicationsof Chinese materia medica. Singapore: World Scientific, 1986:1041-1046. 61. Zhao KS, Mancini C, Dona G. Enhancement of the immune response in mice by Astragalus membranaceus extracts. Immunopharmacology 1990;20225-233. 62. Chu DT, Wong WL, Mavligit GM. h u n o t h e r a p y with Chinese medicinal herbs. I. Immune restoration of local xenogeneic graftversus-host reaction in cancer patients by fractionated Astragalus membranaceus in vitro. J Clin Lab Immunol 1988;25:119-123.

Intestinal Protozoan Infestation and Systemic Illness

C H A P T E R CONTENTS Introduction 655 Protozoan 655 Giardia spp. 655 Entamoeba histolytica 656

Therapeutic Considerations 657 Artemisia annua 657 Berberine 657 Allium sativum and Juglans nigra 657 Intestinal Bacterial Milieu 657

Diagnostic Considerations 657

Conclusion 657

INTRODUCTI0N The gastrointestinal tract is the largest organ of immune surveillance in the body, home to two thirds of the total lymphocyte popu1ation.l Intestinal lymphocytes manifest a variety of responses that depend on their CD phenotype, histologic location, and communication with other effector cells. Stimulation of intestinal immune response networks by lumen-dwelling microbes may produce a variety of systemic responses that are independent of gastrointestinal symptoms? Immunologic hypersensitivity to Giurdia lumbliu, for example, has been shown to provoke asthma,3~~ arthritis,"-15 and uveitis.16 Hypersensitivity reactions may occur in In none of these the absence of digestive ~omplaints.6,'~,*~ cases was the mechanism of hypersensitivity known; eosinophilia was a feature in only two cases.lo,llA high frequency of preexisting atopic disease is seen in patients with chronic giardiasis"J8 and may be a factor in susceptibility to infection.

PROTOZOAN Giardia spp. Immunologic mechanisms other than hypersensitivity reactions may also be associated with chronic giardiasis. In humans, chronic giardiasis has been associated with deficiency of secretory immunoglobulin A (IgA)19and with impaired macrophage cytotoxicity?O characteristics that may predispose to systemic illness. Athymic mice chronically infected with Giardia muris do not demonstrate mucosal darnage.2I Gillon et alZ proposed that the

release of enteropathic lymphokines by intraepithelial T cells is the cause of the intestinal injury in chronic giardiasis. In humans, the severity of malabsorption observed with chronic giardiasis is more closely related to the presence of intraepithelial lymphocytes and the antibody titer to Giardiu cyst antigen than to the estimated parasite burden.= A normal immunologic response to the parasite may be necessary to avoid chronic infection but also creates much of the tissue damage associated with chronic giardiasis. Giurdiu may provoke systemic illness by nonimmunologic mechanisms. G . lumbliu can cause intestinal protein loss without producing diarrhea.24Specific micronutrient deficiencies have also been described in chronic giardiasis. Low levels of carotene and folatG5and abnormal absorption of vitamin A, folic acid, and vitamin occur in a large minority of patients with chronic symptoms. Nutritional deficiency associated with chronic giardiasis may add to the burden of illness. Bacterial overgrowth of the small bowel has been described in giardiasis and may contribute to m a l a b ~ o r p t i o n . In ~~,~~ one study, colonization of the jejunum with Cundidu ulbicuns was reported in 30% of patients with giardiasis and was absent in A role for intestinal candidosis in provoking systemic illness has been debated for more than a quarter century (review in reference 2). Some strains of G. larnblia contain double-stranded RNA viruses?8 The role of Giurdiu as a vector for viral infection requires further study. My colleagues and I conducted a 2-year retrospective study of 218 patients who presented to our medical 655

Systemic symptoms of patients with CFIDS Symptom

With giardiasis (?!) (n= 63)

Without giardiasis (%) (n= 157)

Depression

61

Muscle weakness Headache

46

19

41

36

Sore throat

41

11

Lymphadenopathy

36

8

Arthralgia

36

27

Myalgia

34

18

Flulike symptoms

34

6

Poor exercise tolerance

30

10

41

Modified from Galland L, Lee M, Bueno H, Hiernowitz C. J Nutr M e d 1990;2:27-32. CNDS, Chronic fatigue immune dysfunction syndrome.

clinic with a chief complaint of chronic fatigue.’* G. lumbliu infection was identified in 61 patients. The symptoms of patients with and without giardiasis are shown in (Table 58-1). All patients with giardiasis and 86%of patients without giardiasis complained of digestive symptoms, but these were generally mild. The most interesting difference between the two groups lies in the positive association between giardiasis and symptoms such as myalgia, muscle weakness, flulike feelings, sweats, and adenopathy.In fact, 61%of fatigued patients with giardiasis had been diagnosed elsewhere as suffering from chronic fatigue immune dysfunction syndrome (CFIDS), compared with only 19% of fatigued patients who did not have giardiasis. Cure of giardiasis resulted in clearing of fatigue and related “viral” symptoms (myalgia, sweats, flulike feelings) in 70% of cases and in some palliation of fatigue in l8%, and was of no benefit in 12%. The association between intestinal protozoa and chronic fatigue in patients without prominent digestive complaints may not be limited to giardiasis. In an unpublished presentation, I reported that 80% of patients with a diagnosis of CFIDS who were infected with the protozoan Blustocystis hominis showed signrficant improvement of fatigue associated with treatment that cleared the protozoa from stool specimens.29

Entamoeba histolytica Chronic infestation with Entumoebu histolyticu, another common protozoan parasite, has been associated with autoimmune phenomena, including the appearance of antibodies to colonic epithelial cellsw and the development of ulcerative colitis after cure of amebic Extraintestinal autoimmune reactions to intestinal amebiasis include a case of antiphospholipid antibody syndrome with deep vein thrombosis and pulmonary

embolism3* and development of symmetrical polyarthritis very similar to rheumatoid arthritis Singh et aP measured amebic antibody levels in 41 Indian patients with a primary diagnosis of RA, 35 age- and sexmatched healthy volunteers, 162 hospital inpatients, and 26 patients with other arthritides. Amebic antibody values were elevated in 39%of patients with RA and zero to 11% of the various control groups. Only two patients with RA had experienced recent diarrheal disease. These researchers suggest that an excessive and prolonged antibody response to E. histolyticu or other enteric organisms may contribute to joint inflammation in RA. Galland15 described a patient with rheumatoid-like arthritis and antinuclear antibodies whose arthritis went into rapid and complete remission upon treatment of G. lamblia infection with metronidazole. Relapse occurred when the patient acquired E. histolyticu during a trip to Egypt; remission occurred slowly after treatment of amebiasis. Diarrhea, polyarthritis, and circulating antinuclear antibodies developed in a U.S.serviceman heavily infested with Endolimx mm,an allegedly nonpathogenic ameba?’ Metronidazole rapidly reversed all abnormalities. The reported cases of amebic arthritis may represent a variant of parasitic rheumatism, an inflammatory polyarthropathy produced by circulating antigen-antibodycomplexes.%The presence of autoantibodies, however, is not characteristicof parasitic rheumatism, and suggests other mechanisms of immune dysfunction: Either a preexisting disease is exacerbated by intercurrent amebic infection or amebic infection itself provokes autoimmunity, perhaps mediated by the action of immune response genes.= Reiter syndrome (arthritis, uveitis and urethritis) has been reported as a complication of infection with two other and Cyclosporu.40 intestinal protozoa, Cryptosp~ridium~~ Cyclospora cuyetanensis has also provoked Guillain-Bad syndrome, a severe autoimmune neuropathy4’ E. histolyticu contains a soluble lectin that is mitogenic for T lymphocytes.42*43 Activation of helper T cells by this lectin may induce replication of human immunodeficiency virus (HIV)in vivo. In one report, soluble E. histolyficu protein, although not mitogenic itself, induced HIV replication in tissue culture of lymphocytes obtained from three of seven men with chronic HIV infection.44Infection with E . histolytica and other parasites may promote the development of acquired immunodeficiency syndrome (AIDS)in HIV-infected indi~iduals.4~,~ Epidemiologic evidence associates preexisting intestinal protozoan infection with the appearance of Kaposi sarcoma among homosexual men in the United Although the influence of treating intestinal protozoan infection on the course of HIV infection has not been systematically studied, treatment of intestinal helminth infestation decreases the HIV viral load among African patients with AIDSa Synergism between intestinal parasites and other lymphotrophic retroviruses has been advanced as an explanation for the

Intestinal Protozoan Infestation and Systemic Illness

pathogenesis of Burkitt lymphoma49 and adult T-cell leukemia/lymphoma.50

DIAGNOSTIC CONSIDERATIONS Protozoan infection is usually diagnosed with stool examination; however, comparison of results of stool microscopy and duodenal aspiration has consistently shown that stool may fail to contain identifiable parasites even at the height of acute giardiasis.5lS2Collecting multiple specimens over several days increases the sensitivity to 85% to 90%.53Laboratories that specialize in tropical medicine or parasitology are more likely to find organisms in stool specimens than are general or hospital laboratories. Some authorities have suggested empirical treatment for intestinal parasites in high-risk groups, such as immigrants to the United States from Asia, the Middle east, sub-Saharan Africa, Eastern Europe, Latin America, and the Caribbean and have justified this approach on a cost-effective basis, given the safety of current medical therapies.54 A similar case might be made for treating chronically ill patients at high risk for parasitic infection because of residence, travel, sexual practices, or the context in which illness occurred.

THERAPEUTIC CONSIDERATIONS Artemisia annua Numerous naturally occurring substances have antiprotozoan activity. The most extensively studied is Artemisia unnua (sweet Annie or qinghao), a plant that yields the lactone artemisinin (qinghaosu), which is the basis for a new class of antimalarial compounds widely used in Asia and Africa.55Artemisinin is thought to owe its antiprotozoan effects to its content of endoperoxides and to kill parasites through oxidation. Its activity, at least in the treatment of Simian malaria, is enhanced by coadministration of cod liver oil and diminished by coadmjnistration of vitamin E. Artemisinin has low toxicity. In addition to its antibiotic activity, it stimulates macrophages, an important component of the immune response to protozoan infestation.% Artemisinin may induce abortion if given during pregnancy.

Berberine The alkaloid berberine can be extracted from the roots of several plant species, notably Berberis aquifolium (Oregon grape), Hydrastis canadensis (goldenseal)root, and Coptis

chinensis (goldthread). Berberine has protostatic and protocidal activity against E. histolyticu, G. Zumbliu and B. h~rninis.~’-~~ It has shown benefit in the treatment of giardiasis in children.60

Allium sativum and Juglans nigra Allium sativum (garlic) and Jugluns nigu (black walnut) have a long history of use as antimicrobials. Allicin inhibits growth of E. histolyticu in culture61and may be responsible for the antimicrobial activity of Human studies on the efficacy of garlic and black walnut in treatment of protozoan infections is lacking.

Intestinal Bacterial Milieu The intestinal bacterial milieu may be important in the treatment of protozoan infestation, especially for colonic organisms like E. histolyticu. Pathogenic strains of E. histolyticu are able to evade lysis by both classic and alternative pathways of complement. Intestinal bacteria, Escherichia coli in particular, are necessary for complement resistance and for amebic v i r ~ l e n c e . ~ ~ Gitler and MirelmarP suggested that ingested bacteria lower the redox potential within the parasite and allow the amebae to escape destruction by oxidative enzymes.@ Mirelman et alS reported that one can reversibly change the zymodeme patterns of E . histolyticu isolates from nonpathogenic to invasive by culturing amebae with the gut flora of patients who have either invasive disease or no symptoms. Optimal treatment of protozoan infection requires not only the administration of antimicrobial substances but also strategies aimed at enhancing the function of intestinal resistance factors such as secretory IgA and phagocyte function and creating a bacterial milieu that is not parasite friendly.

CONCLUSION Intestinal protozoan infestation is a significantly underrecognized cause of systemic illness. Undiagnosed infestations with Giurdiu spp., E. histolyticu, and other organisms have been associated with diverse diseases such as arthritis, asthma, Reiter syndrome, urticaria and uveitis, CFIDS, increased rate of progression of HIV infection, and a wide range of systemic dysfunction, such as fatigue, malabsorption, muscle weakness, and myalgia. Effective eradication of protozoa can result in surprisingly quick and complete clinical response.

Syndromes and Special Topics

1.Targan SR, Kagnoff MF$ Brogan MD, Shanahan F. Immunologic mechanisms in intestinal disease. Ann Intern Med 1987;106:854-870. 2.Crandall M. The pathogenetic significance of intestinal Candida Colonization. Int J Hyg Environ Health 2004:20779-81. 3.Di Prisco MC, Hagel I, Lynch NR, et al. Possible relationship between allergic disease and infection by Giardia lamblia. Ann Allergy 1993;70210-213. 4. Lopez-Brea M, Sainz T, Camarero C , Baquero M. Giardia lamblia associated with bronchial asthma and serum antibodies, and chronic diarrhoea in a child with giardiasis. Trans R Soc Trop Med Hyg 1979;73600. 5. Harris RH, Mitchell JH. Chronic urticaria due to Giardia lamblia. Arch Dermatol Syphilol 1949;59:587-589. 6. Wilhelm RE. Urticaria associated with giardiasis lamblia. J Allergy 1958;28:351-353. 7. Webster BH. Human infection with Giardia lamblia. Am J Dig Dis 195836%-71. 8. Dellamonica P, Le Fichoux Y, Monnier B, Duplay H. [Dysenteric syndrome and urticaria in giardiasis.] Nouv Presse Med 1976;51913. 9. Weisman BL. Urticaria and Giardia lamblia infection. Ann Allergy 1979;4291. 10. Kennou MF, Jenayah S, Rekhis M, et al. [Skin manifestation of giardiasis: some clinical cases.] A d i Jnst Pasteur Tunis 198057257-260. 11. Farthing MJ, Chong SK, Walker-Smith JA. Acute allergic phenomena in giardiasis. Lancet 1983;2:1428. 12. Goobar Jl?Joint symptoms in giardiasis. Lancet 1977;l:lOlO-1011. 13. Woo,'F Panayi GS. Reactive arthritis due to infestation with Giardia lamblia. J Rheumatol 1984;11:719. 14. Shaw RA, Stevens MB. The reactive arthritis of giardiasis: a case report. JAMA 1987;2582734-2735. 15. Galland L. Intestinal protozoan infection is a common unsuspected cause of chronic illness. J Advancement Med 1989;2529-552. 16.Carroll ME, Anast BP, Birch CL. Giardiasis and uveitis. Arch

Ophthalmol1961;65:775-778. 17. Chester AC, MacMurray FG, Restifo MD, Mann 0. Giardiasis as a chronic disease. Dig Dis Sci 1985;30:215-218. 18. Galland L, Lee M, Bueno H, Heimowitz C. Giardia lamblia infection as a cause of chronic fatigue. J Nutr Med 1990;227-32. 19. Viiyak VK, Venkateswarlu K, Khanna R, Mehta S. Hypo-gammaglobulinaemia in children with persistent giardiasis. J Trop Pediatr 1987;33:140-142. 20.Smith PD, Gillin FD, Spira WM, Nash TE. Chronic giardiask studies on drug sensitivity, toxin production, and host immune response. Gastroenterology 1982;83:797-803. 21. Roberts-Thompson IC, Mitchell GF. Giardiasisin mice. I. Prolonged infections in certain mouse strains and hypothymic (nude) mice. Gastroenterology 1978;7542-46. 22. Gillon J, Al Thamery D, Ferguson A. Features of small intestinal pathology (epithelial cell kinetics, intraepithelial lymphocytes, disaccharidases) in a primary Giardia muris infection. Gut 1982;23:498-506. 23. Solomons NW. Giardiask nutritional implications. Rev Infect Dis 1982;4859-869. 24. Sherman P, Liebman WM. Apparent protein-losing enteropathy associated with giardiasis.Am J Dis Child 1980;134:893-894. 25. Brasitus TA. Parasites and malabsorption. Clin Gastroenterol 1983;12495-510. 26. Tompkins AM, Wright SG,Drasar BS, James WI? Bacterial colonization of jejunal mucosa in giardiasis. Trans R Soc Trop Med Hyg 1978;7233-36. 27. Naik SR, Rau NR,Viayak VK, et al. Presence of Candida albicans in normal and in Giardia lamblia infected human jejunum. Ann Trop Med Parasitol 1978;72;493-494.

28.den Hollander N, Riley D, Befus D. Immunology of Giardia. Parasitol Today 1988;4124-133. 29. Galland L. Patient-centered diagnosis and treatment for chronic fatigue syndrome. Presented to the Annual Scientific Session of the American Academy of Environmental Medicine, Viiginia Beach, VA, October 7,1994. 30.Salem E, Zaki SA, Moneim WA, et al. Autoantibodies in amoebic colitis. J Egypt Med Assoc 1973;56113-118. 31. Sturgess I, Greenfield SM, Teare J, ODoherty MJ. Ulcerative colitis developing after amoebic dysentery in a haemophiliacpatient with AIDS. Gut 199233:408-410. 32. Korkmaz C, Harmanci E, Metintas I, Gulbas Z. Antiphospholipid syndrome associated with intestinal amoebiasis. Scand J Infect Dis 2001;33938-940. 33. Zinneman HH. Ten cases of amebiasis with arthritic complaints. Am J Dig Dis 1950;17343-344. 34. Rappaport EM, Rossieu AX, Rosenblum LA. Arthritis due to intestinal amebiasis. Ann Intern Med 1951;34:12241231. 35. Kasliwal RM. Colon and disease. J Assoc Physicians India 1970;18:739-744. 36. S i g h IF', Das SK, Sharma P, et al. Antibodies to Entamwba histolytica in patients with rheumatoid arthritis. Trop Gastroenterol 1985;6141-144. 37. Bumstein SL, Liakos S. Parasitic rheumatism presenting as rheumatoid arthritis. J Rheumatol 1983;10:514-515, 38. Bocanegra TS,Espinoza LR, Bridgeford PH, et al. Reactive arthritis induced by parasitic infestation. Ann Intern Med 1981;94207-209. 39.Cron RQ, Sherry DD. Reiter's syndrome associated with cryptosporidial gastroenteritis.J Rheumatol1995;22:1962-1963. 40.Connor BA, Johnson EJ, Soave R. Reiter syndrome following protracted symptoms of Cyclospora infection. Emerg Infect Dis 2001;7453-454. 41. Richardson RF Jr, Remler BF, Katirji B, Murad MH. Guillain-Bad syndrome after Cyclospora infection. Muscle Nerve 1998;21:669-671. 42. Chen ZC, Herrmann F, Koleski F, Diamantstein T. Mitogenic factor for T inducer/helper cells in Entarnoeba histolytica extracts. Ada Acad Med Wuhan 1985;5213-216. 43. Petri WA Jr, Ravdin JI. Treatment of homosexual men infected with Entamoeba histolytica. N Engl J Med 1986;315393. 44.Croxson S, Mildvan D, Mathews H, Poiesz BJ. Entumoebu histolytica antigen-specific induction of human immunodeficiency virus replication. J Clin Microbiol1988;261304-1308. 45. Pearce RB, Abrams DI. Entamoeba histolytica in homosexual men. N h g l J Med 1987316690-692. 46.Archer DL, GlinsmanWH. Enteric infections and other co-factors in AIDS. Immunol Today 1985;6292-294, 47. Abrams DI. The relationship between Kaposi's sarcoma and intestinal parasites among homosexual males in the United States. J Acquir Immune Defic Syndr 1990;3:S44-S46. 48. Wolday D, Mayaan S, Mariam ZG, et al. Treatment of intestinal worms is associated with decreased HIV plasma viral load. J Acquir Immune Defic Syndr 200291:56-62. 49.Burkitt DP. The discovery of Burkitt's lymphoma. Cancer 198351~1777-1786. 50. Tajima K, Tominaga S, Shimizu H, Suchi T. A hypothesis on the etiology of adult T-cell leukemia/lymphoma. Gann 1981;72: 684-691. 51. Rosenthal P, Liebman WM. Comparative study of stool examinations,duodenal aspiration, and pediatic Entero-Test for giardiasis in children. J Pediatr 1980;96278-279. 52. Kamath KR, Murugasu R. A comparative study of four methods for detecting Giardia lamblia in children with diarrheal disease and malabsorption. Gastroenterology1974;66:16-21.

Intestinal Protozoan Infestation and Systemic Illness 53. Gillon J. Giardiasis: review of epidemiology, pathogenetic mechanisms and host responses. Q J Med 1984;53:29-39. 54. Muennig P, Pallin D, Sell RL, Chan MS.The cost effectiveness of strategies for the treatment of intestinal parasites in immigrants. N Engl J Med 1999;340:773-779. 55. Hien 'IT, White NJ. Qinghaosu. Lancet 1993;341:603-608. 56.Tang W, Eisenbrand G. Chinese drugs of plant origin. Berlin: Springer-Verlag, 1992, p p 159-174. 57. Kaneda Y, Torii N, Tanaka T, Aikawa M. In vitro effects of berberine sulfate on the growth and structureof Entamoeba histolyticu, Giardia lamblia and Trichomonus vaginulis. Ann Trop Med Parasitol 1991;85: 417-425. 58. Subbaiah TV, Amin AH. Effect of berberine sulphate on Entamoeba histolytica. Nature 1967;215:527-528. 59. Yang LQ, Singh M, Yap EH, et al. In vitro response of Blustocystis hominis against traditional Chinese medicine. J Ethnopharmacol 1996;55:35-42.

60. Gupte S. Use of berberine in treatment of giardiasis. Am J Dis Child 1975;129866. 61. Mirelman D, Monheit D, Varon S. Inhibition of growth of En tarnoeba histolyticu by allicin, the active principle in garlic extract (Allium sativum). J Infect Dis 1987;156243-244. Natural products and the development 62. Wright CW, Phillipson JD. of selective antiprotozoal drugs. Phytother Res 1990;4127-139. 63. Wittner M, Rosenbaum RM. Role of bacteria in modifymg virulence of E. histolyticu: studies of amoebae from axenic cultures. Am J Trop Med Hyg 1970;19:755-761. 64.Gitler C, M k h a n D. Factors contributing to the pathogenic behavior of Entamoeba histolytica. Annu Rev Mcrobiol 1986;40: 237-261. 65. Mirelman D, Bracha R, Chayen A, et al. Entamoeba histolytica: effect of growth conditions and bacterial associates on isoenzyme patterns and virulence. Exp Parasitol 1986;62:142-148.

Maldigestion Michael T. Murray, ND Joseph E.Pizzorno Jr, ND CHAPTER CONTENTS Introduction 661 Therapeutic Considerations 661 Indigestion 661 Hypochlorhydria 662 Pancreatic lnsufficiency 663

INTRODUCTION Proper digestion, absorption, and elimination are necessary in order to gain the nutritional benefits from foods. Any disruption of these processes causes substantial, and usually progressive, health problems throughout the body. This chapter provides some overview of digestive dysfunction and ways to improve digestion. For specific digestive tract disorders (e.g., irritable bowel syndrome, peptic ulcers, inflammatory ulcers) see Section 6. For information on the various laboratory procedures for evaluation of digestive function (e.g., comprehensive digestive stool analysis, intestinal permeability assessment, small intestinal bacterial overgrowth breath test) see Section 2.

THERAPEUTIC CONSIDERATIONS Indigestion The term indigestion is often used by patients to describe a feeling of gaseousness or fullness in the abdomen. It can also be used to describe "heartburn." Indigestion can be attributed to a great many causes, including not only increased secretion of acid but also decreased secretion of acid and other digestive factors and enzymes. Indigestion is commonly treated with antacids and histamine (H2) receptor antagonists, either chosen by patients or prescribed by medical practitioners. The use of these agents will typically raise the gastric pH above 3.5, effectively inhibiting the action of pepsin, the enzyme involved in protein digestion that can be irritating to the stomach. Although raising the pH can reduce symptoms, it also substantiallyimpairs protein digestion

and mineral disassociation. In addition, the change in pH can adversely affect gut microbial flora, including the promotion of an overgrowth of Helicobucter pylori. Finally, most nutrition-oriented physicians believe that lack of acid, not excess, is the true culprit in most patients with indigestion. According to surveys, most people use antacids to relieve symptoms of reflux esophagitis.' However, reflux esophagitis is most often caused by overeating, not excessive acid production. Other common causes are as follows: Obesity Cigarette smoking Chocolate Fried foods Carbonated beverages Alcohol Coffee These factors either increase intraabdominal pressure or decrease the tone of the esophageal sphincter. Chronic heartburn may also be a sign of a hiatal hernia. However, although 50% of people older than 50 years have hiatal hernias, only 5% of patients with hiatal hernias actually experience reflux esophagitis. Perhaps the most effective treatment of chronic reflux esophagitis and symptomatic hiatal hernias is to utilize gravity. The standard recommendation is to simply place 4-inch blocks under the bedposts at the head of the patient's bed. This elevation of the head is very effective in many cases. Another recommendation to heal the esophagus is the use of deglycyrrhizinated licorice (DGL). 661

Hypochlorhydria In the patient with chronic indigestion, rather than focus on blocking the digestive process with antacids, the natural approach focuses on aiding digestion. Although much is said about hyperacidity conditions, a more common cause of indigestion is a lack of gastric acid secretion. Many symptoms and signs suggest impaired gastric acid secretion, and a number of specific diseases have been found to be associated with insufficient gastric acid output."12 They are listed in Boxes 59-1 and 59-2. Several studies have shown that the ability to secrete gastric acid decreases with Some studies found low stomach acidity in more than half of the subjects older than 60 years. The best method of diagnosing a lack of gastric acid is the Heidelberg gastric analysis (see Chapter 2l).I7 Wright1*has suggested that the response to a bicarbonate challenge during Heidelberg gastric analysis, not simply resting pH, is the true test of the functional ability of the stomach to secrete acid. Because the Heidelberg gastric acid analysis is not widely available, a clinical trial of HC1 supplements can be used as described in Appendix 7.

Etiology Like peptic ulcer disease,achlorhydria and hypochlorhydria have been linked to the overgrowth of the bacteria H. pylori. Approximately 90% to 100°/~of patients with duodenal ulcers, 70% of patients with gastric ulcers, and about 50% of people older than 50 years test positive for H. p y l ~ r i . '"he ~ presence of H. pylori is determined by measuring the level of antibodies to H. pylori in the blood or saliva or by culturing material collected during an endoscopy as well as measuring the breath for urea. More recently, a breath test has become available for assessment of current H. pylori activity. Low gastric output is thought to predispose to H.pylori colonization, and H. pylori colonization increases gastic pH, thereby setting up a positive feedback scenario and increasing the likelihood of colonization of the stomach

Bloating, belching, burning, and flatulence immediately after meals A sense of "fullness" after eating Indigestion, diarrhea, or constipation Multiple food allergies Nausea after taking supplements Itching around the rectum Weak, peeling, and cracked fingernails Dilated blood vessels in the cheeks and nose Acne Iron deficiency Chronic intestinal parasites or abnormal flora Undigestedfood in stool Chronic Candid infections Upper digestive tract gassiness

Addison's disease Asthma Celiac disease Dermatitis herpetiformis Diabetes mellitus Eczema Gallbladder disease Graves' disease Chronic autoimmune disorders Hepatitis Hyperthyroidisrdhypothyroidism Hives (chronic) Myasthenia gravis Osteoporosis Pernicious anemia Psoriasis Rheumatoid arthritis Rosacea Sjdgren's syndrome Systemic lupus erythematosus Thyrotoxicosis Vitiligo

and duodenum by other Not surprisingly, HCL antisecretory drugs (H2 receptor antagonists and proton pump inhibitors) may actually promote H. pylori overgrowth. Patients with H. pylori experience an exaggerated response in elevations of pH with antisecretory therapy.2I Although the typical conventional medicine approach is to focus only on the infective agent, the usual host defense factors are equally or more important. Unfortunately, the research has focused on eradicating the organism, and there is little information on protective factors against infectivity. Proposed protective factors against H. pylori-induced intestinal damage are maintaining a low pH and ensuring adequate antioxidantdefense mechanism~.~-" Low levels of vitamin C and vitamin E and other antioxidant factors in the gastric juice appear not only to lead to the progression of H.pylori colonization but also to contribute to the ulcer formation, because the mechanism by which H. pylori damages the stomach and intestinal mucosa is oxidative damage.25Furthermore, antioxidant status and gastric acid output appear to explain the observation that most people infected with H. pylori do not experience peptic ulcer disease or gastric cancer; for more information on natural approaches for eradicating H. pylori, see Chapter 200. One natural medicine that may be useful against H. pylori that is not discussed in Chapter 200 is bovine lactoferrin. Lactoferrin exerts broad-spectrum antimicrobial action because it has been shown to be effective in inhibiting the growth of disease-causing protozoa, yeast, bacteria, and viruses. More important than its ability to actually kill organisms is the later discovery that lactoferrin prevents the attachment of disease-causing organisms to cells that line the mouth and entire

gastrointestinal tract. At the same time, lactoferrin is a powerful booster of health-promoting bacteria like Bzj5dobacferia and Lacfobacillus species. By preventing growth of harmful bacteria while promoting the growth of beneficial bifidobacteria, lactoferrin assists in the development of a proper intestinal flora. The standard medical treatment of H. pylori infection is a 1- or 2-week course of treatment called triple therapy. It involves taking two antibiotics to kill the bacteria and an acid suppressor drug. On the basis of results of clinical trials, lactoferrin alone or in combination with triple therapy may soon be the treatment of choice. In one study, 151 patients testing positive for H. pylori and suffering from indigestion symptoms were given either triple therapy alone or with lactoferrin. H. pylori status assessed 8 weeks after the end of the treatment indicated a 95.9%eradication rate for the group receiving the lactoferrin; the other group had only a 72.5% eradication rate.26Theeffective dose of lactoferrin in this application is 300 mg a day.

Pancreatic lnsufficiency The most severe level of pancreatic insufficiency is seen in cystic fibrosis. Next in severity is the pancreatic insufficiency associated with the late stages of pancreatitis. These more severe causes of pancreatic insufficiency are most often easily recognized, but causes of mild pancreatic insufficiency are more insidious and difficult to diagnose. Both physical symptoms and laboratory tests can be used to assess pancreatic function in patients in whom mild pancreatic insuffiaency is suspected.Common symptoms of pancreatic insufficiencyare abdominal bloating and discomfort, gas, indigestion, and the passing of undigested food in the stool. For laboratory diagnosis, the comprehensivestool and digestive analysis (discussed in Chapter 14)is quite useful. In addition, the measurement of fecal elastase 1 concentrations by means of an enzyme-linked immunosorbent assay (ELISA) is an accepted indirect test of the exocrine pancreatic function.

1. Graham DY, Smith JL, Patterson DJ. Why do apparently healthy people use antacid tablets? Am J Gastroenterol 1983;78257-260.

2.Bray GW. The hypochlorhydria of asthma in childhood. Quart J Med 1931;24181-197. 3. Rabinowitch IM.Achlorhydria and its clinical significance in diabetes mellitus.Am J Dig Dis 1949;18322-333. 4. Capper WM, Butler TJ,Kilby JO, et al. Gallstones, gastric secretion, and flatulent dyspepsia. Lancet 1967;1:413-415. 5. Rawls WB, Ancona VC. Chronic urticaria associated with hypochlorhydria or achlorhydria. Rev Gastroenterol 1951;18: 267-271. 6. Giannella RA,Broitman SA, Zamcheck N. Influence of gastric acidity on bacterial and parasitic enteric infections: a perspective. Ann Intern Med 1973;78271-276.

It shows higher sensitivity and specificity for exocrine pancreatic insufficiency than the fecal chymotrypsin determination and is comparable to oral pancreatic function tests such as the pancreolauryl test.27

Pancreatic Enzyme Supplements Pancreatic enzyme products are an effective treatment for pancreatic insufficiency and are widely used. Most commercial preparations are prepared from fresh hog pancreas (i.e., pancreatin) (see Chapter 112 for a full discussion). The dosage of pancreatic enzymes is based on the level of enzyme activity of the particular product as defined by the United States Pharmacopoeia (USP). A l x pancreatic enzyme (pancreatin) product has in each milligram not less than 25 USP units of amylase activity, not less than 2.0 USP units of lipase activity, and not less than 25 USP units of protease activity. Pancreatin of higher potency is given a whole-number multiple indicating its strength. For example, a full-strength undiluted pancreatic extract that is 10 times stronger than the USP standard would be referred to as lox USP. Full-strength products are preferred to lower-potency pancreatin products because lower-potency products are often diluted with salt, lactose, or galactose to achieve desired strength (eg., 4x or lx). The dosage recommendation for a lox USP pancreatic enzyme product is typically 350 to lo00 mg three times/day immediately before meals when used as a digestive aid and 10 to 20 minutes before meals or on an empty stomach when antiinflammatoryeffects are desired. Enzyme products are often enteric-coated. However, numerous studies have shown that non-enteric-coated enzyme preparations actually outperform enteric-coated products if they are given before a meal (for digestive purposes) or on an empty stomach (for antiinflammatory effects). For vegetarians, bromelain, papain, and enzymes extracted from AspergilZus oryzae can substitute for pancreatic enzymes.

7. De Witte TJ, Geerdink PJ, Lamers CB, et al. Hypochlorhydria and hypergastrinaemia in rheumatoid arthritis. AM Rheum Dis 1979;38:1417. 8. Ryle JA, Barber HW. Gastric analysis in acne rosacea. Lancet 1920;21195-1196. 9. Ayres S. Gastric secretion in psoriasis, eczema and dermatitis herpetiformis.Arch Dermatol 1929;Jd.854-859. 10.Dotevall G, Walan A. Gastric secretion of acid and intrinsic factor in patients with hyper and hypothyroidism. Acta Med Scand 1969;186529-533. 11. Howitz J, Schwartz M. Vitiligo, achlorhydria, and pernicious anemia. Lancet 1971;1:1331-1334. 12. Howden CW, Hunt RH.Relationship between gashic secretion and infection.Gut 1987;28:96-107.

Syndromes and Special Topics 13.Rafsky HA, Weingarten M. A study of the gastric secretory response in the aged. Gastroenterology 1947;May:348-352. 15.Davies D, James TG. An investigation into the gastric secretion of a hundred normal persons over the age of sixty. Br J Med 1930; k1-14. 16. Baron JJd.Studies of basal and peak acid output with an augmented histamine test. Gut 1963;413&144. 17. Mojaverian,'F Ferguson RK,Masses PH, et al. Estimation of gastric msidence time of the Heidelberg capsule in humans: effect of varying food composition. Gastroenterology 1985;89:392-397. 18. Wright J. A proposal for standardized challenge testing of gastric acid secretory capaaty using the Heidelberg capsule radiotelemetry system. J John Bastyr Col Nat Med 1979;1:3-11. 19. Berstad K, Berstad A. Helicobacfer pylori infection in peptic ulcer disease. Scand J Gastroenterol 1993;28:561-567. 20. Sarker SA, Gyr K. Non-immunologicaldefence mechanisms of the gut. Gut 199233987-993. 21. Verdu EF, Armstrong D, Fraser R, et al. Effect of Helicobacfer pylon' status on intragastric pH during treatment with omeprazole. Gut 1995;36:539-43.

22. Shibata T, Imoto I, Taguchi Y, et al. High acid secretion may protect the gastric mucosa from injury caused by ammonia produced by Helicobacter pylori in duodenal ulcer patients. J Gastroenterol Hepatol 1996;11:674-680. 23. Rokkas T, Papatheodorou G, Karameris A, et al. Helicobucfer pylm' infection and gastric juice vitamin C levels: impact of eradication. Dig Dis Sci 1995;40:615-621. 24. Phull PS,Price AB, Thomiley MS, et al. Vitamin E concentrationsin the human stomach and duodenum: correlation with Helicobucfer pylori infection. Gut 1996;39:31-35. 25. Baik SC,Youn Hs, Chung MH, et al. Increased oxidative DNA damage in Helicobacfer pylori-infected human gastric mucosa. Cancer Res 1996361279-1282. 26. Di Mario F, Aragona G, Dal Eb N, et al. Use of bovine ladoferrin for Helicobacfer pylori eradication. Dig Liver Dis 2003;35:706-710. 27. Dominici R, Franzini C. Fecal elastase-1 as a test for pancreatic function: a review. Clin Chem Lab Med 2002;40:325-332.

Role of Dietary Fiber in Health and Disease Michael T. Murray, ND Peter B,Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS

Dietary Fiber and Chronic Degenerative Disease 666 Trends in US. Food Consumption 666

Diseases Associated with a Low-Fiber Diet 670 Diseases of the Colon and Gastrointestinal Disorders 670 Heart Disease and Gallstones 671 Obesity 671 Diabetes Mellitus 671

Definition and Composition of Dietary Fiber 666 Cellulose 667 Noncellulose Polysaccharides 667 Lignins and Lignans 669 Phytic Acid 669

Clinical Use of Dietary Fiber 671 Irritable Bowel Syndrome 672 Elevated Cholesterol Values 672 Obesity 673 Cancer Prevention 674 Dosage 674

Physiologic Effects of Dietary Fiber 669 Satiety/Palatability of Food 669 Stool Weight and Transit Time 669 Digestion 670 Short-Chain Fatty Acids 670 Intestinal Bacterial Flora 670

Toxicology 674 Mineral Malabsorption 674

Introduction 665 The Primitive Diet 665

INTRODUCTION The appreciation of the role of diet in determining the level of health deservedly continues to grow. A substantial body of research has now established well that certain dietary practices cause as well as prevent a wide range of diseases. In addition, the research is now showing that certain diets and foods can provide immediate therapeutic benefit. This chapter discusses the major diseases of Western society and how they relate to one key component of the diet: dietary fiber. The dietary fiber hypothesis has the following basic components: A diet rich in foods that contain plant cell walls (i.e., whole grains, legumes, fruits, and vegetables) is protective against a wide variety of diseases, in particular those that are prevalent in Western society. A diet providing a low intake of plant cell walls is a causative factor in the etiology of these diseases and

Drug Interactions 674 Summary 674

provides conditions under which other etiologic factors are more active. The term Wesfem diet is used throughout this chapter as well as in many other parts of the textbook. It refers to the typical diet of Western peoples, also referred to as ”foods of commerce.” This diet consists of a high intake of refined carbohydrates, saturated fats, processed foods, salt, and cholesterol and an extremely low intake of dietary fiber.

The Primitive Diet Detailed anatomic and historical evidence suggests that humans evolved as “hunter-gatherers”-that is, humans appear to be omnivores capable of surviving on both gathered (plant) and hunted (animal) foods.’ However, although the human gastrointestinal (GI) tract is capable of digesting both animal and plant foods, there are indications that it functions better with plant foods? A tremendous amount of evidence shows that deviating from a predominantly plant-based diet is a major factor 665

in the development of heart disease, cancer, strokes, arthritis, and many other chronic degenerative diseases. It is now the recommendationof many health and medical organizationsthat the human diet should focus primarily on plant-based foods: vegetables, fruits, grains, legumes, nuts, seeds, and so on. Such a diet is thought to offer significant protection against the development of chronic degenerative d i ~ 2 a . w . ~ ~

DIETARY FIBER AND CHRONIC DEGENERATIVE DISEASE The belief in the benefiaal effects of fiber in the diet goes back to at least 1585. However, the link between dietary fiber and chronic disease in the medical literature originated to a great extent from the work of two medical pioneers, Denis Burkitt and Hugh Trowell, who wrote “Western Diseases: Their Emergence and Preuenfion,” first published in 1981.3On the basis of extensive studies examining the rate of diseases in various populations (epidemiologic data) and his own observationsof primitive c u l m , Burkitt formulated the following sequence of events:

First stage. The primal diet of plant eaters contains large amounts of unprocessed starch staples; chronic degenerative diseases like osteoarthritis,heart disease,type 2 diabetes, and cancer OCCUT infrequently. Second stage. When Westernization of diet commences, obesity and diabetes commonly appear in privileged groups. Third stage. With moderate Westernization of the diet, constipation, hemorrhoids, varicose veins, and appendicitisbecome common complaints. Fourfh stage. Finally, with full Westernization of the diet, chronic degenerative diseases like osteoarthritis, rheumatoid arthritis, gout, heart disease, and cancer are extremely common. Although now extremely well-recognized, the work of Burkitt and Trowell is actually a continuation of the landmark work of Weston A. Price, a dentist and author of Nutrition and physical degeneration.6 In the early 1900s, Price traveled the world, observing changes in teeth and palate (orthodontic) structure as various cultures discarded traditional dietary practices in favor of a more ”civilized” diet. Price was able to follow individuals as well as cultures over periods of 20 to 40 years and carefully documented the onset of degenerative diseases as their diets became more westernized. It is now well documented that diet is the major factor responsible for many chronic degenerative diseases. In 1984, the National Research Council’s Food and Nutrition Board established the Committee on Diet and Health and undertook a comprehensive analysis on diet and major chronic diseases? Their findings, as well as those of the U.S. Surgeon General and other research groups, brought to the forefront the need for Americans

Metabolic Obesity, gout, diabetes, kidney stones, gallstones Cardiovascular Hypertension, cerebrovascular disease, ischemic heart disease, varicose veins, deep vein thrombosis, pulmonary embolism Colonic Constipation, appendicitis, diverticulitis, diverticulosis, hemorrhoids, colon cancer, irritable bowel syndrome, ulcerative colitis, Crohn’s disease Other Dental caries, autoimmune disorders, pernicious anemia, multiple sclerosis, thyrotoxicosis, dermatologicalconditions

to change their eating habits to reduce their risk for chronic disease. Box 60-1 lists diseases with convincing linksto a diet low in dietary fiber and plant foods. Many of these now common diseases were extremely rare before the twentieth century.

Trends in U.S. Food Consumption During the twentieth century, food consumption patterns changed dramatically in the United States (Table 60.1).Total dietary fat intake increased from 32% of the calories in 1909 to 43% by the end of the century overall; carbohydrate intake dropped from 57%to 46%; and protein intake has remained fairly stable at about 11%.Compounding these detrimental changes are the individual food choices accounting for the changes. There were sigruficant increases in the consumption of meat, fats and oils, and sugars and sweetners in conjunction with the decreased consumption of noncitrus fruits, vegetables, and whole grain products. But the biggest change in the last 100 years of human nutrition is the switch from a diet with a high level of complex carbohydrates, as found naturally occurring in grains and vegetables, to a tremendous and dramatic increase in the number of calories consumed from simple sugars. Currently, more than half of the carbohydrates being consumed are in the form of sugars such as sucrose (table sugar) and corn syrup, which are added to foods as sweetening agents. High consumption of refined sugars and a low consumption of dietary fiber is linked to many chronic diseases, including obesity, diabetes, heart disease, and cancer.

DEFINITION AND COMPOSITION OF DIETARY FIBER Generally, dietary fiber refers to the components of plant cell wall and nonnutritive residues. Originally, the

Role of Dietary Fiber in Health and Disease

Dietary fiber constituents of the food groups

Trends in quantities of foods consumed per capita (poundslyear) Foods Meat, poultry, and fish: Beef Pork Poultry Fish TOTAL

Eggs Dairy products: Whole milk Low-fat milk Cheese Other TOTAL

Fats and oils: Butter Margarine Shortening Lard and tallow Salad and cooking oil TOTAL

Fruits: Citrus Noncitrus Fresh Processed TOTAL

Vegetables: Tomatoes Dark green and yellow Other Fresh Processed TOTAL

Potatoes, white: Fresh Processed TOTAL

Dry beans, peas, nuts, andsoybeans Grain products: Wheat products Corn Other grains TOTAL

Sugar and sweeteners: Refined sugar Syrups and other sweeteners TOTAL

1909

1967

1985

1999

62 18 12

81 61 46 15

73 62 70 19

66 50 68 15

146

203

224

199

37

40

32

32

54

Food group

Main dietary fibers

Fruits and vegetables

Cellulose, hemicellulose, lignin, pectic substances, cutin, waxes

Grains

Cellulose, hernicellulose, lignin, phenolic esters

Seeds (other than grains)

Cellulose, hemicellulose, pectic substances, guar endosperm

Seed husk of Planfago

Arabinogalacturonosyl-phamno-xylan

ovafa

(mucilage) Gum arabic, alginate, carrageenan, carboxymethylcellulose

232 44 15 159 -

122 112 26 190 -

112 101 30 210 -

Food additives

339

450

450

453

18 1 8 12 2 -

6 10 16 5 16 -

5 11 23 4 25 -

5 8 22 6 29 -

41

53

68

70

17

60

72

79

154 8

73 35

87

34

115 37

179

168

193

231

46

34

36 25

38 31

55 39

definition was restricted to substances that are not digestible by the endogenous secretions of the human digestive tract. This original definition is specious, because it depends on a precise understanding of what exactly is not digestible. The composition of the plant cell wall varies according to the species of plant. Typically,the dry cell wall contains 35% cellulose, 45% noncellulose polysaccharides, 17”/0 lignins, 3% protein, and 2% ash.810It is important to recognize that dietary fiber is a complex of these constituents, and supplementation of a single component does not substitute for a diet rich in high-fiber foods. In some clinical conditions, however, the use of specific components is a useful adjunct to a healthy diet. Tables 60-2 and 60-3 summarize the classificationsof dietary fibers.

136 8

87 35

96

34

126 39

224

183

199

259

182 0

67 19

55 28 -

49 91

182

86

83

140

16

16

18

22

216 56 19

116 15 13 144

122 17 26

150 28 24 __

165

202

100 22

63 90

68 91

-

-

122

153

159

223

64 5 47

291

77 14 91

Data from United States Department of Agriculture. Food Review 2000;23:8-15.

CelIulose The best-known dietary fiber component is cellulose. This unbranched 1-4-beta-Dglucose polymer ranges in size from 3000 to 100,OOO glucose units. It is a relatively insoluble, hydrophilic material. This ability to bind water accounts for its effect of increasing fecal size and weight. Although indigestible by humans, cellulose is partially degraded by the microflora of the gut. This anaerobic process (fermentation) occurs in the colon, results in the degradation of about 50% of the cellulose, and is an important source of short-chain fatty acids (SCFAs).Sp9SCFAs have very important properties in the colon, as discussed later.

Noncellulose Polysaccharides The majority of polysaccharides in the plant cell wall are a noncellulose type, that is, they are water-soluble and posses diverse properties. Included in this class are hemicelluloses, pectin substances, gums, mucilages, and algal polysaccharides.

Hemicelluloses Hemicelluloses contain a mixture of pentose and hexose molecules in branched-chain configurations much

Classification of dietary fiber Fiber class I. Cellulose II. Noncellulose polysaccharides A. Hemicelluloses

Chemical structure

Plant part

Food sources

Physiologic effect

Unbranched 1-4-betao-glucose polymer

Principal plant wall component

Wheat bran

Increases fecal weight and size

Mixture of pentose and hexose molecules in branching chains

Plant cell walls

Oat bran

Increases fecal weight and size; binds bile acids

Karaya. gum arabic

Laxative

Guar gum, legumes, psyllium

Hydrocolloids that bind steroids and delay gastric emptying, heavy metal chelation

Citrusgum, rind, apple, onion skin

As above

B. Gums

Branchedchain uronic acid containing polymers

C. Mucilages

Similar to hemicelluloses

D.Pectins

Mixture of methyl esterified galacturan, galactan, and arabinose in varying proportions

E. Algal polysaccharides 111. Lignins

Endosperm of plant seeds

Polymerized o-mannuronic acid and L-glucuronic acid

-

Algin, agar, carrageenan

As above

Noncarbohydrate polymeric phenylpropene

Woody part of plant

Wood (40%-50%), wheat (25%), apple (25%), cabbage (6%)

Antioxidants, anticarcinogenic

smaller than cellulose. Their ability to increase fecal weight depends on the pentose fraction. The hemicelluloses are also an important source of SCFAs via bacterial degradation.

Pectin and Pectinlike Substances Pectins are found in all plant cell walls as well as in the outer skins and rind of fruits and vegetables. For example, the rind of an orange contains 30% pectin; an apple peel, 15%;and onion skins, 12%. The gel-forming properties of pectin are well known to anyone who has made a jelly or jam. These same gel-forming qualities are responsible for the cholesterol-lowering effects of pectins. Pectins lower serum cholesterol by binding the cholesterol and bile acids in the gut and promoting their excretion.

Gums Plant gums are a complex group of water-soluble, branched-chain, uronic acid-containing polymers. They are produced by the plant in response to injury and are commercially produced through incision of a plant or tree and collection of the fluid extract. Gums are used as emulsifiers, thickeners, and stabilizers by the food industry and as laxatives in pharmaceuticals.

Mucilages Structurally, mucilages resemble the hemicelluloses, but they are not classed as such because of their unique location in the seed portion of the plant. Mucilages are

generally mixed with the endosperm of the plant seeds, where they retain water, preventing seed desiccation. Guar gum, found in leguminous plants, is the most widely studied mucilage. It is isolated from the endosperm of Cyumopsis tetragonolobus, a plant cultivated in India for livestock feed. Guar gum is used commercially as a protective colloid, stabilizer, thickening, and film-forming agent for paper sizing, cheese, salad dressings, ice cream, soups, toothpaste, pharmaceutical jelly, lotion, skin cream, and tablets. It is also used as a laxative. Guar gum and other mucilages are perhaps the most potent cholesterol-lowering agents of the gel-forming hydrocolloids, including pectin and glucomannan.Guar gum has been shown to reduce fasting and postprandial serum glucose and insulin levels in both healthy and diabetic subjects;and it has reduced body weight and hunger ratings when taken with meals by obese subjects. Psyllium seed husk (Plantago ovuta) is another example of a mucilage that is widely used as a bulking and laxative agent.

Algal Polysaccharides Included in the category algal polysaccharides are alginic acid, agar, and carrageenan. Marine-derived polysaccharides are used extensively by the food industry. Alginate has been shown to inhibit heavy metal uptake in the gut, as do other gel-forming fibers. Agar is used as a thickening agent and as a gel for holding microbiologic media. It has laxative and fecal bulkincreasing activity.

Role of Dietary Fiber in Health and Disease

Carrageenan is used in milk and chocolate products because of its ability to react with milk proteins. However, unlike other plant polysaccharides, it adversely affectsthe intestinal mucosa. It has been shown in rats to induce ulcer formation in the cecum by promoting release of lysosomal enzymes by mucosal macrophages. Other rat studies have shown carrageenan to enhance carcinogen induction of neoplasia, colorectalcarcinoma, birth defects, and hepatomegaly."

Lignins and Lignans Lignins are composed of aromatic polymers of coniferyl, para-coumaryl, and sinapyl alcohols in varying ratios. Vanillin (artificial vanilla) and other aromatic chemicals are synthesized from lignins. Lignans are fiber compounds related to lignins that are typically composed of cinnamic acid, cinnamyl alcohol, propenylbenzene, and allylbenzene precursor units.Many plant lignans show important properties, such as anticancer, antibacterial, antifungal, and antiviral activities. Plant lignins are metabolized by the gut flora into the animal lignins enterolactone and enterodiol, both of which posses antiestrogenic activity and are believed to be protective against cancer.12

Phytic Acid In the plant, phytic acid (inositol hexaphosphoric acid) is responsible for storing minerals such as calcium, phosphorus, magnesium, and potassium. There is some concern that phytates can adversely affect the uptake and utilization of many minerals, including calcium, iron, and zinc. The major sources of phytate in the diet are cereal grains and legumes (Table 60-4). Phytate is destroyed by heat and by the enzyme phytase during the leavening of bread?r9 Phytic acid exerts impressive antioxidant and antitumor effects.ls15 When administered in drinking water or injected, phytic acid has demonstrated a consistent

Plant phytic acid

antitumor effect in animals against colon cancer and fibrosarcomas. Preclinical trials have yielded encouragingresults; larger, better-designed studies are in process.1s15

PHYSIOLOGIC EFFECTS OF DIETARY FIBER It is beyond the scope of this chapter to detail all known effects of dietary fiber on humans. Instead, we cover effects of greatest clinical sigruficance (stool weight, transit time, digestion, colon function, SCFAs, and colon Beneficial effects of dietary fiber are listed in Box 60-2.

Satiety/Palatability of Food High-fiber foods, because of their relatively lower energy density and overall palatability, tend to be more satiating than low-fiber foods. Furthermore, dietary fiber may promote satiety and fat oxidation through several hormonal pathways. For instance, some research has shown prolonged increases in circulating cholecystokinin concentrations after ingestion of fiber-rich meals compared with energy-matched, low-fiber meals. Fiber may also affect secretion of gut hormones, independent of glycemic response, that act as satiety factors or to alter glucose homeostasis (for more information, see Chapter 168).1618

Stool Weight and Transit Time Fiber has long been used in the treatment of constipation. Dietary fiber, particularly the water-insoluble, hydrophilic fibers such as cellulose (e.g., bran), increases stool weight as a result of water-holding properties. Transit time, the time taken for passage of material from the mouth to the anus, is greatly reduced with a high-fiber diet. Cultures consuming a high-fiber diet (100-170 g/day) usually have a transit time of 30 hours and a fecal weight of 500 g. In contrast, Europeans and Americans who eat a typical, low-fiber diet (20 g/day) have a transit time of more than 48 hours and a fecal weight of only 100 g3 Interestingly, when fiber is added to the diet of subjects

Percentage dry weight

Soybeans

1.4

Wheat

0.9

Corn

1.1

Rice

0.9

Peanuts

1.9

Sesame seeds

5.4

Lima beans

2.5

Barley

1.o

Oats

0.8

Decreased intestinal transit time Delayed gastric emptying resulting in reduced postprandial hyperglycemia Increased satiety Increased palatability Increased pancreatic secretion Increased stool weight More advantageous intestinal microflora Increased production of short-chain fatty acids Decreased serum lipids More soluble bile

with abnormally rapid transit times (less than 24 hours), it causes prolongation of the transit t i ~ n e . ~ , ~ Dietary fiber’s effect on transit time is apparently directly related to its effect on stool weight and size. A larger, bulkier stool passes through the colon more easily, requiring less intraluminal pressure and, subsequently, less straining.14 It has been hypothesized that the decreased intraluminal pressure (due to the greater leverage the colon mucosa has on a larger stool) results in less hydrostatic stress on the colon wall and therefore avoids the ballooning effect that results in diverticula. The increased intestinal transit time associated with the Western diet allows prolonged exposure of the intestinal flora to various compounds, both natural and manufactured, resulting in greater conversion of such compounds to potential ~arcinogens.~,~,”

Digestion Although dietary fiber increases the transit through the GI tract, it slows gastric emptying, thus reducing postprandial hyperglycemia in both normal and diabetic subjects. Pancreatic enzyme secretion and activity also rise in response to fiber, although excessive levels of fiber (more than 10% of the meal by weight) have a converse effedF0A number of research studies have examined the effects of fiber on mineral absorption. Although the results have been somewhat contradictory, it now appears that large amounts of dietary fiber may result in impaired absorption and/or negative balance of some minerals. Fiber as a dietary component does not appear to interfere with the minerals in other foods, but supplemental fiber, especially hemicelluloses, may cause a negative mineral balanceF4

Short-Chain Fatty Acids The fermentation of dietary fiber by the intestinal flora produces the following three main end-products: XFAs Various gases Energy The SCFAs-acetic, propionic, and butyric acids-are the main anions in the large intestine and have many important physiologic functions. SCFAs seem to decrease hepatic output of glucose and circulating concentrations of free fatty acids and stimulate secretion of glucagon-likepeptide-1. These actions may, in turn, alter insulin sensitivity, insulin secretion patterns, the partitioning of metabolic fuels, and regulation of satiety.16For every 20 g of fiber consumed each day, approximately 200 mmol of XFAs is produced, of which 62 mmol is acetate, 25 propionate, and 16 butyrate? Propionate and acetate are transported directly to the liver and utilized for energy production, whereas butyrate provides an important energy source for the

colonic mucosa. In fact, butyrate is the preferred substrate for energy metabolism in the distal ~0lon?,~2* Butyrate production may also be responsible for the anticancer properties of dietary fiber. Even at extremely low concentrations, butyrate has been shown, in vitro, to profoundly affect gene expression and other nucleic processes, such as DNA synthesis, resulting in suppressed cell proliferation in both normal and malignant cells. Butyrate has trophic effects on normal colonocytes, stops the growth of neoplastic colonocytes, inhibits the preneoplastic hyperproliferation induced by certain tumor promoters in vitro, inhibits the expression of certain protooncogenes, and promotes differentiation of colon cancer cell linesz Some of these effects are due to the acetylation of histones and the stabilization of the chromatin structure. Butyrate is also being used in enemas for the treatment of ulcerative colitis. Certain fibers appear to be more effective than others in increasing the levels of SCFAs in the colon. Pectins (both apple and citrus, guar gum, and other legume fibers) and vegetable fiber isolates produce more SCFAs than wheat fiber, corn fiber, or oat bran.8~~

Intestinal Bacterial Flora Dietary fiber appears to improve all aspects of colon function. Of central importance is the role it plays in maintaining a ”suitable” colonic bacterial flora. A lowfiber intake is associated with both an overgrowth of Enterobacteriaceae and other endotoxin-producing bacteria and a lower percentage of Lactobacillus and other acidophilic b a ~ t e r i a .A ~ ,diet ~ high in dietary fiber promotes acidophilic bacteria through the greater synthesis of colonic SCFAs, which reduces the colon pH, a condition conducive to the growth of beneficial bacteria.

DISEASES ASSOCIATED WITH A LOW-FIBER DIET Because of the important physiologic effects of dietary fiber, a diet low in dietary fiber obviously leads to altered physiology or disease. The diseases having the strongest correlation with a lack of dietary fiber are those of the colon and GI tract, heart disease and gallstones, obesity, and diabetes. Each is briefly discussed here.

Diseases of the Colon and Gastrointestinal Disorders The epidemiologic and experimental data documenting the protective effect of dietary fiber on colon cancer are overwhelming. For digestive conditions in which bacteria play a causative role, such as Crohn’s disease, fiber may inhibit the adherence of these pathogens.23There is evidence of similar strong links with other common diseases of the colon-diverticulitis, diverticulosis, irritable

Role of Dietary Fiber in Health and Disease bowel syndrome (IBS), ulcerative colitis, and appendicitis as well as hemorrhoids, peptic ulcers, and hiatal hernia.3,4,8,9Furthermore, the same diseases often respond to a high-fiber diet.

Heart Disease and Gallstones Dietary fiber has been shown to be quite protective against heart disease and gallstones. Increasing fiber intake clearly appears to be a safe and inexpensive dietary strategy for reducing the risk of coronary heart disease.2427A diet high in dietary fiber is known to reduce total serum cholesterol and triglyceride levels while raising serum high-density lipoprotein (HDL)cholesterol levels and the production and storage of less saturated bile acids. A survey of 4900 adults found that after data were controlled for demographic factors, body mass index, smoking, alcohol consumption, exercise, and total caloric intake, subjects who had the highest consumption of fiber had a sigruficantly lower C-reactive protein One cohort study of 43,757 U.S. male health professionals 40 to 75 years of age who were free of diagnosed cardiovascular disease and diabetes were asked to complete a detailed 131-item dietary questionnaire used to measure usual intake of total dietary fiber and specific food sources of fiber and then were monitored for 6 years. A 10-g increase in total dietary fiber corresponded to a 20% reduction in relative risk for myocardial. Within the three main food contributors to total fiber intake (vegetable, fruit, and cereal), cereal fiber seemed to offer the greatest protection against a cardiac event.* The binding of bile acids and micellar components to various grains, food fibers, and isolated fiber compounds leads to reduction of the enterohepatic circulation of bile salts and cholesterol. Loss of cholesterol and bile salts through the feces is the major pathway for elimination of these compounds from the body. Dietary fiber also reduces cholesterol biosynthesis and promotes the conversion of cholesterol to the bile acids via activation of the vitamin C-dependent enzyme 7-alphahydroxylase, the rate-limiting step in bile acid synthesis. This enhancement of bile acid synthesis and excretion is the result of dietary fiber’s preferential binding of deoxycholic acid, resulting in a compensatory increase in circulating levels of chenodeoxycholic acid. Chenodeoxycholic acid has been shown to inhibit cholesterol absorption and synthesis at its rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reducta~e.~ Binding of chenodeoxycholic acid by dietary fiber results in an increase in the taurocholate-toglycocholate ratio. The ultimate result of these alterations in bile salt concentrations and ratios is a less saturated bile that solubilizes cholesterol more effectively and is resistant to stone formation.

Obesity A dietary fiber-deficient diet is an important etiologic factor in the development of obesity.I8 Dietary fiber plays a role in preventing obesity by: Increasing the amount of necessary chewing, thus slowing the eating process. Increasing fecal caloric loss. Altering digestive hormone secretion. Improving glucose tolerance. Inducing satiety through greater gastric filling, stimulation of cholecystokininrelease, and intestinal bulking action. Other effects of dietary fiber on obesity are discussed here with diabetes mellitus-60% to 90% of patients with type I1 diabetes mellitus are obese.

Diabetes Mellitus Epidemiologic and experimental data show diabetes mellitus to be one of the diseases most clearly related to inadequate intake of dietary fiber.3~4,7-9 Clinical trials that have demonstrated the beneficial therapeutic effect of dietary fiber on diabetes have further substantiated this association (discussed later).29sDietary fiber’s prevention and modulation of diabetes is due to its effects on serum glucose and, subsequently, insulin levels. Fiber may account for almost half of the variance in the area under the glucose-response curve after consumption of various starchy foods. A high-complex carbohydrate, high-fiber diet reduces postprandial hyperglycemia (largely by delaying gastric emptying and thereby reducing insulin secretion) and increases tissue sensitivity to insulin (how, or whether, this relates to chromium uptake and metabolism has not been determined). Fermentation products of fiber, chiefly SCFAs, enhance hepatic glucose metabolism and may further contribute to the ameliorating effects of dietary fiber on diabetes.8r9

CLINICAL USE OF DIETARY FIBER The best and most cost-effective way of using dietary fiber in a clinical setting is via encouraging a diet rich in plant foods (Table 60-5 lists dietary fiber content of selected foods). A good goal for dietary fiber intake is 25 to 35 g daily, which can easily be achieved if the dietary focus is on whole, unprocessed, plant foods. In addition to the well-known use of dietary fiber as a laxative, the principal use of supplemental dietary fiber is in the treatment of IBS and other functional disturbances of the colon, elevated serum cholesterol values, and obesity. The best fiber sources for nonlaxative effects are psyllium, guar gum, glucomannan, gum karaya, and pectin, because they are rich in water-soluble fibers. Although there are many fiber supplements to choose from, the

Syndromes and Special Topics

Dietary fiber content of selected foods Food

Serving

Calories

Grams of fiber

Food

Serving

Fruits Apple (with skin)

1 medium

81

3.5

Banana

1 medium

105

2.4

Rice, Breads, Pastas, and Flour Bran muffins 1 muffin

Cantaloupe Cherries (sweet)

X melon

30

1.o

Bread (white)

10

49

1.2

Calories

Grams of fiber

104

2.5

1 slice

78

0.4

1 slice

61

1.4

2 crackers

50

2.0

Grapefruit

'x medium

38

1.6

Bread (whole wheat) Crisp bread, rye

Orange Peach (with skin)

1 medium

62

2.6

Rice, brown (cooked)

% cup

97

1.o

1

37

1.9

Rice, white (cooked)

% cup

82

0.2

Pear (with skin)

% large

61

3.1

Spaghetti (reg. cooked)

x cup

155

1.1

Spaghetti (whole wheat, cooked) Breakfast Cereals All-Bran

% cup

155

3.9

% cup

71

8.5

Bran Chex

55 cup 55 cup

91

4.6

Prunes

3

60

3.0

Raisins

5 cup

106

3.1

Raspberries

% cup

35

3.1

1 cup

45

3.0

'h cup

13

1.5

Corn Bran Cornflakes

10

1.1

Cucumber

x cup x cup

8

0.4

Lettuce

1 cup

10

Mushrooms

10

Pepper (green)

x cup x cup

9

0.5

Spinach

1 cup

8

1.2

Tomato Vegetables (cooked) Asparagus (cut)

1 medium

20

1.5

1 cup

30

2.0

Beans (green)

1 cup

32

3.2

Broccoli

1 cup

40

4.4

Brussels sprouts

1 cup

56

4.6

Cabbage (red)

1 cup

30

2.8

Carrots

1 cup

48

4.6

Cauliflower

1 cup

28

2.2

Corn

x cup

87

2.9

Kale Parsnip

1 cup

44

2.8

1 cup

102

5.4

Potato (with skin)

1 medium

106

2.5

Potato (without skin)

1 medium

97

1.4

Spinach

1 cup

42

4.2

Sweet potatoes Zucchini Legumes Baked beans

1 medium

Dried peas (cooked) Kidney beans (cooked)

Strawberries Vegetables (raw) Bean sprouts Celery (diced)

98

5.4

1% cups

110

0.3

Grape Nuts

% cup

101

1.4

Oatmeal

x cup

108

1.6

0.9

Raisin Bran-type

4.0

Shredded Wheat Nuts Almonds

55 cup 55 cup

115

1.5

102

2.6

79

1.1

160

3.4

1 cup

22

3.6

'h cup

155

8.8

x cup

115

4.7

% cup

110

7.3

Lentils (cooked) Lima beans (cooked)

x cup x cup

97

3.7

64

4.5

Navy beans (cooked)

'h cup

112

6.0

10 nuts

Filberts

10 nuts

54

0.8

Peanuts

10 nuts

105

1.4

clinically most effective are those that are rich in watersoluble fiber and low in added sugar or other sweeteners.

Irritable Bowel Syndrome The treatment of IBS by increasing the intake of dietary fiber has a long, although irregular, history. In general, consuming a diet rich in complex carbohydrates and dietary fiber while avoiding sugar and refined foods is effective. The most effective fiber supplements are the water-soluble forms. However, the type of fiber often used in both research and clinical practice is wheat bran. Because wheat is among the foods most commonly implicated in malabsorptive and allergic conditions, the use of wheat bran is usually not indicated in individuals with symptoms of IBS, in which food allergy is a sigruficant causative factor. Also, although patients with constipation are likely to respond to wheat bran, those with diarrhea may actually experience a worsening of their symptoms.

Elevated Cholesterol Values A review article concluded that soluble-fiber supplementation was very effective in lowering cholesterol levels.3l

Role of Dietary Fiber in Health and Disease

Specifically, a significant reduction in the level of serum total cholesterol was found in 68 of the 77 (88%)studies reviewed. The effect of soluble fiber supplementation was clearly dose-dependent. In other words, the higher the intake of soluble fiber, the greater the reduction in serum cholesterol. The average doses and reductions noted in clinical trials are shown in Table 60-6. Many of the studies utilized oat bran or oatmeal as the source of fiber. The overwhelming majority of these studies demonstrated that individuals with high cholesterol levels experiencesigruficant reductionswith frequent consumption of oatmeal or oat bran. In contrast, individuals with normal or low cholesterol levels experiencelittle change. In individualswith high cholesterol levels (above 220 mg/dl) the consumption of the equivalent of 3 g of soluble oat fiber lowers total cholesterol by 8% to 23%. This is highly sigruficant,as with each 1%drop in serum

Fiber

Typical reduction in total cholesterol (%)

Dosage (9) 50-100

20

Guar gum

Oat bran (dry)

9-15

10

Pectin

6-10

5 10-20 10

Psyllium

10-20

Vegetable fiber

27

cholesterol level, there is a 2% decrease in the risk for development of heart disease. Three grams of fiber would be provided by approximately one bowl of ready-to-eat oat bran cereal or oatmeal. Although oatmeal's fiber content (7%) is less thanthat of oat bran (15%-26%),it has been determined that the polyunsaturated fatty acids contribute as much to the cholesterol-loweringeffects of oats as the fiber content. Oat bran has a higher fiber content, but oatmeal is higher in polyunsaturated fatty acids. In practical terms, the dosage level for dry oat bran would be '/3 to 1cup; for dry oatmeal, 1to 1*/s C U ~ S . ~ ~ ~ ~

Obesity When taken with water before meals, water-soluble fiber sources bind to the water in the stomach to form a gelatinous mass that makes an individual feel full and less likely to overeat. However, the benefits of fiber go well beyond this mechanical effect. Fiber supplements have been shown to enhance blood sugar control and insulin effects as well as actually reduce the number of calories absorbed by the intestines? In some of the clinical studies demonstrating weight loss, fiber supplements were shown to reduce the number of calories absorbed by 30 to 180 calories/day. Over the course of a year, this could result in a reduction of 3 to 18 lbs. It is estimated that a person can lose 50% to 100% more weight by supplementing the diet with fiber than by simply restricting calories alone; see Table 60-7 and Chapter 194 for information on clinical studies of the treatment of obesity with dietary fiber supplements.

Clinical studies of the treatment of obesity with dietary fiber supplements

Fiber Guar

Number of subjects

Length of study

Dosage (@day)

Calorie restriction?

Average Weight Loss (Ibs) Fiber

9

2 months

20

None

9.4

7

1 year

20

None

61.9

2.5 months

20

None

15.6

21

Placebo No placebo group No placebo group No placebo group 0.9

Reference 28

29 30

33

2.5 months

15

None

5.5

20

2 months

3

None

5.5

Weight gain of 1.5 Ibs

32

20

2 months

3

None

8.14

0.44

33

Citrus pectin

14

4 weeks

5.56

Yes

12.8

34

Mixture A*

60 89

12 weeks 11 weeks

5 10

Yes Yes

18.7 13.9

No placebo group 14.7 9.2

45

3 months 3 months 6 months

7 7 7

Yes Yes Yes

13.6 10.8 12.1

Glucomannan

Mixture B'

97

52

9 7.3 6.1

'Mixture A, 80% fiber from grains/20% fiber from citrus; mixture 6, 90% insoluble/lO% soluble fiber from beet, barley, and citrus fibers.

31

35 36 37 38 39

Syndromes and Special Topics

Cancer Prevention The body of research documenting the cancer-preventing effects of a high-fiber diet has continued to accumulate. In addition to the epidemiologic associations, researchers have now also performed prospective and supplementation studies. Most, but not all, studies have shown a sigruficant protective effect of dietary fiber for a wide range of cancers. Several studies have shown benefit for prevention of breast cancer.% One representative study evaluated the association between breast cancer and dietary intake in two Chinese populations (Shanghai and Eanjin) who are at low risk for breast cancer. These populations have onefifththe rate of breast cancer for U.S.white women. There were two case-controlledstudies. In the 834 women studied, the intake of crude fiber, carotene, and vitamin C showed a strong sigruficant inverse association with breast cancer risk.The effect was closely associated with the intake of green vegetables. The women in the lowest tertile intake of crude fiber intake and the highest tertile intake of fat intake had a 2.9-fold higher risk for breast cancer relative to those in the highest tertile of crude fiber intake and the lowest tertile of fat intake.% The same protective effect has also been found in fibrocystic disease of the breast. In a study of the diet of 354 women with benign proliferative epithelial disorders of the breast who were compared with 354 matched controls and 189 unmatched controls, an inverse association between dietary fiber and the risk of benign, proliferative, epithelial disorders of the breasts was observed.% The protective effects of supplemental dietary fiber have also been demonstrated even in those with previous colon cancer. A total of 411 patients with colorectal adenomas were started on a 25%fat content diet, supplemented with 25 g of wheat bran daily and a capsule of 20 mg of beta-carotene daily. Patients with the combination of a low-fat diet and added wheat bran had no large adenomas at both 2 and 4 years, a statistically significant effect compared with the control g r o ~ p . ~

Dosage The clinician using dietary fiber supplements should encourage patients to start out with a small dose and increase gradually. Because water-soluble fibers are fermented by intestinal bacteria, a great deal of gas can be produced. If a patient is not accustomed to a high-fiber diet, an increase in dietary fiber can lead to greater flatulence and abdominal discomfort. The patient should start with a dosage between 1and 2 g before meals and at bedtime and gradually increase to 5 g.

TOXICOLOGY If a patient has a disorder of the esophagus, fiber supplements in a pill form are contraindicated because they may expand in the esophagus and lead to obstruction.3’ Fiber supplements in capsules appear to be slightly better tolerated than tablets but should still be used with caution. The difference is in how the tablets and capsules interact with water. One study showed that fiber (glucomannan) tablets swelled to seven times their original size within 1minute of coming into contact with water.= In contrast, fiber-filled gelatin capsules took 6 minutes to begin to swell. One very important recommendation is to consume sufficient amounts of water with the fiber supplement.

Mineral Malabsorption A number of research studies have examined the effects of fiber on mineral absorption. Although the results have been somewhat contradictory, it now appears that large amounts of dietary fiber may result in impaired absorption and/or negative balance of some minerals. Fiber as a dietary component does not appear to interfere with the minerals in other foods. However, supplemental fiber, especially wheat bran, may result in mineral deficiencies.

DRUG INTERACTIONS Fiber supplements may also inhibit the absorption of certain drugs. A good recommendation would be for the patient to take the fiber supplement at times separate from the taking of all medications.

SUMMARY A diet high in plant foods is associated with a decreased incidence of most of the degenerative diseases of Western society. Although this effect is largely due to increased levels of dietary fiber, such a diet is also high in other important nutrients, most of which are also deficient in the Western diet. It is clear from the literature that the best source of dietary fiber is whole foods, although fiber supplements do have a place in the treatment phase of specific diseases. It must be stressed that even with a diet high in dietary fiber and in which as little as 18% of the total calories are in the form of refined carbohydrates, many of the beneficial effects of dietary fiber are greatly reduced. There is no substitute for a healthy diet, that is, a diet composed of foods as close to their original forms as possible.

Role of Dietary Fiber in Health and Disease

1.Eaton SB, Eaton SB 3rd. Paleolithic vs. modem diets-selected pathophysiological implications. Eur J Nutr 2000;3967-70. 2. Ryde D. What should humans eat? Practitioner 1988;232415418. 3.Trowell H, Burkitt D. Western diseases: their emergence and prevention. In Trowell H, Burkitt D, Heaton K, eds. Dietary fibre, fibre-depleted foods and disease. London: Academic Press, 1985. 4. United States Public Health Service. Office of the Surgeon General. The Surgeon General’s report on nutrition and health. Washington, DC: U.S. Dept. of Health and Human Services, 1988. 5. National Research Council (US.). Committee on Diet and Health. Diet and health: implications for reducing chronic disease risk. Washington, DC: National Academy Press, 1989. 6. Price WA. Nutrition and physical degeneration; a comparison of primitive and modem diets and their effects. Santa Monica, C A Price-Pottenger Foundation, 1970. 7. United States Department of Agriculture. Major trends in U.S. food supply, 1909-1999.Food Review 2000;23&15. 8. Spiller GA. Dietary fiber in health and nutrition. Boca Raton, EX: CRC Press, 1994. Dietary fiber: the influence of dehition on analysis and 9. Devries JW. regulation. J AOAC Int 2004;87682-706. 10. Selvendran RR. The plant cell wall as a source of dietary fiber: chemistry and structure. Am J Clin Nutr 1984;39320-337. 11. Watt J, Marcus R. Harmful effects of carrageenan fed to animals. Cancer Detect Prev 1981;4129-134. 12. Setchell KDR. Discovery and potential clinical importance of mammalian lignans. In Cunnane SC,Thompson LU, eds. Flaxseed in human nutrition. Champaign, E AOCS Press, 199583-98. 13. Jariwalla RJ. Inositol hexaphosphate (IP6) as an anti-neoplasticand lipid-lowering agent. Anticancer Res 1999;19(5A):3699-3702. 14. Vucenik I, Shamsuddin AM. Cancer inhibition by inositol hexaphosphate (Ip6) and inositol from laboratory to clinic. J Nutr 2003;133:3778S3784S. 15.Shamsuddin AM. Metabolism and cellular functions of IP6 a review. Anticancer Res 1999;19:3733-3736. 16. Marlett JA, McBumey MI, SlavinJL. American Dietetic Association. Position of the American Dietetic Association: health implications of dietary fiber. J Am Diet Assoc 2002;102:993-1OOO. 17. Pereira MA, Ludwig DS.Dietary fiber and body-weight regulation: observations and mechanisms. Pediatr Clin North Am 2001;48: 969-980. 18. Howarth NC, Saltzman E, Roberts SB. Dietary fiber and weight regulation. Nutr Rev 2001;59129-139. 19. Reddy B, Engle A, Katsifis S, et al. Biochemical epidemiology of colon cancer: effect of types of dietary fiber on fecal mutagens, acid, and neutral sterols in healthy subjects. Cancer Res 1989;49: 4629435. 20. Sommer H, Kasper H. Effect of long-term administrationof dietary fiber on the exocrine pancreas in the rat. Hepatogastroenterology 1984;31:176-179.

21. Andoh A, Tsujikawa T, Fujiyama Y. Role of dietary fiber and shortchain fatty acids in the colon. Curr pharm Des 2003;9:347-358. 22. Velazquez OC, Lederer HM, Rombeau JL. Butyrate and the colonocyte: implications for neoplasia. Dig Dis Sci 1996;41: 727-739. 23. Martin HM, Campbell BJ, Hart CA, et al. Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer. Gastroenterol2004;12780-93. 24. Lupton JR, Turner ND.Dietary fiber and coronary disease: does the evidence support an association? Cum Atheroscler Rep 2003;5: 500-505. 25. Rimm EB, Ascherio A, Giovannucci E, et al. Vegetable, fruit, and cereal fiber intake and risk of coronary heart disease among men. JAMA 1996;275447-451. 26. Liu S, Buring J, Sesso HD, et al. A prospective study of dietary fiber intake and risk of cardiovascular disease among women. J Am Coll Cardiol2002;3949-56. 27. Wok A, Manson JE,Stampfer MJ, et al. Long-term intake of dietary fiber and decreased risk of coronary heart disease among women. JAMA 1999;281:199&2004. 28. King DE, Egan BM, Geesey ME. Relation of dietary fat and fiber to elevation of C-reactive protein. Am J Cardiol2003;921335-1339. 29. Chandalia M, Garg A, Lutjohann D, et al. Beneficial effects of high dietary fiber intake in patients with type 2 diabetesmellitus. N Engl J Med 2000;342:1392-1398. 30.Giacco R, Parillo M, Rivellese AA, et al. Long-term dietary treatment with increased amounts of fiber-rich low-glycemic index natural foods improves blood glucose control and reduces the number of hypoglycemic events in type 1 diabetic patients. Diabetes Care 2000;23:1%1-1466. 31. Brown L, Rosner B, Willett WW, Sacks FM. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr 1999;69: 30-42. 32. Ripsin CM, Keenan JM, Jacobs DR Jr, et al. Oat products and lipid lowering: a meta-analysis.JAMA 1992;2673317-3325. 33.Cohen LA. Dietary fiber and breast cancer. Anticancer Res 1999;19(5A):3685-3688. %.Yuan JM, Wang QS, Ross RK, et al. Diet and breast cancer in Shanghai and Eanjh, China. Br J Cancer 1995;71:1353-1358. 35. Baghurst PA, Rohan TE. Dietary fiber and risk of benign proliferative epithelial disorders of the breast. Int J Cancer 1995;63: 481-485. 36. MacLennan R, Macrae F, Bain C, et al. Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas: the Australian Polyp Prevention Project. J Natl Cancer Inst 1995;871760-1766. 37. Halama WH, Maudlin JL. Distal esophageal obstruction due to a guar gum preparation (Cal-Ban 3000).South Med J 1992;85:642-645. 38. Henry DA, Mitchell As,Aylward J, et al. Glucomannan and risk of oesophageal obstruction. Br Med J 1986;292:591-592.

Sports Nutrition Gregory S. Kelly, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Introduction 677 Sports Nutrition for Strength Athletes 677 Creatine Monohydrate 677 beta-Hydroxy-beta-Methylbutyrate 680 Whey Protein 681 Soy 682 Phosphatidylserine 683 Arginine 683 Branched-Chain Amino Acids 683 Glutamine 684 Ornithine alpha-Ketoglutarate 685 Vitamin C 685 Boron 685 Chromium 685

INTRODUCTION The greater focus on fitness and the subsequent research in the exercise field have expanded the role of nutrition in sports performance. Because there is widespread belief among athletes that special nutritional practices will enhance their achievements in competition, the use of supplements has become common. This chapter reviews the efficacy of some of supplements currently promoted to athletes. The topic has been divided into two broad categories, sports nutrition for strength athletes and sports nutrition for endurance athletes. This division is to a degree arbitrary, so some of the supplements discussed might be applicable for athletes in both categories. For more information comparing and contrasting the physiology of muscular endurance and strength, see Chapter 37.

SPORTS NUTRITION FOR STRENGTH ATHLETES Creatine Monohydrate Creatine monohydrate has become one of the most popular supplements in the history of body-building. The original version of this chapter was reprinted with permission from Alternative Medicine Review 1997:2:282-295.

Selenium 686 Vanadium (Vanadyl Sulfate) 686 Zinc 687 Summary 687 Sports Nutrition for Endurance Athletes 687 Panax ginseng 687 Eleutherococcus senticosus 689 Carnitine 689 Choline 691 Coenzyme Qjo (Ubiquinone) 691 Pyridoxal-alpha-Ketoglutarate 691 Pyruvate 692 Performance Drinks 693 Summary 695

It is used primarily to increase strength and lean body mass and may enhance muscle energy recovery.' Having been extensively studied since 1927, creatine has shown consistent results in promoting these effects in experimental subjects? In humans, more than 95% of the total creatine content is located in skeletal muscle. Approximately one third is in its free form as creatine, also known as methylguanidinoacetic acid, and the remainder is present in a phosphorylated form as creatine phosphate (also called phosphocreatine). Creatine phosphate is utilized within skeletal muscle storing high-energy phosphate bonds. Creatine is formed in the liver, kidney, and pancreas. Initially, arginine and glycine combine to produce guanidinoacetate. A methyl group from Sadenosylmethionine (SAMe) is then transferred, resulting in the formation of creatine. The by-product of this reaction, S-adenosylhomocysteine, is subsequently hydrolyzed into homocysteine and adenosine. For optimal endogenous production of creatine, the amino acids arginine, glycine, and methionine must be available as substrates. Additionally, magnesium is required as a cofactor to form SAMe from methionine, and BIZ, folic acid, and betaine are required to recycle the homocysteine to methionine for reuse as SAMe. 677

Although creatine can be synthesized endogenously as just described, it is also found in a variety of foods in varying concentrations. The richest source overall is wild game, but the richest source in domesticated animals is beef (lean red meat); 1.1 kg of fresh uncooked steak contains about 5 g of ~reatine.~ Fish is also a good source, especially herring, salmon, and tuna. However, it is believed that creatine in foods may be destroyed or reduced signhcantly by cooking. Creatine is transported to muscle tissue where it exists in equilibrium with creatine phosphate. Creatine phosphate spontaneously converts to creatinine (estimated to be at a rate of about 2 g/day for a 150-lb male) and is then excreted in the urine.4 Although part of this turnover can be replaced through dietary sources of creatine, especially meat and fish, the remainder must be supplied by endogenous synthesis. For this reason, there is a constant drain on arginine, glycine, methionine, and nutritional cofactors to maintain a supply of creatine and creatine phosphate. In vegetarians, daily needs must be met exclusively by endogenous synthesis. When dietary creatine is high, the synthetic pathway is correspondingly regulated d ~ w n w a r d . ~ In addition to its use in skeletal muscle, some creatine is used by cardiac muscle. Patients with chronic heart failure might have decreased stores of creatine and have been shown to have better exercise capacity after administration of creatine.6One week of creatine supplementation (20 g/day) to patients with chronic heart failure increased skeletal muscle energy-rich phosphagens and performance for both strength and endurance.' Creatine phosphate produces energy in the form of adenosine triphosphate (ATP) in muscle cells for about 10 seconds of activity.After it is depleted, the muscle shifts to anaerobic glycolysis for fuel. It is thought skeletal muscles are capable of storing sigruficantly more creatine than is generally supplied by the diet and by endogenous synthesis. For this reason, after an oral dose of creatine monohydrate, more serum creatine is available for storage in muscle tissue. Over time, this greater dietary consumption can allow the muscle to become saturated with creatine. When the muscle has this extra creatine, it should theoretically be able to delay fatigue and refuel itself more quickly during high-intensity, short-duration exercise and so should be capable of greater work. It is hypothesized that when muscle absorbs creatine, the creatine brings water intracellularly with it, so the muscle becomes more "hydrated." It is estimated that muscles are about 70% water, so this process results in a larger, fuller muscle. Evidence suggests when a cell is well hydrated it might accelerate its synthesis of new proteins and might also minimize protein degradation? One gram of creatine monohydrate or less in water produces only a modest rise in plasma creatine concentration; however, a 5-g oral dose has been shown to significantly

increase plasma creatine concentration. Repeated dosing with 5 g of creatine monohydrate every 2 hours sustains the plasma concentration at around 1000 mmoVL.3 Studies have shown that feeding large amounts of creatine (typically 20-30 g/day for 5 days) raises muscle total creatine (and phosphocreatine) ~ o n t e n t . ~ The ,~ extent of the rise normally observed is inversely related to the presupplementation leve1.3r8Vegetarians, because they have a very low dietary creatine intake and low to normal total creatine content, would be expected to show large increases? Muscle creatine uptake appears to be augmented substantially in individuals adhering to a program of repeated high-intensity exercise during the period of Supplementation? Resynthesis of phosphocreatine after 1 minute of recovery from intense muscular contraction is accelerated in individuals consuming creatine.8 Adequate vitamin E status might also be needed to optimize creatine uptake? In one study of eight subjects, muscle biopsy samples were taken after 5 days of ingestion of 20 g creatine per day. In five of the eight subjects, there were substantially higher muscle total creatine concentration and creatine phosphate resynthesis during recovery. In the remaining subjects, creatine supplementation slightly raised total creatine concentration but did not increase creatine phosphate resynthesis.* In three subjects measured, uptake into muscle was greatest during the first 2 days of supplementation, accounting for 32% of the total creatine monohydrate given orally per day. In these subjects, renal excretion was 40%, 6l%, and 68% of the creatine dose over the first 3 days, respectively. Approximately 20% or more of the creatine taken up was measured as phosphocreatine, but no changes were observed in the muscle ATP ~ o n t e n t . ~ Oral creatine monohydrate supplementation has also been shown, in a patient with extrapyramidal movement disorder and extremely low serum and urine creatinine concentrations, to significantly increase brain creatine levels. Phosphorus magnetic resonance spectroscopy of the brain revealed no detectable creatine phosphate before oral substitution of creatine and a sigrufrcant increase afterward. Partial restoration of cerebral creatine concentrations was accompanied by improvement of the patient's neurologic symptoms. Oral substitution of arginine, a substrate for creatine synthesis, was unable to elevate cerebral creatine levels.1° Four months of 0.10 g/kg/day of creatine monohydrate supplementation has also been shown to improve handgrip strength and increase fat free mass in the dominant hand as well as to reduce a marker of bone breakdown in boys with Duchenne muscular dystrophy.'l Creatine supplementation has been shown to improve performance in situations in which the availability of creatine phosphate is important, such as very-highintensity exercise, especially when repeated bursts of

Sports Nutrition ~

energy are required with short recovery periods.’”16 An investigation of 20 young male soccer players 15 to 19 years of age were randomly assigned to take a creatine-monohydrate supplement (three 10-g doses) or placebo for 7 days. Researchers found that supplementation with creatine resulted in soccer-specific skill performance than placebo, with no changes in endurance.17 Several studies have documented creatine monohydrate’s effect on muscle size and strength. Typically, after a 5- to 7-day loading dose, there is an increase in the amount of work done in repeated bouts of maximal exercise and a gain in body mass of between 0.5 and 1kg.13,15 One group of researchers reported that 28 days of supplementation (20 g/day) produced a fat-free mass increase of 1.7 kg.12 Although creatine supplementation improves performance in sprint-trained cyclists, it does not appear to improve endurance performance.’* One study actually reported a worsening in performance during prolonged continuous exercise after creatine supplementation. This finding remains unexplained, although the researchers believe that the increase in body mass due to supplementation might be a contributing factor.19 Research shows that creatine supplementation has no measurable effect on respiratory gas exchange and blood lactate concentrations during either incremental submaximal exercise or recovery, suggesting that creatine phosphate produces energy in the form of ATP in muscle cells for about 10 seconds of activity. After it is depleted, the muscle must shift to anaerobic glycolysis for fuel. Creatine supplementation does not influence substrate utilization during and after this type of exercise.2O Results of an unpublished human trial indicate that insulin might be a potent upregulator of a muscle’s ability to take in creatine. This has resulted in many users supplement creatine monohydrate with a simple carbohydrate (such as glucose, dextrose, or maltose), which simultaneously causes a release in insulin.In a 4-week trial, large increases in speed, anaerobic power, and lean body mass, along with a reduction in body fat, were reported in individuals receiving doses of 20 g/day of creatine for the first 5 days, followed by 10 g/day for the remainder of the 4 weeks. An even greater response in these parameters was reported in the athletes using a creatine-carbohydrate mix, which contained creatine monohydrate, dextrose, taurine, disodium phosphate, magnesium phosphate, and potassium phosphate.

Dosage Typically, dosing of creatine monohydrate follows a loading and a maintenance cycle. During the loading period, larger doses of creatine monohydrate are ingested for 5 to 7 days. A typical dose for individuals weighing less than 225 pounds is 5 g four times per day, and heavier individuals might take up to six doses per day. The maintenance

dose would be 0.03 g per kg of body weight.21*22 Larger doses are probably not of any greater benefit, because the capability of muscle to take in and store creatine is finite? In fact, this dosing schedule might exceed the ability of most individuals to incorporate creatine into muscle tissue, as evidenced by the renal excretion rate of creatine (40%-68% of the supplemented dose) reported in individuals given 30 g/day3 At least one later study supports the possible use of lower oral doses. One study reported that 3 g/day for 28 days increased muscle creatine and creatine phosphate stores to a level comparable to those in a loading phase.21 Most of the gains in size and strength occur within the first month, after which muscles are generally saturated with creatine. Evidence indicates that these gains will remain while supplementation continues but will gradually disappear after the supplement is discontinued. Typically, levels of creatine drop back to presupplementation levels about 1month after supplementation is discontinued. The increases in size and strength resulting from improved muscle cell hydration also disappear over this time. However, actual gains in muscle mass due to increased work capacity during creatine ingestion remain. Anecdotal reports suggest that 20% to 30%of individuals who take creatine do not experience an increase in muscle mass or strength. Currently, this finding is unexplained; however, individuals with lower initial tissue levels as well as those with greater ability for creatine uptake are most likely to Because of the success of creatine monohydrate, several other forms have become available, including creatine phosphate and creatine citrate. These are claimed to produce similar results; however, creatine monohydrate is the only form shown, to date, to increase strength, lean body mass, and tissue creatine phosphate levels.

Toxicity Reported side effects of creatine supplementation include gastric disturbance, headaches, heat exhaustion, muscle cramping, stroke, clenched teeth, and the sound of blood rushing in the ear. One of us (PBB) has experienced this blood rushing sound while taking a creatine supplement and found it quite disturbing; the tinnitus resolved within 2 days of discontinuing creatine use. Creatine supplementation might cause serum creatinine levels to rise. This rise is due to the increase in muscle creatine phosphate and its subsequent spontaneous conversion to creatinine. Most of the studies of creatine have supplemented creatine for only short periods. In one study, long-term supplementation with only lg/day was utilized.” In a second study, blood chemistry analyses were performed in 19 professional basketball players from Spain, who ingested 5 g of creatine monohydrate daily and were studied during three competition seasons.

Blood samples were collected in the morning after an overnight fast, five times during each of the three official competitions spanning the periods of September 1999 to June 2000, September 2000 to June 2001, and September 2001 to June 2002. Standard blood chemistry values, except levels of creatinine and creatine kinase, were found to be normal at all times.= More study is needed, but at this time, there is no indication that long-term, high-dose creatine supplementation has major adverse side effects. Creatine may serve as a precursor for amino-imidazoazaarenes, a class of mutagens found in creatine-rich foods such as fish, chicken, beef, and pork. It has been postulated that these azaarenes may form DNA adducts and subsequently could interfere with proper functionality of the nucleic acids in the cells. Conversely, some researchers consider creatine a genomeceutical, which means that it can beneficially affect gene expression? Clearly, more information is needed to resolve these apparent paradoxical effects. Some concern exists that use of caffeine(0.5 mg/kg/day) can have a negative impact on the effectiveness of creatine. However, in at least one study, participants were instructed to dissolve the creatine monohydrate in tea or coffee before ingestion. Body weight increase was still observed in seven of eight subjects, and all subjects had increased muscle total creatine and phosphocreatine resynthesis8Further studies demonstrate that there is no measurable effect of caffeine on the analysis of strength change?6 These results suggest that caffeine does not negate the effects of creatine supplementation, but until more is known it might be best to minimize caffeinated substances, or to drink them several hours away from creatine supplementation, for optimal results. Creatine supplementation is widely practiced by athletes in many sports and does not contravene current doping regulations? Because creatine supplementation does not enhance performance in endurance athletes and evidence suggests an actual decline in performance, endurance athletes should avoid creatine supplementation. In athletes concerned with improving strength, body composition, or short-duration, repetitive, high-intensity exercise, one of us (GK) recommends that creatine monohydrate be incorporated into any supplementationprotocol. Although quicker results can be seen after a loading dose, the cost-effectiveness of the 3 g/day dose might be a more appealing option for many athletes. Nursing mothers and children should never be given creatine supplementation?

beta-Hydroxy-beta-Methylbutyrate Beta-hydroxy-beta-methylbutyrate(HMB) is a relatively new product, being available in limited supply only since the end of 1995. The nutritional use of HMB for nitrogen retention has been patented by the Iowa State

University Research Foundation and is licensed to Metabolic Technologies. HMB is a leucine metabolite. How HMB is synthesized from leucine in humans has not yet been established; however, evidence in animals suggests that the majority of circulating HMB is formed after the transamination of leucine to alpha-ketoisocaproate with its subsequent oxidation to HMB.27It has not been determined, either, to what extent HMB is normally produced in vivo or which specific cofactors might influence its production. Although the mechanism of action of HMB is still equivocal, HMB is hypothesized to decrease muscle protein turnover and to possibly work primarily by minimizing protein degradation. Suggestive evidence of HMB’s blocking of catabolism is based on its ability to decrease urinary 3-methylhistidine (a marker of muscle breakdown) and to decrease plasma levels of creatine phosphokinase and lactic dehydrogenase.= Anecdotal reports indicate that individuals who work out more often and more intensely get the best results with HMB. This is important because typically, the more an individual works out, the more muscle catabolism also occurs; so at a certain point, the anabolic gains achieved by stimulating the muscles through training are offset by the catabolic effects of frequent, high-intensity workouts. HMB’s anticatabolic effects might move this balance point further in the direction of anabolic growth, allowing an individual to train more often and still receive positive results in strength and mass gains. In a human study conducted over a 3-week period, 3 g/day of oral HMB supplementation was shown to decrease body fat, increase lean mass and strength, and reduce muscle damage in individuals beginning resistance-training exercises. In this trial, participants also consumed either 117 or 175 g/day of protein. Although protein intake did not seem to affect strength, participants with higher protein intakes, independent of HMB supplementation, appeared to have greater increases in lean body massz8Because these results came from individuals who had not previously engaged in weight training, doubt existed as to whether they would be reproducible in body-builders or other athletes who had already engaged in long-term resistance training. However, in a subsequent abstract, the researchers have indicated that HMB feeding resulted in equal increases in strength, body composition, and decreased fat in both trained and untrained indi~iduals.2~A metaanalysis of HMB research considered studies involving HMB supplementation for at least 3 weeks with resistancetraining 2 or more times a week. HMB was found to sigruficantly increase net lean mass gains by 0.28% per week and strength gains by 1.09%and 1.40%per week.30 At this point, the primary concern about the usefulness of HMB is anecdotal evidence indicating that many individuals have not experienced expected results.

Sports Nutrition

or performance in trained athletes. However, whey has been shown to promote growth and enhance nitrogen balance in experimental animals, low-birth-weight infants, and burn ~ i c t i m s . 3 ~ - ~ ~ Whey protein is rich in substrates for glutathione synthesis%;it also contains substantially more cysteine, Dosage which is considered a rate-limiting step in glutathione synthesis, than casein. Whey contains high amounts of The recommended dosage for HMB is 3 g/day. Because glutamine and glycine. relatively high protein intake was reported in the study Glutathione, a powerful antioxidant, is involved in demonstrating HMB's efficacy, and because whether metabolic detoxification pathways. The role free radithe same results will occur with a low-protein diet is cals play in the development of exercise-induced tissue unknown, a similar protein intake of between 120 and damage, or the protective role antioxidants might play, 175 g/day for athletes supplementing their diets with remains to be completely elucidated. Research has indiHMB might produce best results. cated that free radical production and subsequent lipid Toxicity peroxidation are normal sequelae to the rise in oxygen consumption with e~ercise.3~ However, physical training Because HMB is such a new supplement, no information has been shown to result in an augmented antioxidant is available on its long-term safety. One analysis of nine system and a reduction in lipid peroxidation. Supple3- to 8-week studies in which subjects were fed 3 g HMB mentation with antioxidants appears to further reduce per day found that compared with the placebo, HMB lipid peroxidation but has not been shown to enhance supplementation resulted in some increase of stiff joints, exercise performance.% although the researchers believed that this effect probaGlutathione levels have been shown to diminish with bly occurred by chance. Furthermore, the subjects given e~ercise.3~ Additionally, running a marathon causes a HMB had enhanced appetite, less diarrhea, and positive large rise in the tissue content of oxidized glutathione changes in cardiovascular risk factors such as low(189%)at the expense of reduced glutathione.40Although density lipoprotein (LDL) cholesterol value and blood pressure, as well as a perception of greater ~ e l l - b e i n g . ~ ~no information is available on the effects of resistance exercise and glutathione levels, it is hypothesized that a Whey Protein higher intake of antioxidants might protect against minor muscle injuries?' Whey protein, often referred to as lactalbumin, is currently Whey protein is more efficient at inducing supernorthe supplemental protein source of choice for many bodymal glutathione levels than a cysteine-enriched casein builders and strength athletes. Whey proteins represent A whey-rich diet has been shown to increase the major proteins in human breast milk, as opposed to heart and liver tissue glutathione content in rats. The bovine milk, which is composed primarily of casein with lesser amounts of whey. Whey comprises alpha-lactoglob- whey protein diet appeared also to improve longevity when fed at the onset of senescence.Q Whey-based ulin,beta-lactoglobulin,bovine serum albumin (BSA), and formula enhances cysteine retention and results in greater immunoglobulins (Igs) ( 1 6 1 , IgG2, secretory IgA, and taurine excretion, which is thought to be a reflection IgM). Other components of the ladalbumin fraction are of greater taurine st0res.4~Whey protein fed to three enzymes, iron-binding proteins, calcium, potassium, individuals who were seropositive for human immusodium, phosphorous, and vitamins A, C, B1, BD B3, B,, BID nodeficiency virus (HIV) over a 3 months, at doses folic acid, and biotin. Whey is a balanced source of essenincreasing progressively from 8.4 to 39.2 g/day, resulted tial amino acids and peptides with a high protein effiin progressive weight gain and higher glutathione ciency ratio. It is considered an excellent source of sulfur levels.44 amino acids (methionine and cysteine) as well as Experimental studies suggest that the whey protein branched-chain amino acids (BCAAs) (leucine, isoleucine component of milk might exert an inhibitory effect on the and valine) and glutamine (see sections on BCAAs and development of several types of tumor. It is thought that glutamine for information on their potential benefits). the rich supply of substrates for glutathione synthesis Whey transits the stomach quickly and is rapidly contributes to this inhibitory effe~t.4~ In experimental absorbed from the human intestine. The beta-lactoglobanimals, a diet consisting of 20 g of whey per 100 g of ulin component remains soluble in the stomach and diet has been shown to be more protective than similar empties rapidly as an intact protein needing further diets utilizing casein, soybean, or red meat against hydrolysis by pancreatic enzymes. Casein, on the other dimethylhydrazine-induced intestinal cancers.&Peptides hand, transits the stomach slowly? from whey protein have also been shown to have No studies exist comparing the impact of different antithr~mbotic~' and immunoenhan~ing4~f'~ activities. protein sources on nitrogen balance, body composition, Because HMB is thought to function primarily as an anticatabolic substance, it is possible these individuals did not train with enough intensity to optimize its effect. The other possibility is that, like creatine monohydrate, HMB might be ineffective in some people.

Dosage The routine use of an after-workout whey protein shake might be the most important nutritional supplementation habit for enhancing body composition. It is probably in this manner that whey can be best utilized by athletes concerned with maximizing lean body mass and Strength. Amino acid availability after a workout regulates protein synthesis and degradation. Because of the anabolic effects of insulin on protein synthesis and protein degradation, a rapid synergistic response occurs when both amino acids and insulin rise after a protein-containing It is thought that the body is highly insulinsensitive after exercise and preferentially shuttles carbohydrates and protein into muscle cells rather than fat cells. Experts believe that this sensitivity gradually declines after workout for about 2 hours, until it again reaches normal sensitivity. There is evidence that protein combined with carbohydrates and/or creatine might be more effective than protein alone. A carbohydratewhey protein supplement has been shown to be more effective in generating a plasma insulin response than either a carbohydrate or a protein supplement alone during recovery from prolonged exhaustive exercise. The rate of muscle glycogen storage was also sigruficantly faster during the carbohydrate-protein treatment. The participants in this study ingested 112 g of carbohydrate and 40.7 g of protein immediately after each exercise bout.M Similar studies using protein, carbohydrates, and fats showed improvement in glycogen resynthesis using protein and carbohydrate and no change when fat was included.52 In a &week study, men who supplemented their diets with a combinationof whey protein and creatine together (1.2 g/kg/day and 0.1 g/kg/day, respectively) had significantly greater increases in lean tissue mass and bench press weight than those who took only whey protein or placebo. But not all strength measures are improved with creatine and/or whey supplementation. In this study, subjects who took creatine and/or whey supplements found no difference in squat strength and knee flexion peak torque versus those in subjects who received placebo.% Whey is an excellent choice as a protein source for the after-workout shake because of its rapid transit into the small intestine as well as its high levels of BCAAs and glutamine. Glucose polymers or maltodextrins are considered to be the best form of carbohydrates to use because of their ability to stimulate an insulin response. Fat should not be added because it might slow transit time and reduce the insulinresponse.

Toxicity The primary concerns about supplementing the diet with whey protein are the possibility of food allergies, the

lactose content, and proposed links to insulindependent diabetes mellitus (IDDM).Although the possibility of food allergies from whey must be considered, whey is probably is no more, and is possibly less, antigenic than soy, casein, or egg-based protein supplements. A significant concern might be the method of processing of the whey protein, because high temperatures during heating or drying can generate browning reaction products through covalent interaction of proteins and lactose. Browned proteins have lowered digestibility and are thought to result in greater uptake of intact protein through intestinal mucosa. All whey protein available contains some lactose, although many preparations have very low amounts. The BSA component of whey has been implicated as a possible trigger for IDDM in children. The amino acid sequences of the beta-cell protein, found on the insulinsecreting beta cells of the pancreas, and BSA are similar. Because elevations of anti-BSA antibodies have been found in sera from children who later had IDDM, it has been proposed that absorption of BSA, or partially digested fragments of BSA, stimulates the immune system, which then incorrectly destroys beta cells” One study reported the prevalence of anti-BSA antibodies as 52%in children who had IDDM for less than 1year, 47% in children with IDDM for longer than 1 year, and 28% in the control group. The researchers concluded that the prevalence of anti-BSA antibodies is higher in subjects with IDDM than in control subjects; however, because of the large overlap of antibody titers observed in patients and control subjects, anti-BSA antibodies were neither sensitive nor specific markers of IDDM?5 Other studies have found that IgG antibodies to BSA were not significantly increased at the onset of IDDM.56Currently, the exact nature of the relationship between BSA and IDDM remains unclear.

SOY Soy protein is a source of antioxidant phytochemicals. Research is beginning to show that soy supplementation may help decrease levels of lipid peroxides induced by exercise stress. One study examined the response of serum lipid peroxides to the combination of moderateintensity, weight-resistance exercise plus intake of soy protein. In this study, 18 young adult men consumed either 40 g of soy protein per day or an antioxidant-poor whey protein for 4 weeks before a session of moderateintensity weight-resistance exercise. In the soy group, values for serum lipid peroxides at 5 minutes and 3 and 24 hours after exercise were decreased, whereas the whey group showed the depression only at 24 hours. Interestingly, in both the soy and whey groups, a small rise was seen for the cytokine interleukin-8. The researchers suggest that this finding is consistent with the idea that an exercise session does induce moderate muscle stress and inflammati0n.5~

Sports Nutrition

Dosage The preceding study used 40 g per day for a young adult male. Given the benefits of soy for a number of conditions related to the menstrual cycle, soy may be a good choice for some women. As a well-known highly antigenic food, plus current controversial information regarding estrogen-dependent cancers, high-dose supplementation with soy should be considered on an individual basis.

Phosphatidylserine Phosphatidylserine is being widely used by individuals engaged in resistance training, primarily owing to its presumed ability to prevent muscle tissue degradation. Phosphatidylserinehas been shown to affect the body's production of glucocorticoids.Although the mechanism of action of phosphatidylserine is still unknown, an effect on the hypothalamic-pituitary-adrenal axis has been Phosphatidylserine is formed by adding a serine to a phosphatidyl group. This requires pyridoxal5'-phosphate (active B6) and occurs in the same biochemical loop involved with phosphatidylcholine, choline, betaine, and dimethylglycine metabolism. Physical exercise induces a sigruficant rise in plasma epinephrine,norepinephrine, adrenocorticotmpichormone (ACTH), cortisol, growth hormone (GH), and prolactin (PRL). It is theorized that preventing the increase in cortisol subsequent to intense exercise would prevent the excess muscle tissue breakdown. In one study, pretreatment of eight healthy men with either 50 or 75 mg of intravenous brain cortexderived phosphatidylserine within 10 minutes of the start of exercise blunted the ACTH and cortisol responses to physical stress.59 Oral administration of phosphatidylserinederived from brain cortex, 800 mg/day for 10 days, sigruficantly blunted the ACTH and cortisol responses to physical exercise (p = 0.003 and p = 0.03, respectively), without affecting the rise in plasma GH and PRL. Although participants also experienced reductions in plasma cortisol concentrations at a dose of 400 mg/day of phosphatidylserine, the area under the curve of plasma cortisol was sigruficantly lower after the higher dose of 800 mg/day? Although the results of this preliminary work appear promising, no trials to date have reported an increase in strength or an improvement in body composition after phosphatidylserine supplementation. Until these results are determined, claims of phosphatidylserine's ability to reduce muscle tissue catabolism should be regarded as unsubstantiated.

Arginine The amino acid arginine is used occasionally by bodybuilders to stimulate growth hormone secretion. It was very popular in the mid-198Os, but interest in it has since

waned. Arginine has been shown to stimulate wholebody protein synthesis.@Several studies have shown its ability to stimulate growth hormone and insulin-like growth factor I secretion and improve nitrogen balance after intravenous administration; however, equivocal results have been obtained after oral supplementation. Oral arginine/lysine (3 g/day of each) is apparently not a practical means of enhancing GH secretion in older men over the long term.6l Additionally, it is debatable whether increasing growth hormone levels in people not already deficient has an anabolic effect. Arginine is required for creatine synthesis, and some believe it will enhance synthesis if used as a supplement. In rats, arginine and glycine supplementation increased muscle creatine.62One study reported that individuals receiving arginine and ornithine, 5 days a week for 5 weeks, had higher gains in strength and enhancement of lean body mass than control subjects. Dosages amounted to 2 or 1g each of L-arginine and L-ornithine taken orally, and 600 mg of calcium and 1 g of vitamin C as placebos. Subjects taking the arginine and ornithine also had a significantly lower urinary hydroxyproline value, a marker of tissue breakdown, than subjects receiving placebo. The researchers of this study concluded that arginine and ornithine, in conjunction with a high-intensity strength training program, can improve strength and lean body mass and minimize tissue breakdown.@Arandomized controlled study of patients with congestive heart failure showed that supplementationof oral arginine at 9 g a day for 7 days prolonged exercise duration, probably through its nitric oxide-induced peripheral vasodilatory effects.64

Dosage The typical dosage of arginine is 2 g/day. On the basis of results reported by Elam et a1,63 a combination of arginine and ornithine might exert a positive impact on body composition and strength; however, no additional research has substantiated these findings.

Toxicity See Chapter 174 for a discussion of a possible relationship between increased dietary arginine and the incidence of herpes simplex.

Branched-Chain Amino Acids Leucine, isoleucine, and valine are regarded as BCAAs because of their similar chemical structures and interlocking methyl groups. Exercise results in marked alterations in amino acid metabolism within the body. The BCAAs, especially leucine, are particularly important because they contribute, as both energy substrates and nitrogen donors, to the formation of alanine, glutamine, and aspartate. Calculations indicate that the recommended dietary intake of leucine is inadequate, because it is lower than the measured whole-body rates of

Syndromes and Special Topics leucine oxidation. This inadequacy is exacerbated in individuals who are physically active.65 A larger supply of BCAAs appears to have a sparing effect on muscle glycogen degradation during exercise.% Short-term (3-4 hours) infusion of BCAAs has been shown to suppress muscle protein breakdown.67 In humans nourished parenterally provision of balanced amino acid solutions and of only the three BCAAs cause similar improvements in nitrogen balance for several days." Administration of BCAAs can greatly increase their concentration in plasma and subsequently their uptake by muscle during exercise.& Long-term exercise after BCAA administration results in sigruficantly greater muscle production of ammonia, alanine, and glutamine, as well as lower lactate production, than is observed during exercise without BCAA supplementation.@ Although evidence indicates that BCAAs might be significant in enhancing protein synthesis or minimizing protein degradation, supplementation with these amino acids has not produced sigruficantchanges in body composition. If whey or another top-quality protein formula is being used, adequate amounts of BCAAs are provided.

GIutamine Glutamine is the most abundant amino acid in the blood and in the free amino acid pool of skeletal muscle. Glutamine stimulates the synthesis and inhibits the degradation of proteins, is an important vehicle for the transport of nitrogen and carbon within the tissues, stimulates the synthesis of hepatic glycogen, and is an energy source for cell division.69Because glutamine deficiency can occur during periods of metabolic stress, it has led to the reclassification of glutamine as a conditionallyessential amino acid.7O Glutamine is also a precursor for the synthesis of amino acids, proteins, nucleotides, glutathione, and other biologically important molecules. Glutamine is considered to have an anabolic effect on skeletal muscle. It stimulates the synthesis and inhibits the degradation of proteins. Experiments with various animal models have demonstrated that glutamine supplementation can result in better nitrogen homeostasis with conservation of skeletal muscle?O The mechanism by which glutamine affects skeletal muscle protein turnover and, thus, muscle protein balance is unknown. However, glutamine has an anabolic effect of promoting protein synthesis and also might reduce protein breakdown?' Glutamine has been shown to increase cell volume, whereas insulin and glutamine together seem to work synergisticallyto enhance cellular hydration. The effects of glutamine in skeletal muscle include the stimulation of protein synthesis,which occurs in the absence or presence of insulin, the response being greater with insulin.n During various catabolic states, such as infection, surgery burns, and trauma, glutamine homeostasis is under stress, and glutamine reserves, particularly in

the skeletal muscle, are depleted. In these conditions, the body requirements for glutamine appear to exceed the individual's muscle deposits, resulting in a loss of muscle mass.73In critically ill patients, parented administration of glutamine reduces nitrogen loss and lowers mortality? With regard to glutamine metabolism, exercise stress can be viewed similarly to other catabolic stresses. Plasma glutamine concentrations increase during prolonged, high-intensity exercise. However, during the postexercise recovery period, plasma concentrations diminish sighcantly. Several hours of recovery are required before plasma levels are restored to preexercise levels. If recovery between exercisebouts is inadequate, the acute effects of exercise on plasma glutamine concentrations can be cumulative. It has been observed that overtrained athletes appear to maintain low plasma glutamine levels for months or ~ e a r s .Some 7 ~ experts believe that reduced concentration of plasma glutamine can provide a good indication of severe exercise stress.75Research suggests that, after exercise, greater availability of glutamine promotes muscle glycogen accumulation by mechanism possibly including diversion of glutamine carbon to After trauma there is a loss of nitrogen, with a concomitant reduction of skeletal muscle protein synthesis. This is accompanied by a decrease in the stores of muscle free glutamine. Nutritional support with either glutamine or its carbon skeleton, alpha-ketoglutarate, has been shown to counteract the postoperative drops in muscle free glutamine stores and muscle protein synthesis." One small study suggests that oral glutamine increases growth hormone release. In this work, an oral glutamine load (2 g) was administered to nine healthy subjects to determine the effect on plasma glutamine, bicarbonate, and circulating growth hormone concentrations. Eight of nine subjects responded with increases in plasma glutamine concentrations at 30 and 60 minutes before returning to the control value at 90 minutes. Ninety minutes after the glutamine administration load, concentrations of both plasma bicarbonate and circulating plasma growth hormone were elevated.78Even with this theoretical support, clinical trials studying glutamine as an exercise performance enhancer are not encouraging. In a double-blind, placebo-controlled, crossover study, six resistance-trained men performed weightlifting exercises after the ingestion of either glutamine or glycine at 0.3 g/kg body weight or of a placebo (two subjects/group). One hour after ingestion, subjects performed four total sets of exercise to momentary muscular failure, including two sets of leg presses at 200% of body weight and two sets of bench presses at 100% of body weight. Despite glutamine's possible role in exercise, there were no actual differences in the average number of maximal repetitions performed in the leg press or bench press exercises among the three group^.^ Other studies using dosages of 0.3 to 0.9 g/kg body weight

Although some advocates recommend as much as 30 g of glutamine, it is likely that only marginal benefits are found at supplementary levels higher than 2 to 3 g/day.

other hand, a suboptimal vitamin C status results in an impaired working capacity that can be normalized by restoring vitamin C body pools.83 A potent antioxidant required for collagen synthesis, ascorbic acid might help protect muscles from excessive damage due to training or trauma. Data suggest that prior vitamin C supplementation might exert a protective effect against exercise-induced muscle damage.84 Ascorbic acid also might decrease cortisol productions5 and may have a role in facilitating an adequate response to stress.%

Ornithine alpha-Ketoglutarate

Dosage

omithine alpha-ketoglutarate (OKG) is a salt formed of two molecules of ornithine and one molecule of alphaketoglutarate. OKG has been successfully used via enteral and parenteral routes in burn, trauma, and surgical patients as well as in chronically malnourished subjects. Depending on the metabolic situation, OKG treatment decreases muscle protein catabolism and/or increases protein synthesis. In addition, OKG promotes wound healing. The mechanism of action of OKG is not fully understood, but the secretion of anabolic hormones (insulin, human growth hormone), and the synthesis of metabolites (glutamine,polyamines, arginine, ketoacids) might be involved.82 This supplement has been available for more than a decade. It has been used successfully in hospitalized bum victims to slow protein loss. Only one study appears to have evaluated the effect of OKG on performance. In this study, OKG (10 g/day with 75 g of carbohydrates) was given for 6 weeks. The subjects receiving OKG experienced a significant increase in bench-press strength and biceps circumference compared with those receiving placebo. Body weight and percentage fat were not different between the groups. No differences in growth hormone levels were seen between the groups. Body composition changes were seen in several individuals in the OKG group, but no sigruficance was found either within or between experimental gr0ups.8~ Anecdotal reports from some individuals supplementing their diets with OKG indicate increased appetite and better disposition to train. Some anecdotal reports claim great results, whereas others describe no improvement.

Because of ascorbic acid’s potential for minimizing muscle damage and cortisol-induced muscle catabolism, 1to 3 g should be taken daily.

also demonstrated no changes in exercise performance, body composition, or muscle protein degradation in young healthy adults.sOfilIt is possible that beneficial effects of glutamine are best detected only in patients with chronic illness and those with compromised physiology rather than in normal, healthy individuals.

Dosage

Dosage The recommended dosage of OKG is 10 g along with a 75-g carbohydrate drink.

Vitamin C There have been several investigations during the past five decades of the potential effect of high-dose vitamin C (ascorbic acid) supplementation on physical performance. However, the results have been equivocal. Most studies could not demonstrate an effect. On the

Boron A proliferation of athletic supplements has been marketed touting boron as an ergogenic aid (a substance that can enhance work output) capable of increasing testosterone. Although this might to be true in some populations under specific conditions, boron’s impact on testosterone is still equivocal. Boron appears to raise testosterone levels in rats in a time- and dose-dependent mar1ner.8~In postmenopausal women, increasing dietary intake of boron from 0.25 to 3.25 mg/day has been reported to more than double plasma testosterone levels.88 In a subsequent study of healthy men, boron supplementation raised the plasma concentrations of both estrogen and testo~terone.~~ However, one study reported that changing boron intake had no impact on testosterone levels in postmenopausal women?O The effect of boron supplementation was investigated in 19 male body-builders age 20 to 27 years. Ten subjects were given a 2.5-mg boron supplement and nine a placebo every day for 7 weeks. Both groups demonstrated sigruficant increases in total testosterone, lean body mass, and one-repetition maximum squat and bench-press. However, analysis of variance indicated no significant effect of boron supplementation on any of the dependent variables. The researchers concluded that the gains were a result of 7 weeks of body-building, not of boron supplementation?l

Dosage It is prudent to supplement the diet with 3 mg/day of boron to ensure against deficiency; however, an expectation of increased strength and improved body composition is unrealistic.

Chromium Chromium is highly promoted in body-building circles as a fat-burning supplement and as an aid in increasing

lean mass. Available research does not support either of these claims. A meta-analysis of studies published from 1967 through 2001 found that chromium did not significantly affect lean gain or strength.3oChanges in body weight, a sum of three body circumferences, a sum of three skinfold measurements, and the one-repetition maximum for the squat and bench-press were examined in 59 collegeage students during a 12-week weight-lifting program. Half of the students were given 200 pg/day of elemental chromium as chromium picolinate, and the other half received a placebo. No treatment effects were seen for the strength measurements. The only s i g h c a n t treatment effect found was an increase in body weight observed in the women supplementing with chr0mium.9~ The effects of 9 weeks of daily chromium supplementation (200 pg chromium as picolinate) were investigated in a double-blind study in football players during sprint training. Chromium picolinate supplementation was ineffective in bringing about changes in body composition or ~trength.9~ The same results were shown in another study of 200 pg of chromium given as supplements to untrained men (23 & 4 years) in conjunction with a progressive, resistive exercise training program. Chromium supplementation was not found to promote either a significant increase in strength or lean body mass or a significant decrease in percentage of body fat.% Increasing dosage and duration of supplementation with chromium also did not help. A double-blind, placebo-controlled study conducted for 16 weeks provided 400 pg of chromium as picolinate or a placebo. At the end of 16 weeks, the chromium group did not show a sigruficantly greater reduction in either percentage body fat or body weight, or a greater increase in lean body mass, than the placebo group. The researchers concluded that chromium picolinate was ineffective in enhancing body fat reduction in this Yet another study, involving 8 weeks of daily chromium supplementation in 36 men in a double-blind design, found that strength, mesomorphy, fat-free mass, and muscle mass increased with resistance training independent of chromium supplementation (p < 0.0001). These findings suggest that routine chromium supplementation has no beneficial effects on body composition or strength gain in men, although it must be noted that the placebo group received a trace level of chromium." Evidence strongly indicates that supplementation of chromium does not enhance strength or body composition. As with boron, chromium-rich foods or a supplement containing chromium should be included in the diet to avoid deficiency; however, it is unrealistic to expect gains in strength or improvement in body composition.

Selenium Selenium is a trace mineral used as a cofactor in several enzymes. It is commonly found in antioxidant formulas because of its role as a cofactor in the enzyme glutathione peroxidase. Evidence suggests that the administration of organic selenium partially compensates for, and decreases the intensity of, oxidative stress in atI1letes.9~ Although optimal antioxidant status is critical to athletes, selenium might have an additional role in the determination of body composition. Selenium deficiency can affect the metabolism of thyroid hormones. Iodothyronine Sdeiodinase, which is mainly responsible for peripheral triiodothyronine (T3)production, has been demonstrated to be a selenium-containing enzyme?* In rats fed a selenium-deficient diet, hepatic iodothyronine 5'-deiodinase is decreased by 47%. Lower concentrations of T3and thyroxine (T4) have also been demonstrated in seleniumdeficient animals." Reduced peripheral conversion of T4 to T3 secondary to a selenium deficiency might create a functional hypothyroidism, which would be expected to adversely affect body composition.

Toxicity There are data suggesting that ingesting more than 750 to 1000 pg/day of selenium over an extended period may be harmful.

Vanadium (VanadyI SuIfate) Vanadium as vanadyl sulfate is widely utilized by athletes seeking to improve body composition. It is generally promoted as having an anabolic effect that enhances the transport of amino acids into cells. Several studies have indicated its ability to reduce fasting glucose and improve hepatic and peripheral insulin sensitivity in humans with non-insulin-dependent diabetes mellitus (NIDDM).*00-*02 However, vanadyl sulfate does not appear to alter insulin sensitivity in nondiabetic subjects.'OZ A single study reported the effect of oral vanadyl sulfate (0.5 mg/kg per day) on anthropometry,body composition, and performance in a 12-week, double-blind, placebocontrolled trial involving 31 weight-training volunteers. No sigruficant treatment effects for anthropometric parameters and body composition were observed. The two groups had similar improvements in performance in most exercises; however, a sighcant improvement in one repetition-maximum leg extension was found in the treatment group. The researchers concluded that although vanadyl sulfate was ineffective in changing body composition in weight-training athletes, its performanceenhancing effect required further investigation.lo3

Toxicity Anecdotal reports indicate that body-builders often supplement their diets with 15 mg tid of vanadium;

Sports Nutrition

however, this practice is ill-advised due to the lack of both demonstrated efficacy and information regarding long-term toxicity of high doses of vanadium. In rats, dietary concentrations of 25 mg/kg of vanadium cause mild diarrhea and growth suppression, and up to 50 mg/kg severely depressed growth and increased diarrhea and mortality. When 12 patients were fed 13.5 mg/day of vanadium for 2 weeks and then 22.5 mg/day for 5 months, 5 of the patients experienced cramps and diarrhea at the high dosage.lM

Zinc Because dietary deficiency of zinc is prevalent, zinc supplements have been widely advocated for athletes. It might not be wise to indiscriminately administer zinc, but evidence suggests that zinc might affect body composition through its interaction with a variety of hormones. It is thought that intense exercise can result in changes in zinc metabolism. Zinc has been demonstrated to be lower in trained adolescent gymnasts and even lower in females in the general population. This reduction might play a role in abnormalities of puberty, growth, or muscular performance.lo5 Some investigators have concluded that zinc might play an important role in modulating serum testosterone levels in normal men. Dietary zinc restriction in normal young men is associated with a sigruficant decrease in serum testosterone concentrations, whereas zinc supplementation of marginally zinc-deficient normal elderly men led to an increase in serum testosterone from 8.3 6.3 to 16 ? 4.4 nmol/L (p = 0.02).'06 However, although zinc deficiency might inhibit testosterone production, zinc supplementation of an individual with adequate levels has not been shown to produce excess testosterone. Zinc deficiency might result in reduced production of GH and/or insulin-like growth factor I (IGF-I).Io7Oral zinc replacement has normalized growth hormone levels and increased growth rate in teenagers found to be GHdeficient.lWZinc supplementationcauses a sigruficantrise in liver synthesis of IGF-I (somatomedin C). In chronic zinc deficiency, reduced liver produdion of IGF-I is responsible for diminished physical growth; moreover, in this situation, receptor resistance to IGF-I (in addition to GH) has been demonstrated. Receptor sensitivity is reestablished after supplementationwith zinc. Zinc might also play a role in increasing the number of receptors.'Og Zinc deficiency might affect the metabolism of thyroid hormones. The structure of nuclear thyroid hormone receptors contains zinc ions, crucial to the functional In experimental animals, zinc properties of the deficiency decreases concentrations of T3and free T4(fTJ in serum by approximately 30% when compared with zinc-adequate controls. The concentration of T4in serum was not affected by zinc deficiency. In these animals,

*

zinc deficiency also decreased the activity of hepatic iodothyronine 5'-deiodinase by 67%.*

Toxicity Zinc supplementation is generally safe if maintained at levels within two to eight times the recommended dietary allowance (RDA). Symptoms of zinc toxicity include gastrointestinal irritation, vomiting, adverse changes in ratio of high-density lipoprotein (HDL) cholesterol to LDL cholesterol, and impaired immunity. The last symptom develops when more than 180 mg/day of zinc is consumed for more than several weeks. Excess intake of zinc may either lower copper levels or aggravate an existing marginal copper deficiency. Because of the multiple interactions of zinc with hormones critical to strength and body composition, it is recommended that athletes undergo a determination of zinc nutriture and receive supplementation if required.

Summary On the basis of available information, strength athletes

are likely to obtain better results by following a supplementation routine that includes the following: Creatine monohydrate (at least 3 g/day) A postworkout protein shake (40 g of protein) Vitamin C (1-3 g/day) A multivitamin/mineral formulationcontaining approximately: 3 mg of boron, 200 pg of chromium, 200 pg of selenium, 100 Fg of vanadium, and 15 mg of zinc The published results to date on HMB are impressive; for athletes utilizing HMB, the recommended dosage is 3 g/day. Although a theoretical argument can be made for the inclusion of phosphatidylserine in a supplement routine, the high cost and the lack of information on bottom-line results in terms of improved strength or body composition make it difficult to justify its use. Compelling evidence could be used to make an argument for many of the isolated amino acids, but a high-quality protein supplement, such as whey, provides adequate levels of all of the amino acids for the majority of athletes. Because of the correlation of low glutamine levels with overtraining, supplementation with 2 g/day of glutamine in addition to a protein supplement, in individuals whose training regimen places them at risk for overtraining, seems prudent.

SPORTS NUTRITION FOR ENDURANCE ATHLETES Panax ginseng Panax ginseng, also known as Panax schinseng, is a member of the family Araliaceae. In Mandarin Chinese

it is called Ren Shen, but it is commonly referred to as Korean or Chinese ginseng.Several closely related species are also often sold as ginseng. These include Panax quinquefolium (American ginseng); Panax notoginseng, also known as Panax pseudoginseng (Himalayan ginseng), and P a m japonicum (Japanese ginseng). Ginseng was used traditionally as a tonic for a broad range of medical conditions. It was believed to be a revitalizing agent capable of enhancing health and promoting longevity (for a more detailed discussion, see Chapter 111). Soviet scholars, beginning in the early 1950s, were the first to establish the fact that many Araliaceae family plants, especially P. ginseng, are adaptogens.l1° Among their many properties, adaptogens are thought to promote regeneration of the body after stress or fatigue and to rebuild strength. Because of its reputation as an adaptogen, P. ginseng is among the most popular botanical supplements used by athletes. Many animal studies with I? ginseng, or its active components, have demonstrated an enhanced response to physical or chemical stress.111-115 In rats, the aqueous suspensions of roots of P. ginseng were tested for antistress activity by the "mice swimming endurance test" and anabolic activity by noting gain in body weights and muscle. A sigruficant increase in mice swimming time was shown by mice fed ginseng compared with the conP. ginseng extract has also been shown to trol gr0up.5~J'~ increase the activity of glutathione peroxidase and superoxide dismutase. These animals' enhanced antioxidant capacity demonstrated reduced oxidative stress after experiencing exhaustive e~ercise."~ In animal models, administration of ginseng has been shown to affect several hormones that might in turn affect performance. High doses of ginseng have been reported to increase blood testosterone level.Ils Experiments indicate that the bindjng of corticosteroid to certain brain regions is higher in adrenalectomized rats given ginseng saponin.l19Ginseng saponin has also been reported to act on the hypothalamus and/or hypophysis, stimulating ACTH secretion, which results in greater synthesis of corticosterone in the adrenal cortex.120J21 Although results of studies with animals have been compelling, ginseng's value as an ergogenic aid in humans is still equivocal.lZ Extracts of l? gznseng are reported to increase plasma total and free testosterone, dihydrotestosterone, and levels of follicle-stimulating and luteinizing hormones in infertile men.123The addition of ginseng root extract to a multivitamin base is reported to have improved subjective parameters in a population exposed to the stress of high physical and mental activity.'" In a double-blind, randomized, crossover study, 50 healthy men received either two capsules of a preparation containing ginseng extract, dimethyl aminoethanol bitartrate, vitamins, minerals, and trace elements or two capsules of placebo every day

for 6 weeks. The total workload and maximal oxygen consumption during exercise were signhcantly greater after the ginseng preparation than after placebo. The researchers also noted decreases in plasma lactate levels, carbon dioxide production, and heart rate during exercise in participants receiving the ginseng preparation.lZ A randomized controlled study of 92 moderately severe patients with chronic obstructive pulmonary disease observed that those taking 100 mg of ginseng extract twice a day for 3 months experienced improvements in parameters of pulmonary function, maximum voluntary ventilation, maximum inspiratory pressure, and maximal oxygen consumption, with no side effects.lZ6 Other researchers evaluated the effect on performance of a ginseng saponin extract (8 or 16 mg/kg body weight) ingested daily for 7 days. Although time to exhaustion was significantly less during the presupplementation control trial than during the placebo and ginseng trials, no significant difference was found between the placebo and the ginseng trials.127Another double-blind trial of 38 adults using 400 mg/day of ginseng for 8 weeks found no change in physical performance and heart rate recovery after exhaustive exercise.lZ8It should be noted that the duration of the supplementation period was only 1 week in this trial. Because historically ginseng has been used as a tonic for prolonged periods and positive results have been reported after 6 weeks of supplementation, a longer trial might have demonstrated an ergogenic effect. Research in support of the use of l? ginseng as an ergogenic aid, although equivocal, is promising. Because of the anecdotal reputation and allure this plant holds, many athletes are likely to continue to use it.

Dosage The quality of available ginseng preparations can vary greatly, so it is imperative to use I? ginseng with documented potency. A typical dose for general tonic effect would contain at least 25 mg of the saponin ginsenoside.lZ9I? ginseng contains 2% to 3% ginsenosides, so a dose of 8 to 12 g of crude herb, assuming it is of high quality, will provide adequate saponin content. Because of the variability in quality of P.ginseng available, utilizing a preparation standardized for ginsenoside content may be preferable. The dosage for a product standardized to 5% ginsenosides would be 500 mg/day, and for a product standardized to 14% ginsenosides, about 180 m g / d a ~ . For ' ~ ~anyone using ginseng for a prolonged period, some authoritieshave recommended discontinuing supplementationperiodically for 2-week intervals.

Toxicity The problem of quality control makes toxicology of ginseng difficult to address. Studies performed on standardized extracts of ginseng have demonstrated

the absence of side effects and mutagenic or teratogenic effects. However, toxicity has been reported with products of uncertified constituents.

Eleutherococcus senticosus EZeutherococcus sen ticosus, also known botanically as Acunthopunux senticosus, is a member of the Araliaceae family that also contains P.ginseng.In China, the plant is called Ci Wu Jiu;however, it is most commonly referred to as Siberian ginseng. Because of its wide availability and lower cost, the dried root and rhizome are commonly used as a ginseng substitute; however, ginsenosides, characteristic of Punux spp., are not found in the roots of Elm therococcus sentic~sus.'~~ (For a more detailed discussion of both of these botanicals, see Chapters 90 and 111.) E. senticosus is classified as an adaptogen and is believed to promote recovery and improve endurance. It has a long history of use in Chinese herbal medicine, in which it was used to enhance general health, longevity, appetite, and memory. Because of the rarity of I? ginseng, Soviet scientists shifted the focus of their research in the late 1950s to other members of the Araliaceae family in order to find suitable substitutes.Four adaptogenic plants were identified, studied, and finally introduced into therapeutic practice, between 1955 and 1964. E. senticosus was considered to be the most important of these substitutes."O Reports indicate that Eleutherococcus was used routinely by both Soviet Olympic athletes and military officers. Extracts of Eleutherococcus prolong the exercise time to exhaustion in swimming and modulate changes of the hypophyseal-adrenal system in rats under extreme condition^.'^^ Famsworth et reviewed the results of clinical trials of Eleutherococcus in humans. The data they gathered indicated that ingestion of extracts from the plant increased the ability to accommodate to adverse physical conditions, improved mental performance, and enhanced the quality of work under stressful conditions such as during athletic perf~rmance.'~~ Other researchers, however, have concluded that supplementation of E. senticosus had no ergogenic effect on the measured parameters associated with submaximal and maximal aerobic exercise tasks. The effect of this substance on performance during submaximal and maximal aerobic exercise was measured in 20 highly trained distance runners randomly assigned to matched pairs. Participants consumed either 3.4 ml of E. senticosus extract or placebo daily for 6 weeks. During the 8-week double-blind study, subjects completed five trials of 10-minute rufls on a treadmill at their 10-km race paces and a maximal treadmill test. No sigruficant differences were observed between Elmtherococcus- and placebosupplemented groups for heart rate, oxygen consumption, respiratory exchange ratio, and rating of perceived exertion during the 10-km run and maximal treadmill test.133Other human studies evaluating steady-state

substrate utilization or 10-km cycling performance time also found no benefit.lM Eleutheracoccus senticosus has received attention in the popular press under the name Ci Wu Jiu.Trials of its effect on Performance have been sponsored by PacificHealth Laboratories, Inc., the manufacturer of a standardized extract and the holder of a patent for the use of Ci Wu Jia to enhance stamina and physical performance during, and enhance recovery after cessation of, exercise. All reports on Ci Wu Jia's effect on performance have been based on information provided by this manufacturer. Ci Wu Jia reportedly has a carbohydrate-sparing action, shifting metabolism to a higher utilization of fat for energy. The carbohydrate shift is also reported to delay the lactic acid buildup associated with muscle fatigue. Reports indicate that Ci Wu Jia might slightly reduce heart rate during exercise and recovev. Participants have usually consumed 800 mg/day of the standardized extract for 2 weeks. Overall, the evidence for an ergogenic effect of E. senticosus is fair. The reported benefits Russian athletes received from supplementation remain the most compelling evidence to date of the ergogenic potential of this plant.

Dosage Recommended doses vary depending on the form of Eleutherococcus used. The dose of a 1:l fluid extract (33% ethanol) is usually between 2 and 4 ml one to three times/day; however, doses up to 16 ml have been used. A standardized 201 solid concentrate is also available. In this form, a minimum recommended dosage would be 300 mg/day, equivalent to 6 g of powdered root. Better results might be experienced at higher doses. In order to avoid accommodation, Eleutherococcus should be used for no longer than 60 consecutive days, followed by a period of 2 to 3 weeks of abstinence before resumption of ~upp1ementation.l~~

Toxicity Toxicity studies in animals have demonstrated that Eleutherococcus extracts are virtually nontoxic. Human clinical studies have shown that in the recommended dosage range, the extracts (33%ethanol) are well tolerated and side effects are infrequent. A few studies found mild side effects at higher dosages (4.5-6.0ml three times/day) when used for long periods (60 days). The symptoms included insomnia, irritability, melancholy, and anxiety.

Carnitine Carnitine is promoted as a supplement needed to improve the body's ability to use stored fat as fuel. Supplementation purportedly enhances lipid oxidation, increases maximum oxygen consumption (Vo2,,J (a measurement of maximal aerobic power), and decreases plasma lactate accumulation during exercise.

Carnitine is a trimethylated amino acid roughly similar in structure to choline. The synthesis of carnitine begins with the methylation of lysine by Sadenosylmethionine. Cofactors required for optimal synthesis of carnitine are as follows: Magnesium Iron Ascorbic acid Folic acid Methylcobalamin Betaine Pyridoxal5'-phosphate Niacin Carnitine is located in the mitochondrial membrane and is a cofactor needed for the transformation of free long-chain fatty acids (LCFAs) into acyl-camitines for subsequent transport into the mitochondrial matrix. Inside the mitochondria, LCFAs are metabolized into energy by the process of beta-oxidation. Several investigators have suggested that L-carnitine supplementation might benefit athletes. One study investigated the effect of giving 2 g/day of L-carnitine for 6 weeks to seven male marathon athletes. Improvement in running speed by 5.68% and decreases in average oxygen consumption and heart rate in the treadmill test followed supplementation. The researchers suggest that for carnitine to be effective as an ergogenic aid, several preconditions must be met: (1) a n adequate supply of lipids available as fuel, (2) shift of metabolism toward the utilization of fats as an energy source, and (3) a relative shortage of available endogenous camitine. Because the average free and total plasma carnitine levels were below the normal ranges before supplementation in these subjects, the L-carnitine might have helped them overcome a relative endogenous defi~iency.'~~ In a double-blind crossover study of 10 moderately trained male subjects, either 2 g of L-carnitine or placebo were provided orally 1hour before exercise. supplementation with L-carnitine induced a significant postexercise decrease in plasma lactate and pyruvate levels and a concurrent increase in acetylcarnitine carnithe.'% In another study, 2 g of L-camitine or a placebo was given to subjects 1 hour before they began exercise. At the maximal exercise intensity, treatment with L-carnitine increased both maximal oxygen uptake and power output. The researchers also reported that, at similar exercise intensities, oxygen uptake, carbon dioxide production, pulmonary ventilation, and plasma lactate levels were reduced in participants receiving ~-carnitine.'~' Although some of the results with L-carnitine supplementation have been promising, not all research is in

agreement. One review of carnitine and physical exercise concluded that carnitine supplernentationl3: Has an equivocal effect on performance in athletes. Does not enhance fatty acid oxidation, spare glycogen or postpones fatigue during exercise. Does not stimulate pyruvate dehydrogenase activity. Does not reduce body fat or help with weight loss. One research group found that long-term carnitine supplementation, 6 g/day, resulted in no differences in volume of oxygen consumption (Vo,), respiratory exchange ratio, heart rate, or utilization of carbohydrate and fat. They also reported that muscle carnitine concentration at rest was unaffected by ~upplementation.'~~ Similar results were reported with carnitine supplementation at 4 g/day for 14 days; although effective at increasing plasma total acid-soluble and free carnitine concentrations, this measure had no significant effect on muscle carnitine concentrations.'40Another group found that loading of athletes with L-carnitine for the 10 days before a marathon abolished the exercise-induced drop in plasma free carnitine concentration and increased the production of acetylcarnitine but yielded no detectable improvement in perf0rman~e.l~~ Still another study investigated the effects of ~-carnitine supplementation on metabolism and performance of endurance-trained athletes during and after a marathon run.In a double-blind crossover field study, seven male subjects received 2 g of L-carnitine 2 hours before the start of a marathon run and again after 20 km of running. Although the administration of L-carnitine was associated with a significant rise in the plasma concentration of all analyzed carnitine fractions, there were no significant changes in running times; plasma concentrations of carbohydrate metabolites (glucose, lactate, and pyruvate), fat metabolites (free fatty acids, glycerol, and betahydroxybutyrate), or hormones (insulin, glucagon, and cortisol); or levels of enzyme activities (creatine b a s e and lactate dehydrogenase).'" Although available data on L-carnitine as an ergogenic aid is not compelling, pretreatment has favored aerobic processes under some experimental conditions. It is possible that L-camitine might exert a beneficial effect only in persons in whom there are actual deficiencies.Availability of fat as a substrate for fuel might also affect the ability of carnitine to act as an ergogenic aid.

Dosage Ingestion of 2 g L-camitine 1hour before intensive exercise might provide some benefits; however, because of the mixed results of studies and the cost of the supplement, long-term administration of L-carnitine is difficult to justify.

Sports Nutrition

Toxicity Given twice daily at a dosage of 6 g twice daily to boys aged 6 to 13 years in a study of attention deficit hyperactivity disorder (a dosage much higher than the suggested preexercise dose for adults), L-camitine was well-t01erated.l~~ Other 3-month investigations using 2 to 3 g/day in cardiac patients also found L-carnitine safe, with no side effect^.'^,^^^ There have been some reports of excessive body odor in people taking carnitine, possibly owing to the greater formation of trimethylamines; supplemental riboflavin is thought to remedy this problem.

Choline Choline supplements have been advocated as a means of preventing the decline in choline reported to occur during exercise. Choline in the diet consists primarily of phosphatidylcholine, which after absorption by the intestinal mucosa is metabolized to choline in the liver. Most choline is rephosphorylated to phosphatidylcholine; however, a small amount of choline is carried to the brain via the blood stream, where it is converted to acetylcholine, a chemical messenger required for adequate nerve impulses and memory storage and retrieval. Running a 26-km marathon reduces plasma cholineby approximately 40% according to one study.'& The decline has been proposed to lower acetylcholine levels, resulting in a reduction in the transmission of contractiongenerating impulses across skeletal m ~ s c 1 e .Itl ~has ~ been proposed that this reduction might negatively affect endurance perf~rmance.'~,'~~ Another study investigated the effect of lecithin on the plasma choline concentrations during continuous strain in ten top-level triathletes (four women and six men). The participants received either a placebo or 0.2 g lecithin/kg body mass 1hour before each exercise. Bicycle exercise without lecithin supply decreased plasma choline concentrations in all the triathletes, on average by 16.9%.When lecithin was given before exercise, average plasma choline concentrations remained at the same level as the initial values. In a second trial, with 13 adolescent runners (three girls and ten boys), mean plasma choline concentrations remained stable when subjects were running without lecithin supplementation.lM Yet another research group, however, found that trained cyclists do not deplete choline during supramaximal brief or prolonged submaximal exercise, nor do they benefit from choline supplementation, given as choline bitartrate (2.43 g) to delay fatigue under these conditions.'" Other double-blind crossover studies of subjects participating in load carriage tests found that the placebo group did not have choline depletion, nor did intake of choline have any effect on performance of

physical reaction time, logical reasoning, vigilance, spatial memory, or working m e m ~ r y . ~ ~ J ~ ~ No evidence to date provides compelling justification for supplementation of the diet with choline as an ergogenic aid. Its potential efficacy for improving physical performance remains largely theoretical.

Coenzyme Qlo (Ubiquinone) Because of its role in mitochondria1 energy production, coenzyme Qlo (CoQlo), also known as ubiquinone, is reputed to enhance performance; however, no studies have demonstrated a sigruficant improvement in any aspect of athletic performance. Biopsy of muscle found that CoQlo levels were positively correlated to exercise capacity and marathon perf ~ r m a n c e . Providing '~~ 150 mg/day of CoQlo orally for 2 months to a group of middle-aged men resulted in higher circulating blood levels of CoQlo and improved perceived level of vigor; no improvement in aerobic capacity was found.'53 Giving cyclists 100 mg/day of CoQlo for 8 weeks produced no measurable effect on performance, Vo-, submaximal physiologic parameters, or lipid peroxidation.154Other researchers have found that oral ubiquinone was ineffective as an ergogenic aid in both young and older trained men.155 On the basis of available research, CoQlo appears to have no value as an ergogenic aid.

Pyridoxal-alpha-Ketoglutarate Pyridoxal-alpha-ketoglutarate (PAK) consists of pyridoxine (about 54%) and alpha-ketoglutarate (about 46%). It is thought to improve the generation of highenergy phosphate bonds, such as ATP and guanosine triphosphate (GTP). In addition, a higher level of alphaketoglutarate, along with pyridoxal 5'-phosphate, in the mitochondria might enhance the transamination of pyruvate to alanine, thereby possibly preventing or reducing lactic acid formation.'56 Administration of PAK was shown to reduce the plasma concentration of lactate in response to isometric exercise in a group of nonketotic patients with NIDDM.157 The administration of 30 mg/kg of PAK for 30 days has been reported to increase V h , and to decrease lactic acid accumulation during short supramaximal workloads. The administration of alpha-ketoglutarate or pyridoxine separately did not alter V b sigruficantly.156 Individually and in combination, the use of PAK and sodium bicarbonate in short-term maximal exercise capacity was studied in eight cyclists. Oral tablets of sodium bicarbonate and PAK were given in doses of 200 and 50 mg/kg, respectively. The investigators found no sigruficant differences between treatments in the ability to sustain maximum power during the exercise trial; however, the best results obtained were from individuals

Syndromes and Special Topics utilizing both PAK and bicarbonate. PAK supplements by themselves did not improve participants' ability to sustain maximum power.'"

Dosage The typical dose of PAK is 1800 to 3000 mg/day, depending on body weight. Although PAK might be complementary to athletic training, particularly in conjunction with sodium bicarbonate, available information is limited. PAK supplementation appears to positively influence some physiologic parameters associated with enhanced aerobic performance; however, to date this supplement has not been shown to produce a "bottom-line" improvement in actual performance.

Pyruvate Supplementation with pyruvate is popular with some athletes because of reports of its endurance-improving and weight loss-enhancing effects. Pyruvate is a stable salt form of pyruvic acid, the naturally occurring endproduct of the metabolism of carbohydrates. It is stabilized by the addition of sodium, potassium, calcium, or magnesium to pyruvic acid. Pyruvic acid occurs naturally in the diet, fruits and vegetables being good sources. Red apples are possibly the best source, with an estimated 450 mg of pyruvic acid per apple. Pyruvate is a three-carbon compound containing a carboxylic acid and a ketone group. During the process of glycolysis, glucose is converted to pyruvate. Pyruvate is then either converted to acetyl coenzyme A, for entry into the citric acid cycle under aerobic conditions, or to lactate under anaerobic conditions. Pyruvate's mechanism of action for weight loss and for enhancing endurance is unknown. In published research, most of which has been conducted by Stanko et a1,'59-163pyruvate has usually been given in conjunction with dihydroxyacetone. This combination has been reported to be useful in weight loss routines, in which it is partially and isocalorically substituted for glucose in obese women. Participants in one study were started on severely restrictive hypocaloric diets for 21 days while housed in a metabolic ward. In one study, participants fed dihydroxyacetone and pyruvate (DHAP) showed greater weight loss (6.5 k 0.3 kg, vs. 5.6 f 0.2 kg for the placebo group) and higher fat loss (4.3 f 0.2 kg, vs. 3.5 f 0.1 kg for the placebo In another trial, pyruvate and dihydroxyacetone, given as approximately20%of energy intake, reduced the reaccumulation of body weight (1.8 f 0.2 kg vs. 2.9 k 0.1 kg) and fat (0.8 k 0.2 kg vs. 1.8 k 0.2 kg) associated with refeeding after a calorie-restricted @ d'ei.t ' Pyruvate alone has been reported to be an effective addition to a weight loss program. In one study, participants were obese women housed in a metabolic ward and consuming a 4.25 MJ/day liquid diet for 21 days with or

without pyruvate partially and isoenergeticallysubstituted for glucose. Participants fed pyruvate showed greater weight loss (5.9 f 0.7 kg, vs. 4.3 f 0.3 kg for the placebo group) and higher fat loss (4 f 0.5 kg, vs. 2.7 f 0.2 kg for the placebo The reports indicate that pyruvate had no impact on enhancing nitrogen balance, serum protein concentrationsor lean body mass in these subje~ts.'~%'~' Because the published studies were conducted on obese women consuming calorie-restricted diets of either 500 or 1000 calories/day, these weight losses should not be extrapolated to athletes or other populations consuming normal or high-calorie diets. Also, in the published trials, pyruvate has been substituted for glucose, a substance that affects fat metabolism in overweight individuals because of its role in insulinsecretion. It is possible, under similar circumstances, that partially and isocalorically substituting protein or fat for glucose might have produced similar,if not better, results. Pyruvate has been reported to increase the time required to reach exhaustion and to decrease perceived exertion. In the published studies, pyruvate was again given in relatively high amounts in conjunction with dihydroxyacetone. In both studies, untrained men received either 100 g of DHAP or 100 g of a glucose polymer derived from the hydrolysis of cornstarch as a placebo for 7 days. Arm endurance was 133 f 20 minutes after placebo and 160 k 22 minutes after DHAP.162Leg endurance was 66 k 4 minutes after placebo and 79 k 2 minutes after DHAP.la Muscle glycogen levels, at rest and exhaustion, determined through biopsy, did not differ in the placebo and DHAP subjects.la Plasma levels of free fatty acids, glycerol, and beta-hydroxybutyrate were similar during rest and exercise for placebo and DHAP subjects in both s t u d i e ~ . ' ~ Supplementation ~J~~ of a DHAP mixture has also been reported to reduce the perceived level of exertion.Ia Feeding DHAP for 7 days appears to increase submaximal endurance in untrained athletes; however, whether similar results would be obtained with trained athletes is unresolved. In the published studies 25 g/day of pyruvate were given along with 75 g/day of dihydroxy-acetone; however, in the lay press, Stanko has been quoted as saying: "We see a linear response between 2 and 5 g a day and then the response plateaus. In other words, the response with 10 or 15 g or more is the same as with 5 g."Supporting documentation for this assertion has apparently not been published in scientific literature to date, nor has any research been published on the endurance effects of the supplementation of pyruvate without dihydroxyacetone.

Dosage Dosage recommendations for pyruvate are 2 to 5 g/day, taken with food. Better results might be obtained by dividing the 5 g into two or three doses.

Because the reported results on endurance were obtained in trials comparing DHAP with a glucose polymer, the only justifiable conclusion is that subjects consuming 100 g of DHAP rather than 100 g of hydrolyzed cornstarch, a substance with no nutritional value, experienced better endurance. Research evaluating the performance effects of adding 2 to 5 g of pyruvate to the diet of trained athletes is yet to be published. The available evidence suggesting that pyruvate acts as an ergogenic aid in high dosages in combination with dihydroxyacetone is questionable. No evidence exists in support of claims of ergogenic action for pyruvate supplementation at the recommended dose of 2 to 5 g.

Performance Drinks Performance drinks are commonly consumed as ergogenic aids during endurance sports activities. These drinks are designed to maintain normal hydration, electrolyte balance, and blood glucose levels during exercise. Current evidence indicates that ingestion of performance drinks during exercise enhances athletic performance and normalizes markers of thermoregulation. A variety of beverages formulated to provide fluid, carbohydrates, and electrolytes during and after exercise are commercially available. These beverages commonly contain 4% to 8% carbohydrate (as glucose, fructose, sucrose, or maltodextrins) and small amounts of electrolytes (most often sodium, potassium, and chloride). Contrary to popular belief, rates of sweating and urine flow are not influenced by fluid ingestion during exercise.'& Studies have shown that 5% to 10% solutions of glucose, glucose polymers (maltodextrins), and other simple sugars all have suitable gastric-emptying characteristics for the delivery of fluid and moderate amounts of carbohydrate substrate. The optimal concentration of electrolytes, particularly sodium, remains unknown. Most currently available sports drinks provide a low level of sodium (10-25 mmol/L) in recognition of the fact that sodium intake can promote intestinal absorption of fluid as well as assist in rehydration.'& Exercise and dehydration lead to increases in core temperature,body fluid osmolality, and heart rate; losses of plasma and other body fluid volumes; and depletion of glycogen. All of these homeostatic disturbances can be ameliorated by fluid consumption during exercise.167 During exercise, water and electrolytes are lost from the body in sweat. Sweat rate is determined primarily by the metabolic rate and the environmental temperature and humidity. Under some conditions, the sweat rate can exceed the maximum rate of gastric emptying of ingested fluids. If this OCCUTS, some degree of dehydration is observed. Excessive replacement of sweat losses with plain water or fluids with low sodium content after prolonged exercise has resulted in hyponatremia, so

sodium replacement is considered essential for postexercise rehydration.]@ For moderate-intensity exercise, water ingestion 30 to 60 minutes before exercise seems to minimize homeostatic disturbances;however, at higher intensitiesof athletic performance, it probably has little effect.167During exercise, ingestion of both water and carbohydratebeverages has been shown to minimize homeostatic disturbances. Subjects allowed to drink a carbohydrate-electrolyte beverage (4.85% polycose, 2.65% fructose) or distilled water ad libitum during 3 hours of continuous exercise in the heat (31.5" C) showed no significant differences between drinks for rectal temperature, heart rate, or sweat rate during exercise.169No differences in thermoregulatory responses in individuals consuming either carbohydrate beverages or water have been observed.170 The efficacy of a given drink is limited by the rate of absorption of fluid from the intestines, which is in turn limited by gastric emptying. Several factors influence gastric emptying, including exercise intensity and the carbohydrate composition of the solution.171The gastricemptymg rate might also be influenced by the caloric content, volume, osmolality, temperature, and pH of the ingested fluid; the metabolic state and biochemical individuality of the athlete; and the ambient temperature.ln The caloric content of the ingested fluid might be the most important variable governing gastric-emptying rate. At rest and during running, water has a faster gastric-emptying time than all other drinks. Gastric emptying is progressively slowed as the caloric content of the fluid rises.171During moderate exercise, gastric emptying occurs at a rate similar to that during rest; however, more intense exercise appears to inhibit gastric emptying. Evidence indicates that beverages containing less than 10% carbohydratehave gastric-emptying rates closest to that of water.ln Drinks containing less than or equal to 8% to 10% carbohydrate are absorbed into the body at similar rates and should behave similarly in replenishing body fluids lost in sweat during exercise.174 Several other factors have been shown to affect gastric emptying. Isotonic drinks appear to empty quickly throughout exercise, whereas the gastric-emptying rate of hypertonic drinks has been shown to decrease over time.175Fat is believed to delay gastric emptying; however, medium-chain triglycerides (MCTs) might not inhibit gastric emptying as most fat does. Research indicates that MCT-containing drinks have faster gastric-emptying times than drinks containing 100% maltode~trins."~ It has been suggested that maltose might be a superior source of carbohydratefor endurance athletes. Some researchers have suggested that ingestion of an 8% solution of maltodextrin or sucrose every 15 minutes during exercise might provide optimal fluid and carbohydrate rep1acement.l" The rates of gastric emptying and the

peak rates of exogenous carbohydrate oxidation are not sigruficantly different between maltose and glucose.'78 Although ingestion of 13 g carbohydrate per hour did not improve performance during prolonged moderateintensity cycling in one stUdy,ln most studies report that ingestion of carbohydrate beverages has a beneficial effect on performance. Carbohydrate ingested during exercise appears to be readily available as a fuel for the working muscles, at least when the exercise intensity does not exceed 70% to 75% of maximum oxygen uptake.ls0 Rating of perceived exertion is reported to be higher in athletes consuming water than in athletes consuming carbohydrate drinks.'81 For exercise leading to exhaustion in less than 30 minutes, carbohydrate ingestion is not effective in minimizing homeostatic perturbations or improving exercise perf~rmance'~~; however, for exercise of longer duration, ingestion of performance beverages appears to enhance performance. Research has shown that 275 ml of a 6%carbohydrate-electrolyte beverage consumed every 20 minutes maintained blood glucose levels and enhanced performance better than water during endurance cycling.182One study compared the effects of orange flavored drinks containing 0, 6.4%, and 10% carbohydrate. The solutions, given at 3 ml per kg body weight, were given in a double-blind and counter-balanced protocol at time 0 and every 20 minutes during exercise. Blood glucose and lactate levels and temperature were similar for all solutions; however, performance improved with consumption of a carbohydrate drink during exercise. The best results were obtained with ingestion of a 10% carbohydrate drink.'= In another study, eight well-trained men cycled for up to 255 minutes at a power output corresponding to V q at lactate threshold (approximately 68%Vo,,) on three occasions separated by at least 1 week. Subjects drank 5 ml per kg body weight of either a water placebo or a liquid beverage containing a moderate (6%) or high (12%) concentration of carbohydrate, beginning at minute 14 of exercise and every 30 minutes thereafter. Exercise time to fatigue was shorter in subjects receiving placebo (190 minutes) than in those receiving the 6% carbohydrate (235 minutes) and 12% carbohydrate (234 minutes) beverages.lM In a further study, 12 subjects were exercised to exhaustion on a cycle ergometer at a workload corresponding to 70%of maximum oxygen uptake. In one trial, no drinks were given, and in the other trials subjects drank 100 ml every 10 minutes. Median exercise time was greatest (110.3 minutes) for individuals receiving a hypotonic glucose-electrolyte solution (90 mmol/L glucose; 60 mmol/L Na'; 240 mosm/kg), compared with individuals receiving an isotonic glucose-electrolyte solution (200 mmol/L glucose; 35 mmol/L Na'; 310 mosm/kg) (107.3 min), water (93.1 min), and no drink (80.7 min).

Sigruficant treatment effects on heart rate, rectal temperature, and serum osmolality were also observed.185 Twelve highly trained male runners ran 15 km at selfselected pace on a treadmill in warm conditions to demonstrate differences in physiological responses, fluid preferences, and performance when ingesting sports drinks or plain water before and during exercise. One hour before the start of running, an equal volume (1000 ml) of either water or a 6% or 8% carbohydrateelectrolyte drink was ingested. Blood glucose concentration was significantly higher 30 minutes after ingestion of the 6% and 8% carbohydrate-electrolyte beverages than after water, significantly lower at 60 minutes after ingestion in subjects receiving both sports drinks than in those receiving water, but similar after 7.5 km of the run in subjects receiving all beverages. During the first 13.4 km, oxygen uptake and run times were not different between trials; however, the final 1.6-km performance run was faster with both carbohydrate-electrolytedrinks than with water.'% Research indicates that a sugar drink immediately before exercise can impair performance. Carbohydrates invoke an insulin response that increases the likelihood of hypoglycemia during exercise. A drop in blood glucose concentration results from the ingestion of glucose solutions ingested 15 to 45 minutes before prolonged exercise; however, the consumption of 18%to 50% solutions of glucose or glucose polymers 5 minutes before prolonged exercise has potential for improving endurance perf0rman~e.l~~ Many experts recommend consuming a beverage high in carbohydrates within 1 hour after exercise. Exerciseinduced depletion of muscle glycogen levels can be rapidly restored by glucose ingestion. Provided that adequate carbohydrate is consumed, the frequency of intake, the form (liquid vs. solid) and the presence of other macronutrients do not appear to affect the rate of glycogen ~ t 0 r a g e . lDuring ~~ the postexercise recovery period, ingesting a carbohydrate-electrolyte beverage is effective in minimizing physiologic disturbances. Subjects drink more; plasma volume rises to a higher level; plasma osmolality, glucose, and potassium values are greater; and body weight increases more with the ingestion of carbohydrate beverages than with pure water.lm

Dosage The optimum frequency, volume, and composition of recommended performance drinks vary widely according to the intensity and duration of the exercise, the environmental conditions, and the physiology of the individual. However, in general, isotonic beverages with glucose, glucose polymers, or maltodextrins as the carbohydrate source produce the best results. Before exercise, only water should be consumed. Drinking carbohydrate solutions 15 to 60 minutes before exercise

should be avoided because doing so can impair performance; however, their ingestion immediately prior to the start of exercise might be beneficial. This is because once endurance exercise is started, the insulin level is generally not increased, so the carbohydrates will likely be available as energy substrates. The staggered ingestion of performance drinks is beneficial when exercise duration exceeds 30 minutes; however, during shorter exercise and especially for weight-lifting, there appears to be no additional benefit in ingesting anything other than water.

Summary On the basis of available information, evidence remains mixed but promising on supplementation of the diet with I? ginseng and E. senticosus. The role of L-carnitine as an ergogenic aid remains something of a mystery; the mixed results reported in the literature and the high cost

of the supplement make it difficult to justify long-term administration of 2 g/day. No evidence to date supports supplementation with choline as an ergogenic aid. CoQl,,'s failure in several studies to demonstrate any performance-enhancing effect should end any debate or recommendations about the routine administration of this nutrient as an ergogenic aid. Although PAK supplementation has been shown to enhance certain parameters associated with aerobic exercise, it has not yet demonstrably improved performance. Evidence suggests that pyruvate acts as an ergogenic aid in high dosages in combination with dihydroxyacetone, but available evidence does not support claims of an ergogenic action for pyruvate supplementation at a dose between 2 and 5 g. The staggered ingestion of isotonic, 6% to 10% carbohydrate performance drinks should be a routine practice in endurance exercise activities of more than 30 minutes' duration.

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Stress Management Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 701 The General Adaptation Syndrome 701 Stress: A Healthy View

702

Diagnostic Considerations 702 Interpretation 702

Lifestyle Factors 704 Exercise 705 Dietary Guidelines 705 Nutritionaland Botanical Support 706 Nutritional Supplements 706 Botanical Medicines 707 Stress Management Programs 708

Therapeutic Approach 702 Calming the Mind and Body 703

INTRODUCTION Stress is defined as any disturbance-eg, heat or cold, chemical toxin, microorganisms, physical trauma, strong emotional reaction-that can trigger the ”stressresponse.” How an individual handles stress plays a major role in determining their level of health. Comprehensive stress management involves a truly holistic approach designed to counteract the everyday stresses of life. Most often the stress response is so mild it goes entirely unnoticed. However, if stress is extreme, unusual, or long-lasting, the stress response can be overwhelming and quite harmful to virtually any body system. Before one can discuss methods for helping patients deal effectively with stress, it is important to understand the stress response. Ultimately, the success of any stress management program depends on its ability to improve an individual‘s immediate and long-term responses to stress.

THE GENERAL ADAPTATION SYNDROME The stress response is actually part of a larger response known as the general adaptation syndrome, a term coined by the pioneering stress researcher Hans Selye. To fully understand how to combat stress, one must understand the general adaptation syndrome. The syndrome is composed of three phases: alarm, resistance, and exhaustion.] These phases are largely controlled and regulated by the adrenal glands. The initial response to stress is the alarm reaction, which is often referred to as the fight-or-fight response.

The fight-or-flight response is triggered by reactions in the brain that ultimately cause the pituitary gland to release adrenocorticotropic hormone (ACTH), which causes the adrenals to secrete adrenaline and other stress-related hormones. The fight-or-flight response is designed to counteract danger by mobilizing the body’s resources for immediate physical activity. As a result, the heart rate and force of contraction of the heart increase to provide blood to areas necessary for response to the stressful situation. Blood is shunted away from the skin and internal organs, except the heart and lung, while the amount of blood supplying required oxygen and glucose to the muscles and brain is increased. The rate of breathing rises to supply necessary oxygen to the heart, brain, and exercising muscle. Sweat production increases to eliminate toxic compounds produced by the body and to lower body temperature. Production of digestive secretions is severely reduced because digestive activity is not critical for counteracting stress. Blood sugar levels rise dramatically as the liver converts stored glycogen into glucose for release into the blood stream. Although the alarm phase is usually short-lived, the next phase-the resistance reaction-allows the body to continue fighting a stressor long after the effects of the fight-or-flight response have worn off. Other hormones, such as cortisol and other corticosteroids secreted by the adrenal cortex, are largely responsible for the resistance reaction. For example, these hormones stimulate the conversion of protein to energy, so that the body has a 701

Syndromes and Special Topics large supply of energy long after glucose stores are depleted, and promote the retention of sodium to keep blood pressure elevated. As well as providing the necessary energy and circulatory changes required to deal effectively with stress, the resistance reaction provides the changes required to meet emotional crisis, perform strenuous tasks, and fight infection. The effects of adrenal cortex hormones are quite necessary when the body is faced with danger, but prolongation of the resistance reaction or continued stress inmases the risk of si@cant disease (including diabetes, high blood pressure, and cancer) and results in the final stage of the general adaptation syndrome, exhaustion. Exhaustion may manifest as a partial or total collapse of a body function or specific organ. Two of the major causes of exhaustion are loss of potassium ions and depletion of adrenal glucocorticoid hormones like cortisone. Loss of potassium results in cellular dysfunction and, if severe, cell death. Adrenal glucocorticoid store depletion diminishes glucose control, leading to hypoglycemia. Another cause of exhaustion is weakening of the organs. Prolonged stress places a tremendous load on many organ systems, especially the heart, blood vessels, adrenals, and immune system, and is associated with many common diseases, as listed in Box 62-1.

STRESS: A HEALTHY VIEW The father of modem stress research was Hans %lye. Having spent many years studying this subject, Selye developed valuable insights into the role of stress in disease. According Selye, stress in itself should not be viewed in a negative context. It is not the stressor that determines the response; instead it is the individual’s internal reaction, which then triggers the response. This internal reaction is highly individualized. What one

Angina Asthma Autoimmune disease Cancer Cardiovascular disease Common cold Depression Diabetes (adult onset-type 2) Headaches Hypertension Immune suppression Irritable bowel syndrome Menstrual irregularities Premenstrual tension syndrome Rheumatoid arthritis Ulcerative colitis Ulcers Modifiedfrom Benson H. The relaxation response. New York: William Morrow, 1975.

person may experience as stress, the next person may view entirely differently. %lye perhaps summarized his view best in the following passage from his book The Stress of Life2: No one can live without experiencing some degree of stress all the time. You may think that only serious disease or intensive physical or mental injury can cause stress. This is false. Crossing a busy intersection, exposure to a draft, or even sheer joy are enough to activate the body’s stress mechanisms to some extent. Stress is not even necessarily bad for you; it is also the spice of life, for any emotion, any activity causes stress. But, of course, your system must be prepared to take it. The same stress which makes one person sick can be an invigorating experience for another.

The key statement %lye made may be ”your system must be prepared to take it.” A sigruficant body of knowledge has now accumulated delineating methodologies for helping patients develop healthful, rather than disease-facilitating, responses to both short-term and long-term stress.

DIAGNOSTIC CONSIDERATIONS Many people who are ”stressed out” may not be able to identify exactly what is causing them to feel stressed. Typical presenting symptoms are insomnia, depression, fatigue, headache, upset stomach, digestive disturbances, and irritability. To determine the role that stress may play, the “social readjustment rating scale” developed by Holmes and M e 3may be used (Table 62-1). The scale was originally designed to predict the risk of a serious disease due to stress. Various life-changing events are numerically rated according to their potential to cause disease. Notice that even events commonly viewed as positive, such as an outstanding personal achievement, carry stress. If a person is under a great deal of immediate stress or has endured a fair amount of stress for a few months or longer, it is appropriate to assess adrenal dysfunction more accurately with laboratory methods.

Interpretation The standard interpretation of the social readjustment rating scale is that a total of 200 or more units in 1year are considered to be predictive of a high likelihood of experiencing a serious disease. However, rather than using the scale solely to predict the likelihood of serious disease, the clinician can use the scale to evaluate a patient‘s level of stressor exposure, because everyone reacts differently to stressful events.

THERAPEUTIC APPROACH Whether currently aware of it or not, the patient has developed a pattern for coping with stress. Unfortunately, most people have found patterns and

Stress Management

The Social Readjustment Rating Scale Rank

1 2 3 4 5 6 7

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37

Life event Death of spouse Divorce Marital separation Jail term Death of a close family member Personal injury or illness Marriage Fired at work Marital reconciliation Retirement Change in health of family member Pregnancy Sex difficulties Gain of a new family member Business adjustment Change in financial state Death of a close friend Change to different line of work Change in number of arguments with spouse Large mortgage Foreclosure of mortgage or loan Change in responsibilitiesat work Son or daughter leaving home Trouble with in-laws Outstanding personal achievement Spouse begins or stops work Beginning or end of school Change in living conditions Revision of personal habits Trouble with boss Change in work hours or conditions Change in residence Change in schools Change in recreation Change in church activities Change in social activities Small mortgage

38

Change in sleeping habits

39 40 41 42 43

Change in number of family get-togethers Change in eating habits Vacation Christmas Minor violations of the law

From HolmesTH, Rahe RH. J Psychosom Res 1967;11:213-218.

Mean value

100 73 65 63 63 53 50 47 45 45 44 40 39 39 39 38 37 36 35 31 30 29 29 29 28 26 26 25 24 23 20 20 20 19 19 18 17 16 15 15 13 12 11

methods that ultimately do not support good health. Negative coping patterns must be identified and replaced with positive ways of coping. The clinician should try to identdy any negative or destructive coping patterns listed in Box 62-2 that the patient may have developed and to replace that pattern with more positive measures for dealing with stress. Stress management can be substantially improved by assisting the patient in the following six equally important areas: Techniques to calm the mind and promote a positive mental attitude Lifestyle factors Exercise A healthful diet designed to nourish the body and support physiologic processes Dietary and botanical supplements designed to support the body as a whole, but especially the adrenal glands Supervised stress management program

Calming the Mind and Body Learning to calm the mind and body is extremely important in relieving stress. Among the easiest methods for the patient to learn are relaxation exercises. The goal of relaxation techniques is to produce a physiologic response known as a relaxation response-a response that is exactly opposite to the stress response. Although an individual may relax by simply sleeping, watching television, or reading a book, relaxation techniques are designed specifically to produce the relaxation response. Relaxation response was a term coined by Harvard professor and cardiologist Herbert Benson in the early 1970s to describe a physiologic response that is just the opposite of the stress response.' With the stress response (Box 62-3), the sympathetic nervous system dominates. With the relaxation response (Box 62-4), the parasympathetic nervous system dominates. The parasympathetic nervous system controls bodily functions such as digestion, breathing, and heart rate during periods of rest, relaxation, visualization, meditation, and sleep. Although the sympathetic nervous system is designed to protect against immediate danger, the parasympathetic

Dependence on chemicals: legal and illicit drugs, alcohol, smoking Overeating Too much television Emotional outbursts Feelings of helplessness Overspending Excessive behavior

Syndromes and Special Topics

The heart rate and force of contraction of the heart increase to provide Mood to areas necessary for response to the stressful situation. Blood is shunted away from the skin and internal organs, except the heart and lung, while at the amount of blood supplying required oxygen and glucose to the muscles and brain is increased. The rate of breathing rises to supply necessary oxygen to the heart, brain, and exercising muscle. Sweat production increases to eliminate toxic compounds produced by the body and to lower body temperature. Production of digestive secretions is severely reduced because digestive activity is not critical to counteracting stress. Blood sugar levels are raised dramatically as the liver dumps stored glucose into the blood stream.

*The heart rate is reduced and the heart beats more effectively. Blood pressure is reduced. Blood is shunted towards internal organs, especially those organs involved in digestion. The rate of breathing decreases as oxygen demand is reduced during periods of rest. Sweat production diminishes, because a person who is calm and relaxed does not experience nervous perspiration. Production of digestive secretions is increased, greatly improving digestion. Blood sugar levels are maintained in the normal physiologic range.

system is designed for repair, maintenance, and restoration of the body. The relaxation response can be achieved through a variety of techniques. The methodology should be determined by patient interest, because all techniques have the same physiologic effect-a state of deep relaxation. The most popular techniques are meditation, prayer, progressive relaxation, self-hypnosis, and biofeedback. To produce the desired long-term health benefits, the patient should use the relaxation technique for at least 5 to 10 minutes each day.

Breathing Producing deep relaxation with any technique requires learning how to breathe. One of the most powerful methods of producing less stress and more energy in the body is by breathing with the diaphragm. Diaphragm breathing activates the relaxation centers in the brain. Box 62-5 lists a 10-step technique for teaching diaphragmatic breathing.

Progressive Relaxation One of the most popular techniques for producing the relaxation response is progressive relaxation. The technique is based on a very simple procedure of comparing

1. Find a comfortable and quiet place to lie down or sit.

2.Place your feet slightly apart. Place one hand on your abdomen near your navel. Place the other hand on your chest. 3.You will be inhaling through your nose and exhaling through your mouth. 4. Concentrate on your breathing. Note which hand is rising and falling with each breath. 5.Gently exhale most of the air in your lungs. 6. Inhale while slowly counting to 4. As you inhale, slightly extend your abdomen, causing it to rise about 1 inch. Make sure that you are not moving your chest or shoulders. 7. As you breathe in, imagine the warmed air flowing in. Imagine this warmth flowing to all parts of your body. 8. Pause for 1 second, then slowly exhale to a count of 4. As you exhale, your abdomen should move inward. 9. As the air flows out, imagine all your tension and stress leaving your body. 10. Repeat the process until a sense of deep relaxation is achieved.

tension with relaxation. Many people are not aware of the sensation of relaxation. In progressive relaxation, an individual is taught what it feels like to relax by comparing relaxation with muscle tension. The basic technique is to have the patient contract a muscle forcefully for a period of 1to 2 seconds and then give way to a feeling of relaxation in that muscle. The procedure systematically goes through all the muscles of the body, progressively producing a deep state of relaxation. The procedure begins with contracting the muscles of the face and neck, then the upper arms and chest, followed by the lower arms and hands. The process is repeated progressively down the body, from the abdomen through the buttocks, the thighs, and calves to the feet. This whole process is repeated two or three times. This technique is often used in the treatment of anxiety and insomnia. Progressive relaxation, deep breathing exercises, or some other stress reduction technique is an important component of a comprehensive stress management program.

Lifestyle Factors A patient’s lifestyle is a major determinant of his or her

stress levels. The two primary areas of concern (other than addressing negative coping patterns) are time management and relationship issues. One of the biggest stressors for most people is time. They simply do not feel they have enough of it. Box 62-6 provides tips on time management for patients. Another major cause of stress for many people is interpersonal relationships. Interpersonal relationships can be divided into three major categories: marital, family, and job-related. The quality of any relationship

Stress Management

Set priorities. Realize that you can only accomplish so much in a day. Decide what is important, and limit your efforts to that goal. Organize your day. There are always interruptions and unplanned demands on your time, but create a definite plan for the day on the basis of your priorities. Avoid the pitfall of always letting the “immediate demands” control your life. Delegate authority. Delegate as much authority and work as you can. You can’t do everything yourself. Learn to train and depend on others. Tackle tough jobs first. Handle the most important tasks first, while your energy levels are high. Leave the busy work or running around for later in the day. Minimize meeting time. Schedule meetings to bump up against the lunch hour or quitting time; that way they can’t last forever. Avoid puffing things off. Work done under pressure of an unreasonable deadline often has to be redone. That creates more stress than if it had been done right the first time. Plan ahead. Don’t be a perfectionist. You can never really achieve perfection anyway. Do your best in a reasonable amount of time, then move on to other important tasks. If you find time, you can always come back later and polish the task some more.

ultimately comes down to the quality of the communication. Learning to communicateeffectivelygoes a very long way in reducing the stress and occasional (or frequent) conflicts of interpersonal relationships. Box 62-7 lists seven tips for effective communication, regardless of the type of interpersonal relationship.

Exercise The immediate effect of exercise is stress on the body. However, with a regular exercise program the body adapts, and exercise becomes an effective stress reduction technique. With regular exercise, the body becomes stronger, functions more efficiently, and has greater endurance. Exercise is a vital component of a comprehensive stress management program and overall good health. People who exercise regularly are much less likely to suffer from fatigue and depression. Tension, depression, feelings of inadequacy, and worries diminish greatly with regular exercise. Exercise alone has been demonstrated to have a tremendous effect in terms of improving mood and the ability to handle stressful life situations. This effect is seen in adolescents as well as adults. In one study, 2223 boys and 2838 girls (mean age, 16.3 years) from 10 teams and 25 different individual sports were studied for the relationship between emotional well-being and psychological well-being. The sport and vigorous recreational activity index was positively associated with emotional well-being independent of other variables?

Dietary Guidelines An individual suffering from stress or anxiety must support the biochemistry of the body by following

The first key to successful communication is the most important: Learn to be a good listener. Allow the person you are communicating with to really share his or her feelings and thoughts uninterrupted. Empathize with the person, put yourself in his or her shoes. If you first seek to understand, you will find yourself being better understood. Be an active listener. This means that you must be truly interested in what the other person is communicating. Listen to what he or she is saying instead of thinking about your response. Ask questions to gain more information or clarify what he or she is telling you. Good questions open lines of communication. Be a reflective listener. Restate or reflect back to the other person your interpretationof what he or she is telling you. This simple technique shows the other person that you are both listening to and understanding what he or she is saying. Restating what you think is being said may cause some short-term conflict in some situations, but it is certainly worth the risk. Wait to speak until the person you want to communicate with is listening. If the person is not ready to listen, your message will not be heard no matter how well you communicate. Don’t try to talk over somebody. If you find yourself being interrupted, relax; don’t try to out-talk the other person. If you are courteous and allow him or her to speak, eventually (unless extremely rude) he or she will respond likewise. If that doesn’t happen, point out that the other person is interrupting the communication process.You can do this only if you have been a good listener. Double standards in relationships seldom work. Help the other person become an active listener. This can be done by asking whether he or she has understood what you were communicating. Ask him or her to tell you what he or she heard. If the other person doesn’t seem to be understanding what you are saying, keep trying until he or she does. Don’t be afraid of long silences. Human communication involves much more than human words. A great deal can be communicated during silences; unfortunately in many situations silence can make us feel uncomfortable. Relax. Some people need silence to collect their thoughts and feel safe in communicating.The important thing to remember during silences is that you must remain an active listener.

some important dietary guidelines. Specifically, he or she must: Eliminate or restrict the intake of caffeine. Eliminate or restrict the intake of alcohol. Eliminate refined carbohydrates from the diet. Eat a diverse range of whole foods. Increase the potassium-to-sodium ratio. Eat regular planned meals in a relaxed environment. Control food allergies. According to %lye? whether or not stress is harmful is based on the strength of the system. From a purely physiologic perspective, it can be strongly argued that delivery of high-quality nutrition to the cells of the body is the critical factor in determining the strength of the system.

When the eating habits of Americans are examined as a whole, it is little wonder that so many people are suffering from stress, anxiety, and fatigue. Most Americans are not providing their bodies with the high-quality nutrition they need. Instead of eating foods rich in vital nutrients, most Americans focus on refined foods high in calories, sugar, fat, and cholesterol.

in sodium. Most Americans have a dietary potassiumto-sodium (KNa) ratio of less than 1:2.In contrast, most researchers recommend a dietary KNa ratio higher than 51 for health. However, even this recommendation may not be optimal. A natural diet rich in fruitsand vegetables can produce a K.Na ratio higher than 50:1, as most fruits and vegetables have a KNa ratio of more than 100:l.

Caffeine

Meal Planning

The average American consumes 150 to 225 mg of caffeine daily, or roughly the amount of caffeine in two cups of coffee. Although most people can handle this amount, some people are more sensitive to the effects of caffeine than other people, owing to decreased activity of phase I detoxification (see Chapter 54). Even small amounts of caffeine can affect sensitive people, whereas those with normal sensitivity respond to large amounts. Excessive caffeine consumption can produce “caffeinism characterized by symptoms of depression, nervousness, irritability, recurrent headache, heart palpitations, and insomnia.” People prone to feeling stress and anxiety tend to be especially sensitive to caffeine?”

Mealtimes should be spent in a relaxed environment. As noted previously, digestion is a process largely controlled by the parasympathetic nervous system. Eating in a rushed manner or in a noisy or hurried environment is not conducive to good digestion or good health.

Alcohol Alcohol produces chemical stress on the body. It also increases adrenal hormone output and interferes with both normal brain chemistry and normal sleep cycles. Although many people believe that alcohol has a calming effect, a study of 90 healthy male volunteers given either a placebo or alcohol demonstrated sigruficant increases in anxiety scores after consumption of alcohol?

Refined Carbohydrates Refined carbohydrates (e.g., sugar and white flour) are known to contribute to problems in blood sugar control, especially hypoglycemia. The associationbetween hypoglycemia and impaired mental function is well known. Unfortunately, most patients experiencing depression, anxiety, or other psychological condition are rarely tested for hypoglycemia, nor are they prescribed a diet that restricts refined carbohydrates. Numerous studies have shown a high percentage of hypoglycemia in depressed patients73 As depression is one of the most common causes of anxiety, this finding provides a link between hypoglycemia and feelings of stress. Simply eliminating refined carbohydrate from the diet is occasionally all that is needed for effective therapy in patients who have depression or anxiety due to hypoglycemia.

Potassium-to-Sodium Ratio One of the key dietary recommendations to support the adrenal glands is to ensure adequate potassium levels within the body. This can best be done by consuming foods rich in potassium and avoiding foods high

Food Allergies People with symptoms of anxiety or chronic fatigue must be concerned about food allergies. As far back as 1930, pioneering allergist Albert Rowe began noticing that anxiety and fatigue were key features of food allerg i e ~Originally, .~ Rowe described a syndrome known as “allergic toxemia” to describe a syndrome that included the symptoms anxiety, fatigue, muscle and joint aches, drowsiness, difficulty of concentration, and depression. Around the 1950s, thissyndrome began to be referred to as the “allergictension-fatigue syndrome.”With the popularity of chronic fatigue syndrome, many physicians and other people are forgetting that food allergies can lead to anxiety as well as chronic fatigue.

NUTRITIONAL AND BOTANICAL SUPPORT Nutritional and botanical support for the individual experiencing signs and symptoms of stress largely involves supporting the adrenal glands. Long-term stress and corticosteroids cause the adrenal glands to shrink and become dysfunctional, aggravating the stress symptoms anxiety, depression, and chronic fatigue. An abnormal adrenal response, either deficient or excessive hormone release, sigruficantly alters an individual‘s response to stress. Often the adrenals become ”exhausted” as a result of constant demands put on them. An individual with adrenal exhaustion usually suffers from chronic fatigue and may complain of feeling “stressed out” or chronically anxious. He or she typically has a reduced resistance to allergies and infection.

Nutritional Supplements The nutrients especially important for supporting adrenal function are vitamin C, vitamin B6, zinc, magnesium, and pantothenic acid. All of these nutrients play a critical role in the health of the adrenal gland as well as the manufacture of adrenal hormones. During stress, the levels of these nutrients in the adrenals decrease substantially. For example, during chemical, emotional, psychological, or physiologic stress, the urinary excretion of

Stress Management

vitamin C is increased. Examples of chemical stressors are cigarette smoke, pollutants, and allergens. Extra vitamin C in the form of supplementation and a higher intake of vitamin C-rich foods is often recommended to keep the immune system working properly during times of stress. Equally important during high periods of stress or in individuals needing adrenal support is pantothenic acid (vitamin B). Pantothenic acid deficiency results in adrenal atrophy, characterized by fatigue, headache, sleep disturbances, nausea, and abdominal discomfort. Pantothenic acid is found in whole grains, legumes, cauliflower, broccoli, salmon, liver, sweet potatoes, and tomatoes. In patients who suffer from chronic stress or have a history of corticosteroid (prednisone) use, the typical level of supplementation is 100 to 500 mg daily. The appropriate daily doses of vitamin B6 is 50 to 100 mg; of zinc, 20 to 30 mg; and of magnesium, 250 to 500 mg.

Botanical Medicines Several botanical medicines support adrenal function. Most notable are the ginsengs. Both Chinese ginseng (Punax ginseng) and Siberian ginseng (EZeutherococcus senticosus) exert beneficial effects on adrenal function and enhance resistance to stress. These ginsengs are often referred to as ”general tonics” or ”adaptogens.” The term general tonic implies that an herb will increase the overall tone of the whole body. The ginsengs are also often referred to as “adrenal tonics” because they improve the tone and function of the adrenal glands. Chinese and Siberian ginseng can be used to achieve the following goals: Restore vitality in debilitated and feeble individuals Increase feelings of energy Improve mental and physical performance Prevent the negative effects of stress and enhance the body’s response to stress Offset some of the negative effects of cortisone Enhance liver function Protect against radiation damage All of these applications are supported by good clinical

The modem term aduptogen is a more descriptive word used to describe the general tonic effects of Siberian and Chinese ginseng. An adaptogen is a substance with the following characteristics: Must be innocuous and must cause minimal disorders in the physiologic functions of an organism Must have a nonspecific action (i.e., it should improve resistance to adverse influences through a wide range of physical, chemical, and biochemical factors) Usually has a normalizing action irrespective of the direction of the pathologic state

According to tradition and scientific evidence, both Siberian and Chinese ginsengs possess this kind of equilibrating, tonic, antistress action, and so the term adaptogen is quite appropriate in describing their general effects. The ginsengs have been shown to enhance the ability to cope with various stressors, both physical and mental.1012Presumably this antistress action is mediated by mechanisms that control the adrenal glands. Ginseng delays the onset and reduces the severity of the alarm phase response of the general adaptation syndrome. People taking either of the ginsengs typically report an increased sense of well-being. Clinical studies have confirmed that both Siberian and Chinese ginsengs sigthcantly reduce feelings of stress and anxiety. For example, in one double-blind clinical study, nurses who had switched from day to night duty rated themselves for competence, mood, and general well-being, and were given a test for mental and physical performance along with blood cell counts and blood chemistry eva1uati0n.l~ The group who were given P. ginseng demonstrated higher scores in competence, mood parameters, and mental and physical performance compared with those receiving placebos. The nurses taking the ginseng felt more alert, yet more tranquil, and were able to perform better than the nurses who were not taking the ginseng. In addition to these human studies, several animal studies have shown the ginsengs to exert significant antianxiety effects. In several of these studies, the stressrelieving effects were comparable to those of diazepam (Valium); however, diazepam causes behavior changes, sedative effects, and impaired motor activity, but ginseng has none of these negative effe~ts.’~ On the basis of the clinical and animal studies, ginseng appears to offer sigrufrcant benefit to people suffering from stress and anxiety. P. ginseng is generally regarded as being more potent than E. senticosus. P. ginseng is probably better for the patient who has experienced a great deal of stress, is recovering from a longstanding illness, or has taken corticosteroids such as prednisone for a long time. For the patient who is under mild to moderate stress and is experiencing less obvious impairment of adrenal function, E. senticosus may be the better choice. Another useful botanical medicine to support stress management is Rhodiolu roseu (artic root), a popular plant in traditional medical systems in Eastern Europe and Asia, where it has traditionally been recommended to help combat fatigue and restore energy. Modem research has confirmed these effects and its qualities as an adaptogen. However, the adaptogenic actions of R. roseu are different from those of Chinese and Siberian ginsengs, which act primarily on the hypothalamus-pituitary-adrenal axis. R. roseu seems to exert its adaptogenic effects by working on neurotransmitters and endorphins. R. rosea appears to offer an advantage over other adaptogens in circumstances of acute stress because it produces a greater feeling

Syndromes and Special Topics

of relaxation and antianxiety effects. A single dose of Rhodwla extract prior to acute stressful events has been shown to prevent stress-induced disruptions in function and performance, but like the ginsengs, R. roseu has also shown positive results with long-term use.1518 On the basis of results of clinical trials with a standardized R. rosea extract, the therapeutic dose varies according to the rosavin content. For a dosage target of 3.6 to 7.2 mg of rosavin, the daily dose would be 360 to 600 mg for an extract standardized for 1%rosavin; 180 to 300 mg for 2% rosavin; and 100 to 200 mg for 3.6% rosavin. When R. roseu is used as an adaptogen, longterm administration is normally begun several weeks before a period of expected increased physiologic, chemical, or biologic strain and continued throughout the duration of the challenging event or activity. When R. roseu is used as a single dose for acute stress (e.g., for an examination or athletic competition), the suggested dose is three times the dose used for long-term supplementation. No side effects have been reported in the clinical trials, but at higher dosages, some individuals might experience greater irritability and insomnia.

Stress Management Programs Supervised stress management programs are thought to offer greater compliance and better results than unsupervised, patient-directed programs. In one study, stress management experts evaluated six widely used

1.Benson H. The relaxation response. New York William Morrow, 1975. 2.%lye H. The stress of life. New York: McGraw Hill, 1978. 3.Holmes TH, Rahe RH. The social readjustment rating scale. J Psychosom Res 1967;11:213-218. 4. Steptoe A, Butler N. Sports participation and emotional wellbeing in adolescents. Lancet 1996s71789-1792. 5. Chou T. Wake up and smell the coffee: caffeine, coffee, and the medical consequences. West J Med 1992;157544-553. 6. Monteiro MG, Schuckit MA, Irwin M. Subjective feelings of anxiety in young men after ethanol and diazepam infusions. J Clin Psychiatry 1990;51:12-16. 7. Wmokur A, Maislin G, Phillips JL, et al.Insulin resistance after oral glucose tolerance testing in patients with major depression. Am J Psychiatry 1988;145325-330. 8. Wright JH, Jacisin JJ, Radin NS, et al. Glucose metabolism in unipolar depression. Br J Psychiatry 1978;132:386-393. 9. Rowe AH, Rowe A Jr. Food allergy: its manifestations and control and the elimination diets: a compendium. Springfield, k CC Thomas, 1972. 10.Davydov M, Krikorian AD. Eleutherococcus smticosus (Rupr. & Maxim.) Maxim. (Araliaceae) as an adaptogen: a closer look. J Ethnopharmacol2OOO;72:345-393. 11. Coleman CI, Hebert JH, Reddy P. The effects of Panax ginmg on quality of life. J Clin Pharm Ther 2003;285-15. 12. Ong YC, Yong EL. Panax (ginsenghpanacea or placebo? Molecular and cellular basis of its pharmacological activity. Ann Acad Med Singapore 2O00;29424.

occupational stress management interventions (relaxation, physical fitness, cognitive restructuring, meditation, assertiveness training, and stress inoculation) on the basis of ten practicality criteria and seven effectiveness objectives. They found that relaxation was the most practical intervention, and that meditation and stress inoculation the least practical. Physical fitness was chosen to be the most effective intervention, and both meditation and assertivenesstraining were rated overall as the least effective. What these results imply is that although relaxation training may be the most practical intervention, physical exercise was the most effective intervention.l9 Meditation was shown to be the least practical and least effective method in this evaluation, but when it is part of supervised program it can be very effective. In one trial of 103 adults, 59% and 61% of the meditation and control groups, respectively, completed the studyz0 The intervention program consisted of an 8-week group stress reduction program in which subjects learned, practiced, and applied “mindfulness meditation” to daily life situations. The control group received educational materials and was encouraged to use community resources for stress management. Compared with the control group, intervention subjects reported significant decreases from baseline in effect of daily hassles (24%), psychological distress, (44%), and medical symptoms (46%)that were maintained at the 3-month follow-up.

13.Hallstrom C, Fulder S, Carruthers M. Effect of ginseng on the performance of nurses on night duty. Comp Med East West 1982;6 277-282. 14.Bhattacharya SK, Mitra SK. Anxiolytic activity of Punaw ginsmg roots: an experimental study. J Ethnopharmacol1991;34:87-92. 15. Kelly GS. Niodiola roseu: a possible plant adaptogen. Altern Med Rev 2001;6293-302. 16. Shevtsov VA, Zholus BI, Shervarly VI,et al. A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine 2003;lO 95-105. 17. Darbinyan V, Kteyan A, Panossian A, et al. Rhodiola rosea in stress induced fatigue-a double blind cross-over study of a standardized extract SHR-5with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine 2000;7365371. 18. Spasov AA, Wikman GK, Mandrikov VB, et al. A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine 2000;785-89. 19. Bellarosa C, Chen PY. The effectiveness and practicality of occupational stress management interventions: a survey of subject matter expert opinions. J Occup Health Psycho1 1997;2247-262. 20. Williams KA, Kolar MM, Reger BE, et al.Evaluation of a wellnessbased mindfulness stress reduction intervention: a controlled trial. Am J Health Promot 2001;15422-432.

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Alkylglycerols 713 AIIium cepa (Onion) 725 AIIiirm satiuum (Garlic) 729 Aloe uern (Cape Aloe) 737 Angelica Species 749 Artemisia absinthiuni (Wormwood) 755 Artemisia aiznua (Sweet Wormwood) 761 Bee Products-Pollen, Propolis, and Royal Jelly 767 Beta-carotene and Other Carotenoids 771 Boron 783 Bromelain 791 Camellia sineiisis (Green Tea) 797 Capsicumfriitescens (Cayenne Pepper) 803 Carnitine 809 Catechin [(+)-cyanidanol-31 823 Centella asiaticn (Gotu Kola) 829 Chinese Prepared Medicines 837 Cimic$iga racemosa (Black Cohosh) 847 Citicoline (CDP-Choline) 853 Coenzyme QIa 859 Coleusforskohlii 871 Cominiphora miikiil (Mukul Myrrh Tree) 877 Crataegus oxyacantha (Hawthorn) 881 Croton lechleri (Dragon’s Blood) 887 Curcuma longa (Turmeric) 893 Dehydroepiandrosterone 899 Echinacea Species (Narrow-Leafed Purple Coneflower) 907 Eleutherococcus senticosus (Siberian Ginseng) 919 Ephedra Species 925 Epilobium Species (Fireweed) 931 Fatty Acid Metabolism 935 Fish Oils (Omega-3 Fatty Acids, Docosahexaenoic Acid, Eicosapentaenoic Acid, Dietary Fish, and Fishoils) 945 Flavonoids-Quercetin, Citrus Flavonoids, and Hydroxyethylrutosides 967 Ginkgo biloba (Ginkgo Tree) 975 Glucosamine 987 Glutamine 993 Glycyrrhiza glabra (Licorice) 1003 Hydrastis canadensis (Goldenseal) and Other Berberine-Containing Botanicals 1013 5-Hydroxytryptophan 1021 Hypericum perforatirm (St. John’s Wort) 1037 Lobelia inflata (Indian Tobacco) 1049 Melaleuca alternifolia (Tea Tree) 1053 Melatonin 1057 Melissa oficinalis (Lemon Balm) 1065 Mentha piperita (Peppermint) 1071 Microbial Enzyme Therapy 1075 Naturally Occurring Antioxidants 1085 Opuntia Species (Prickly Pear) 1113 Panax ginseng (Korean Ginseng) 1119 Pancreatic Enzymes 1131 Phage Therapy: Bacteriophages as Natural, Self-LimitingAntibiotics 1147

114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142

Phosphatidylserine 1163 Piper niethysticum (Kava) 1167 Policosanol 1173 Prebiotics 1183 Probiotics 1195 Procyanidolic Oligomers 1217 Pygeum africanlrm (Bitter Almond) 1221 Ruscus acideatus (Butcher’s Broom) 1227 SAMe (S-Adenosylmethionine) 1235 Sarsaparilla Species 1241 Sereiion repens (Saw Palmetto) 1245 Silybum itiariaiizrni (Milk Thistle) 1251 Soy Isoflavones and Other Constituents 1259 Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements 1275 Tnbebrrin nuellnnedae (LaPacho, Pau D’Arco, Ipe Roxo) 1321 Tniiacetirnr parMeniirni (Feverfew) 1331 Tnraxncirm offrcinnle (Dandelion) 1335 Tnxirs brevifolia (Pacific Yew) 1339 Urtica dioico (Stinging Nettle) 1345 Urm iirsi (Bearberry) 1351 Vmciniunr macrocarpon (Cranberry) 1355 Vncciniiinr myrtillirs (Bilberry) 1365 Vnleriann oficinalis (Valerian) 1371 Viscirnr albiriii (European Mistletoe) 1375 Vitamin A 1381 Vitamin Toxicities and Therapeutic Monitoring 1389 Vitex agnirs castus (Chaste Tree) 1395 Water: The Most Basic Nutrient and Therapeutic Agent 1401 Zingibrr oficinnle (Ginger) 1411

Careful review of the scientific literature reveals a considerable amount of research documenting the clinical efficacy, pharmacologic activity, and toxicology of numerous “natural” medicines. An important purpose of this section is the substantiation, from a scientific standpoint, of the historical use of botanical medicines. Although plants have been used a s medicines since antiquity, appreciation of them as effective medicinal agents has greatly diminished recently. New to this edition is incor-poration of the research that has looked at the potential for interaction between conventional and natural interventions. Hopefully, this section will further revive the appreciation for and the safe and effective use of botanical medicines. Although some plant constituents are discussed as separate entities and in many situations may be the most appropriate therapeutic substances, we believe that the whole herb should be used whenever possible. It has been amply demonstrated that, in many instances, physiologic and pharmacologic effects of a particular plant constituent are diminished when it is given as an isolated component rather than in its naturally occurring environment. Furthermore, besides synergistic and enhancing effects, there appear to be factors in many plants that prevent

709

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many of the side effects of isolated plant constituents. In understanding the pharmacology, pharmacognosy, and historical use of plants, the student of natural medicine is once again inspired by the miracle of nature as well as the intuition and empiricism that ancient herbalists possessed. We hope that this section will help better inform our readers of the impressive uses, and potential dangers, of these

natural medicines. We also want to stress that botanical medicine should not be used simply as substitutes for the drugs commonly used to treat disease. The true physician of natural medicine will use them as part of the treatment of the whole person and in the context of removing the causes of the disease and promoting health, not simply treating symptoms.

Abortifacient a substance that induces abortion. Acrid a pungent, biting taste that causes irritation. Adaptogen a substance that is safe, increases resistance to stress, and has a balancing effect on body functions. Adjuvant a substance that enhances the effect of the medicinal agent or increases the antigeniaty of a cancer cell. Alkaloids naturally occurring amines, arising from heterocyclic and often complex structures, that display pharmacologic activity. Their trivial names usually end in - h e . They are usually classified according to the chemical structure of their main nucleus: phenylalkylamines (e.g., ephedrine), pyridine (e.g., nicotine), tropine (eg., atropine, cocaine), quinoline (e.g., quinine), isoquinolone (e.g., papaverine), phenanthrene (e.g., morphine), purine (e.g., caffeine), imidazole (e.g., pilocarpine), and indole ( e g , physostigmine, yohimbine). Alterative a substance that has a balancing effect on a particular body function. Analgesic a substance that reduces the sensation of pain. Androgens hormones that stimulate male characteristics. Anthelminthic a substance that causes the elimination of intestinal worms. Anthocyanidin a particular class of flavonoids that gives plants, fruits, and flowers colors ranging from red to blue. Antidote a substance that neutralizes or counteracts the effects of a poison. Aphrodisiac a substance that increases sexual desire. Astringent an agent that causes the contraction of tissue. Balm a soothing or healing medicine applied to the skin. Beta-carotene pro-vitamin A. A plant carotene that can be converted to two vitamin A molecules. Carminative a substance that promotes the elimination of intestinal gas. Carotenes fat-soluble plant pigments, some of which can be converted into vitamin A by the body. Cathartic a substance that stimulates the movement of the bowels, more powerful than a laxative. Cholagogue a compound that stimulates the contraction OE the gallbladder.

Choleretic a compound that promotes the flow of bile. Cholestasis the stagnation of bile within the liver. Cholinergic pertaining to the parasympathetic portion of the autonomic nervous system and the release of acetylcholine as a transmitter substance. Coenzyme a necessary nonprotein component of an enzyme, usually a vitamin or mineral. Compress a pad of linen applied under pressure to an area of skin and held in place. Decoctions dilute aqueous extracts prepared by boiling the botanical material with water for a specified period, followed by straining or filtering. Demulcent a substance soothing to irritated mucous membranes. Emulsify to disperse large fat globules into smaller uniformly distributed particles that can remain in suspension in water. Enteric-coated a special way of covering a tablet or capsule to ensure that it does not dissolve in the stomach, so it can reach the intestinal tract. Enzyme an organic catalyst that speeds chemical reactions. Essential oils also known as volatile oils, ethereal oils, or essences. They are usually complex mixtures of a wide variety of organic compounds (e.g., alcohols, ketones, phenols, acids, ethers, esters, aldehydes, oxides) that evaporate when exposed to air. They generally represent the odoriferous principles of plants. Extracts concentrated forms of natural products obtained by treating crude materials containing these substances with a solvent and then removing the solvent completely or partially from the preparation. The most commonly used extracts are fluid extracts, solid extracts, powdered extracts, tinctures, and native extracts. Flavonoid a generic term for a group of flavonecontaining compounds that are found widely in nature. They include many of the compounds that account for plant pigments (anthocyanins, anthoxanthins, apigenins, flavones, flavonols, bioflavonols, etc.). These plant pigments exert a wide variety of physiologic effects in the human body. Fluid extracts these extracts are typically hydroalcoholic solutions with a strength of one part solvent to one part herb. The alcohol content varies with

Pharmacology of Natural Medicines

each product. They are, in essence, concentrated tinctures, constructed to represent 1 grain of the crude drug to 1minim of fluid extract. Glycosides sugar-containing compounds composed of a glycone (sugar component) and an aglycone (nonsugar-containing component) that can be cleaved upon hydrolysis. The glycone portion may be glucose, rhamnose, xylose, fructose, arabinose, or any other sugar. The aglycone portion can be any kind of organic compound (e.g., sterols, triterpenes, anthraquinones, hydroquinones, tannins, carotenoids, anthocyanidins). Infusion tea produced by steeping a botanical in hot water. Laxative a substance that promotes the evacuation of the bowels. LD5,, the dosage that will kill 50% of the animals taking the substance. Lipotropic promoting the flow of lipids to and from the liver. Menstrums solvents used for extraction (e.g., water, alcohol, acetone). Metalloenzyme an enzyme that contains a metal at its active site. Native extracts high-potency extracts prepared via concentration under reduced pressure at low temperatures until all solvent is removed. Oleoresins primarily mixtures of resins and volatile oils. They either occur naturally or are made by extracting the oily and resinous materials from botanicals with organic solvents (e.g., hexane, acetone, ether, alcohol). The solvent is then removed under vacuum, leaving behind a viscous, semisolid extract that is the oleoresin. Examples of prepared oleoresins are paprika, ginger, and capsicum. Powdered extract a solid extract that has been dried to a powder. Putrefaction the process of breaking down protein compounds by rotting.

Recommended dietary allowance (RDA) recommended dietary allowance. Resins complex oxidative products of terpenes that occur naturally as plant exudates or are prepared by alcohol extraction of botanicals that contain resinous principles. Saponins nonnitrogenous glycosides, typically with sterol or a triterpene as the aglycone, that possess the common property of foaming, or making suds, when strongly agitated in aqueous solution. Solid extracts thin to thick, viscous liquids or semisolids prepared from native extracts by adjusting the latter to the specific strength with suitable diluents. Typically, these extracts are 41, that is, one part extract is equivalent to, or derived from, four parts of crude herb. Strength of an extract the potency or strength of a botanical extract is generally expressed in two ways. If they contain known active principles, their strength is commonly expressed in terms of their content of active principles. Otherwise their strength is expressed in terms of their concentration of the crude drug. Thus a strength of 4:l means one part of extract is equivalent to, or derived from, four parts of crude drug. A strength of 1:5 represents one part of extract comparable to 0.2 parts of the crude drug. This ratio method of expressing drug strength does not accurately measure potency because there may be wide variation between manufacturers. Tinctures alcoholic or hydro-alcoholic solutions usually containing the active principles of botanicals in low concentrations. They are usually prepared by maceration or percolation or by dilution of their corresponding fluid or native extracts. The strengths of tinctures are typically 1 : l O or 1:5.Alcohol content varies. Tonic a substance that exerts a gentle strengthening effect on the body.

A1kylglycerols Peter T. Pugliese, MD Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS Introduction 713 History 713 Basic Chemistry of Alkylglycerol Ethers from Shark Liver Oil 714 Some Definitions 714 Absorption, Fate, and Excretion 715 Biologic Effects 716 Bacteriostatic Effects 716 Hemopoietic Effects 716 Protection Against Radiation Damage 717 Immunologic Aspects of Alkylglycerols 717 Overview of the Immune System 717 Complement 717 Macrophage 718

INTRODUCTION Sharks have existed, virtually unchanged, for some 450 million years. Some scientists attribute this long staying power to the well-developed immune system in the shark, an immune system that is quite similar to our own. Sharks have both humoral and cellular components to their immune system and therefore have B cells and T cells. They also have spleens and thymus glands just as humans do, although they possess large quantities of alkylglycerols found mainly in the liver. This chapter explores the use of alkylglycerols from sharks both as immune stimulants and as powerful agents in the treatment of neoplastic disorders.

HISTORY

~_______

Alkylglycerols are ether-linked biologic compounds that have a long and fascinating history. Much of their early history is found in the literature of histochemistry and is related to methods of staining specific cellular components. One of the greatest histologists was Robert Feulgen (1884-1955), a German physiologic chemist who devised the Feulgen reaction. (The Feulgen reaction,

Clinical Uses of Alkylglycerols 719 Cancer 719 Tumor Regression with Alkylglycerol Treatment 719 Protection Against Radiation Injuries 719 Alkylglycerols in Other Medical Conditions 720 Blood-Brain Barrier Permeability 721 Experimental Antitumor Activity with Methoxy-SubstitutedAlkylglycerol 721 Indications and Dosage 722 Toxicology of the Alkylglycerols 722 Toxicity in Animals 722 Toxicity in Humans 722 Conclusions 722

or test, is a method to detect animal nucleic acids. It involves an acid hydrolysis with HCl followed by a 1% solution of decolorized rosaniline, which yields a red color in the presence of nucleic acids.) Feulgen and K. Voit discovered plasmalogens in 1924.' At the time they thought they had discovered an aldehyde, which they called plasmal. The origin of plasmal was believed to be an unknown substance, which they called plasmaZogen. They demonstrated the presence of this compound in many tissues, from protozoa to humans. Plasmalogens, it was learned later, were ether lipid compounds that are formed in the metabolic pathway of phosphoglycerides. They differ from phosphoglycerides in that they contain an ether linkage on the C-1 of the glycerol molecule. Intensive work on the structure and formation of the plasmalogens continued over the next 35 years. It was many years before a formula for plasmalogens was finally agreed on, and the biologic function of plasmalogens and their role in organisms was finally discovered after 1960. As in many discoveries, there are always unsung heroes: scientists who work quietly in some obscure laboratory, publish a paper, and are seen no more. Such was 713

Pharmacology of Natural Medicines

the case with research on the alkylglycerols.The work of Kossel and Edbaches on the starfish Astropecten aurantiacus was unknown until 1943 when Bergmann and Stansbury3 compared their preparation of batyl alcohol, a natural alkylglycerol obtained from the starfish, to the original work of Kossel and Edbaches and found similar physical and chemical properties of both compounds. Backing up in time, in the 1920s, after World War I, to Japan, where Tsujimoto and Toyama4were working on unsaponifiable compounds from liver extracts. (Unsaponifiable fractions are those fatty compounds that do not form soaps when shaken with strong bases such as potassium or sodium hydroxide. Steroids are an example of this class of compounds.) It was the work of these two investigators that identified two major alkylglycerols in shark and ray liver oil. They called the first compound selachyl alcohol from the family name for sharks, Selachoidei, and batyl alcohol from the ray family Batoidei. They were uncertain of the exact chemical structure at the time, due to questions about the role of an oxygen atom in the molecules. In 1924 Toyama5isolated a third compound from the liver oils of the ratfish, Chimera monstrosa, which he called chimyl alcohol. Four years later Heilbron and Owens6described the crucial role of the oxygen atom as an ether linkage. They refluxed batyl alcohol with hydroiodic acid and obtained octodecyl iodide, which was conclusive evidence of a glyceryl ether structure. At about this time, a great deal of work was being conducted on shark liver oil in an attempt to isolate the fat-soluble vitamins A and D. Ether lipids consisting mainly of batyl, chimyl, and selachyl alcohols were purified from shark liver oil as a side product of this isolation. This material provided a ready source for further investigation of the ether lipids. This was fortuitous because the first therapeutic use of ether lipids was in 1930 when Giffin and Watkins7employed yellow bone marrow to treat a patient with leukopenia. At the time they did not know that the active principle in the marrow was batyl alcohol. Eight years later Marberg and Wiles* isolated batyl alcohol from the unsaponifiable fraction of yellow marrow. The biologic function of the ether lipids was not fully elucidated until after 1960, although many investigators ascribed certain biologic functions to these compounds (e.g., the antileukopenic effect described earlier; a central depressant action described by Bergergin 1948; an erythopoietic effect reported by Sandler'O in 1949; a tuberculostatic effect reported by Emmerie et all1 in 1952; a wound healing action reported by Bodman and MaisinI2 in 1958; a radioprotective effect reported by Brohult13in 1960). Alkyl glycerol ethers were found to be widespread in nature, in fact almost universal, although no clear physiologic role was defined for them.

Current research has opened many investigative channels for these compounds, and new information is beginning to shed light on the molecular action of ether lipids. A review of the chemistry of alkyl glycerol ethers helps the reader understand the physiologic action and the potential therapeutic applications.

BASIC CHEMISTRY OF ALKYLGLYCEROL ETHERS FROM SHARK LIVER OIL Some Definitions Students often view lipid chemistry as an impenetrable complexity. The terminology is indeed not easy to master at first, but with time and repetition it becomes easier. Part of this problem rests with the lipid chemists, who have some difficulty agreeing on nomenclature. In the case of ether lipids, we limit this discussion to only a few naturally occurring compounds, specifically those occurring in shark liver oil. Lipids may be broadly defined as a class of water-insoluble organic compounds. They can then be further divided into simple lipids and complex lipids. For example, simple lipids are esters of fatty acids and an alcohol, such as palmitic acid and glycerol, to form a monoglyceride. Another example of a simple lipid is a cholesterol ester. Complex lipids are esters that contain phosphorus or nitrogen bases or sugars, or all three, as well as fatty acids and an alcohol. Lecithin, which is phosphatidyl choline, is an important complex lipid. The plasmalogens, discussed later, are lipid compounds that contain an ether linkage. They also contain both a phosphorus and a nitrogen group, so they are classified as complex lipids. We also discuss neutral lipids, which are not ionically charged, and ionic lipids, or charged lipids. Fats such as common triglycerides found in lard are neutral lipids, while phospholipids are charged lipids. The term alkoxyl refers to an organic group RO, which is part of an ether group ROR. The term has been shortened to alkyl, so we denote ether lipid as alkylglyceride. Note that there is no other oxygen atom associated with the R components. The term acyl refers to R - C = 0. The term curbonyl refers to a C = 0 group, and the term carboxyl refers to a X O O H group, where one oxygen has a double bond to the carbon atom. The ether bond is the key to understanding the unique functioning of the alkylglycerol. This bond, C-O-C, is found throughout nature in many important biologic compounds, the most familiar of which is thyroxin from the thyroid gland. In the plant world, guaiacol is another familiar ether-linked substance. Glycerol ethers are quite widespread, having been isolated from many life forms and in many different molecular arrangements. The basic structure of these

Alkylglycerols compounds consists of a glycerol molecule with one or more of the hydroxyl groups being replaced by longchain fatty acids. The bonding of three fatty acid molecules to the glycerol molecule with an ester linkage is known as a triglyceride, or common fat. The ester linkage is characterized by the -COO group, in which one oxygen is linked in a double bond to a carbon atom. Figures 63-1 and 63-2 illustrate typical triglycerides and alkylglycerols, respectively. Although the chemistry of the alkylglycerols in many animals and plants has been studied extensively, we limit our discussion here to the main ether lipids found in shark liver oil. However, a note on the composition of shark liver oil is in order. Shark liver oil contains high levels of vitamins A and D, along with other constituents besides the ether lipids. In commercial preparations of the alkylglycerols extracted from shark liver oil, all of these components are removed in the extraction process. Therefore when we speak of shark liver-derived alkylglycerols in this chapter, we refer to a highly refined end product containing only the alkylglycerols. One of the major sources of natural alkylglycerols is obtained from the Greenland shark, Somniosus microcephlus, which contains up to 50% of alkylglycerols. Other sources include the elasmobranch fish such as the small shark, Chimaera monstrosu, and the dogfish, Squalus ucunthius. Cod liver oil and certain mollusks are additional sources of alkylgly~erols.'~These compounds have been found in various animal organs including bone marrow fat, spleen, liver, plasma, and erythrocytes and in milk.15J6 These compounds are found in the unsaponifiable fraction of the oils obtained from the animals. Tsujimoto and Toyama4were the first investigators to report the presence of ether lipids in shark liver oil. Three major natural alkylglycerols obtained from the Greenland shark are batyl alcohol, chimyl alcohol, and selachyl alcohol. Figure 63-3 illustrates the chemical structure of these compounds. Although chimyl and batyl alcohol are saturated chains, selachyl alcohol contains one unsaturated bond. All the ether bonds are on the number 3 carbon of glycerol. In the natural state these compounds are usually present as ester compounds, with carbons 1 and 2 esterified with c16 or C18 saturated fatty acids. A fourth natural compound is a

0 H2C-0-C-R

0

R'-

II

C -0-

I I

CH

H2C-O-

II 0

II

C -R"

Figure 63-1 Triglyceride.

H,C-0-R

0 R'-

II

C -0-

I I

CH H2C -0-

0

II

C - R" Ester bond

Figure 63-2 Alkylglycerol.

methoxy-substituted alkylglycerol, shown in Figure 63-4. This active compound comprises only a small percentage of natural shark liver oil-derived alkylglycerols, about 3%. The biologic synthesis of the lipid ethers has been well worked out. Most cells in the human body contain lipid ethers but only in small quantities. A synthesis scheme has been summarized by Mangold and PaltauP' as follows:

Step 1. Coenzyme A derivatives of long-chain fatty acids are reduced to alkyl and alkenyl chains via their alcohols, through an aldehyde. Step 2. The ether bond is formed by reaction of these alcohols with acyldihydroxyacetone phosphates, resulting in the formation of alkylacyldihydroxyacetone phosphates. Step 3. Reduction of the alkylacyldihydroxyacetone phosphates leads to the formation of alkylglycerophosphates. This may be further summarized: fatty acid + aldehyde 4alcohol + alkyl ether + 1-alkenyl ether

It is unlikely that ether lipids exist in nature as free forms; rather, they are esterified. Being ether compounds, they react as aliphatic ethers (i.e., they are stable to most oxidizing and reducing substances but undergo only one general, nonenzymatic reaction, which is acid hydrolysis). The purpose of this chapter is not to discuss the isolation and identification of the alkylglycerols. The scheme for this work is well developed and may be found in referencesby Mangold and Weber.18This chapter focuses instead on the naturally occurring alkylglycerols from shark liver oil and relates the structure and fate of these compounds to their physiologic effects and potential therapeutic use.

Absorption, Fate, and Excretion After oral ingestion of ether lipids, absorption occurs from the intestine. About 95%of radioactive (C14-labeled)

Pharmacology of Natural Medicines H2C -OH HO-

H2C-OH

I I

I CH I

HO-CH

H~C-OO-CCH~-(CH~),,-CCH~

H2C -O-CH2-(CH2)1,-CH, Chirnyl alcohol

Bawl alcohol

H2C -OH

I I

HO-

CH H2C-O-CH2-(CH2)7-

CH=CH -(CH2)7-

CH3

Selachyl alcohol Figure 63-3 Chirnyl, batyl. and selachyl alcohol.

chimyl alcohol is absorbed in the intestine, with 5% being excreted in the feces in one study.'9 In the gastrointestinal tract a large proportion of the ingested ether lipid in the form of 10alkylglycerols is cleaved at the ether bond with the alkyl moieties, giving rise to fatty acids. The remainder is incorporated into 1-0-alkyl 2,3-diacyl-sn-glycerols, l-O-alky-l-2-acyl-sn-glycerols,1-

palmitic acid (a C 16 fatty acid) during its passage through the intestinal mucosa.

BIOLOGIC EFFECTS Bacteriostatic Effects As early as 1952, the bacteriostatic effects of alkylglyc-

O-alkyl-2-acyl-sn-glycerol-3-phosphoethan0lamines.~~erols on tubercle bacillus (Mycobacteriurn tuberculosis) Ether lipids are only minor components of the human in vitro were reported." This material was isolated from diet so that the major portion of ether lipids in the body cod liver oil and consisted of the unsaponifiable fracis synthesized in the body.20Absorption of the intact ether lipid is the rule, since ether lipids are not subject to the action of lipase, which is specific for the ester bond. This means that the "fat" is absorbed rather than the fatty acids. After feeding chimyl alcohol to rats, analysis of the lymph fluid shows that 2% to 4% of the ether lipids are found as fatty acids combined in phospholipids. About 50% is found in the triglyceride fraction, while another 40% is found as the free chimyl alcohol or an esterified alcohol. In the triglyceride fraction, most of the original compound is found as palmitic acid, which indicates that the ether bound in the chimyl alcohol was split during the absorption process. The cetyl alcohol (a C 15 fatty alcohol) moiety of chimyl alcohol is oxidized to

Methoxy group

H2C -OH

I

HO -CH

I

H2C -0+H2-

CH3 A/

I I

0 CH -(CH2)13-

CH3

Figure 63-4 Methoxy-substituted alkylglycerol.

tion. Scant data have been published on the antimicrobial effects of the akylglycerols from natural sources, but a more recent report using a synthetic product, racemic sn-l(3)-dodecylglycerol, showed some activity against Streptococcus mutuns BI-X21 These investigators found that substantial decreases in the viability of this organism were associated with an accumulation of phosphatidic acid. Current research shows that antibiotic resistance in bacteria is associated with the lipid content of the bacteria in both gram-positive and gram-negative organisms.22The action of the alkylglycerol was to inhibit the synthesis of lipids in the microbial cell.

Hemopoietic Effects Bone marrow was found to be a useful therapy in treating secondary anemia more than 60 years ago. Later it was found that the unsaponifiable fraction of the marrow lipids was responsible for this action (i.e., the stimulation of erythrocyte production). Sandler'O found that batyl alcohol had a beneficial effect on erythrocyte production in rats. Further studies with subcutaneous injections in humans showed an increase in reticulocyte levels in the blood. The erythropoietic, thrombopoietic,

Alkylglycerols

and granulopoietic stimulatory activities of l-octadecylglycerol ethers was confirmed by several investigators.B25 Interestingly, chimyl alcohol can stimulate hemopoiesis, but selachyl alcohol cannot.26

Protection Against Radiation Damage The effects of 1-alkylglycerolsin the treatment of radiation-induced leukopenia have been studied extensively. Some investigators have confirmed these beneficial Work by Lorenz and while others have colleaguesmfound that lethal irradiation in mice and guinea pigs was counteracted by postirradiation injection of bone marrow. Sandler'O believed that batyl alcohol might be the active factor in bone marrow that prevented irradiation leukopenia. His observations, however, noted an increase mainly in erythropoiesis. Additional studies by Arturson and Linback3* using intraperitoneal injections of batyl alcohol in mice showed an increase in the production of both erythrocytes and reticulocytes. Other studies have confirmed the positive effect of the alkoxyglycerols on postirradiation damage. The work of Brohult and Hornberg23showed that lethal irradiation is counteracted by postirradiation injections of batyl alcohol. In 1963 BrohulP2 published a thesis on the use of alkylglycerols in radiation treatment. A summary of the major findings in this paper follows: The postirradiation decrease in thrombocytes and white cells is notably less in patients treated with alkylglycerols than in those not given alkylglycerols. Patients with low thrombocyte counts due to radiation treatment or chemotherapy had increased counts after treatment with alkylglycerols. 0 In irradiated rats pretreated with alkylglycerols, there was less of a decrease in megacaryocytes and nucleated cells in the bone marrow compared with untreated irradiated controls. Selachyl alcohol was more effective than batyl alcohol in preventing megacaryocyte decrease. A dose-related response with a maximum response at a certain level occurred, and then a decreased response occurred when that level was exceeded. The alkylglycerolsincrease the growth rate of rats after treatment and irradiation compared with untreated irradiated rats. Batyl alcohol has a greater effect than selachyl alcohol on increasing growth rate in rats. In a series of 350 patients with cervical cancer treated with alkylglycerol and given radiation therapy, there was a greater survival rate for 1year and 5 years than in untreated irradiated controls (thistopic is discussed in more detail later in the section on the clinical uses of the alkylglycerols).

IMMUNOLOGIC ASPECTS OF ALKYLGLYCEROLS Overview of the Immune System Early in the investigation and study of ether lipids, an augmentation of the immune system seen in animals that ingested these compounds was evident. Apparently the macrophage was the key cell in this reaction. A brief introduction to the immune system is provided next to acquaint the reader with the relationship of the macrophage to other immune active cells and to the immune system in general. The immune system comprises a set of physiologic responses used by the body to destroy or neutralize foreign matter, either living or nonliving. Included in this system is a process of maintaining an immune surveillance of the body's own cells to detect and destroy malignant cells. Therefore the essential role of the immune system is one of recognition of the components of "the self" and protection from "nonself entities." Our own cellular constituents make up a vast array of complex molecules to idenhfy and class*. Adding complex biochemicals from bacteria, viruses, and parasites of all kinds increases the complexity of the system manifold. The two basic responses of the immune system are (1)a nonspec$c response that protects nonselectivelyagainst foreign matter or cells without the need for recognition of specific identities (e.g., the barrier provided by the skin, the inflammatory response to injury, the complement system); and (2) a specific response that depends on recognition of a specific substance before an attack by the immune system. The specific response involves highly specialized cells and the formation of specific chemical substances employed in the attack. Among these substances are antibodies, which are adapter molecules that idenhfy foreign organisms and interact with the other components of the immune system. Each of these components has three main regions, two of which communicate with complement and the phagocytic cells, known as the biologic part. The other serves to recognize and bind to microorganisms, known as the external recognitionfunction. The body makes millions of these antibodies. The most common antibodies are the immunoglobulins, known as IgG, IgA, IgM, IgE, and IgD. Chemically, the antibody molecule consists of two active regions, known as the Fc, or constant part, and the Fab, or variable antigen-specific part. Each antibody molecule has two heavy chains and two light chains. The Fc part consists only of heavy chains, while the Fab part consists of light and heavy chains.

Complement A family of proteins known as complement provides a direct means of killing microbes without the need for phagocytosis; however, it plays an important role in

Pharmacology of Natural Medicines

phagocytosis, as discussed later in the discussion of alkylglycerols and macrophage activation. A brief review of the major steps in the complement reaction is outlined. Complement is so named because it complements and amplifies the action of the antibodies. Some of the components of the complement system circulate constantly in the bloodstream in an inactive form and are activated in the presence of infection or tissue damage. The result is a cascade reaction in which some 20 proteins are involved in generating the active moieties. However, only the major components are discussed here. Five of the active proteins resulting from the cascade form a complex known as the membrane attackgroup complex, or MAC. This MAC invades the microbial plasma membrane and disrupts it by creating a leaky channel. Other cascade-generated proteins cause vasodilatation and increased vascular permeability. The major action of the complement proteolytic cascade is to cleave a component known as C3 into two active units, C&and C3b.Complement C3 is an opsonin, a material that helps attach phagocytes to the microbe. Antibodies are required to activate complement in the classic system, but the concern here is with another complement activation pathway that does not require antibodies, the so-called alternate complement pathway. This system is triggered by certain carbohydrates on the bacterial surface that initiate the cascade at a point about halfway through the classic system to generate c3b. The interaction of complement with macrophages is a key step in many immune reactions, as complement enhances the ability of macrophages to bind, ingest, and destroy micr0organisms.3~

Macrophage The macrophage is an extremely versatile and highly regulated cellular system. Besides their microbicidal activity, macrophages are equipped to recognize and destroy both intracellular and extracellular replicating invaders, whether or not these invaders are prokaryotic or eukaryotic types. They are important scavengers for effector cells and molecules of host origin, as well as for exogenous compounds that they can take up, degrade, and detoxlfy or contain. They are known to regulate many body functions including iron and lipid metabolism. The large number of secretory products generated by the macrophage helps to regulate other cells, including the fibroblasts and cells involved in the formation of myeloid component in the bone marrow. Obviously such powerful cells need to be tightly controlled, and so they are. The resident macrophages in the tissues are usually downregulated to a high degree. The process of activation, later discussed in detail, comes from various extracellular stimuli. Over time it has become apparent that the macrophage is a multipotential cell with the capacity to develop in many ways,

depending on the specific signal it receives. This system is far from being fully understood, but the control of this delicate balance of activities is essential to life, so it has become a prime area of intensive investigation. The macrophages originate from precursor cells in the bone marrow and pass into the circulation as rnonocytes. They remain in the bloodstream for several hours and then migrate to various tissues, where they are transformed into macrophages. The macrophage is an activated monocyte and is easily distinguished from the smaller neutrophil by its size and characteristic nucleus. Although both cells are phagocytic, the macrophage has far greater potential for killing bacteria. A greater cytoplasmic volume and more cytoplasmic organelles are present in the macrophage, including more lysosomes, microtubules, microfilaments, and Golgi membranes. After leaving the bloodstream, the macrophage enters the peritoneal cavity, other serous cavities, and the red pulp of the spleen and the lymph nodes. Macrophages possess receptors for the Fc pieces of the immunoglobulins and for the Cbb complement fraction discussed earlier. The adherence of a particle to the macrophage is mediated by complement or by complement plus antibody. Either IgM or IgG is required for this reaction to take place, along with C3.If IgG is bound to the particle, it can be ingested without the addition of complement C3. The concept of immune activation is quite comprehensive in that it embodies many intercellular and molecular eventsMThe lymphocytes play a key role in activating the macrophage, particularly the T-helper lymphocytes. Macrophages are usually downregulated with respect to their surface active receptors when they are resident in most tissues (resident macrophages are usually not activated). They may be fully activated in several stages (e.g., an inflammatory response in tissues evokes a reaction that changes the C3 complement on the surface of the macrophage to fully empower the cell to engulf and destroy bacteria or red cells). They are then further activated to a high killer state by secretions from T-lymphocytes, one of which includes gamma interleukin.

Macrophage Activation by Alkylglycerols Inflamed cancerous tissue releases alkyl-lysophospholipids and other alkylglycerols, which are degradation products of alkyl phospholipids and alkyl neutral lipids. These compounds are found in cancerous tissue in high concentration but are in low concentration in normal tissues. One of these products, dodecylglycerol (DDG), is among the most potent macrophage activators The use of the natural sn-3-octylglycero1, or batyl alcohol, found in shark liver oil produced the same effect as DDG?9 The mechanism of macrophage activation by the natural alkylglycerols is most likely identical

Al kylglycerols to the action of lysophospholipids. Keeping in mind that activated macrophages exhibit increased phagocytosis, one method of assaying substances for activation potency is to measure the ingestion of various particles. Erythrocytes coated with IgG are common target particles used in this assay. Lysophosphatidylcholine has been shown to be effective in increasing macrophage ingestion of IgG-coated erythrocyte^?^,^^ Mice were treated with intraperitoneal injections of batyl alcohol in saline, and the macrophages were harvested 4 to 5 days later. Sheep erythrocyte coated with IgG showed a greatly increased ingestion of erythrocytes.There was no increased ingestion when the cells were coated with IgM or complement, which suggests that batyl alcohol activates the macrophages for Fc-mediated ingestion only. It was interesting that batyl alcohol was more effective at a lower dose than the synthetic compound.37 Evidence indicates that oral intake of natural alkylglycerols results in higher levels of plasmalogens in the erythrocytes in human subjects. (Plasmalogensare ether compounds that are formed in the metabolic pathway of phosphoglycerides. They differ from phosphoglycerides in that they contain an ether linkage on the C-1 of the glycerol molecule.) Plasmalogens protect animal cell membranes against oxidative stress. In rat studies batyl alcohol is incorporated into all tissues except brain tissue, and this action is a stereospecific It has been shown that alkylglycerols are present in human and cow milk,39,41along with other immunologic factors.@ Because the neonate has not developed a mature immune the prospect of transmitting immune functional components in the milk is a practical way to provide some protection for the newborn.44In one study lactating rats were fed alkylglycerols dissolved in corn oil; the composition of the alkylglycerols was similar to that found in shark liver oil in that batyl alcohol, chimyl alcohol, and selachyl alcohol were the major constituents.44 The findings from this study showed that although peripheral blood granulocytes were elevated, there was no elevation of peripheral lymphocytes. Plasma levels of immunoglobulins were elevated in pups whose dams were fed alkylglycerols, but not in the controls. Both IgG and IgM were elevated to a significant degree.

CLINICAL USES OF ALKYLGLYCEROLS Cancer Alkylglycerolshave been used primarily to treat various types of cancer, usually as adjunct therapy combined with radiation. This section covers the work of Brohult and colleagues45on cervical cancer tumor regression and on the decrease of complications resulting from

irradiation therapy. It also addresses a new alkylglycerol, a methoxy-substituted alkylglycerol that occurs naturally at only 3% in shark liver oil but may be available as a synthetic compound.

Tumor Regression with Alkylglycerol Treatment Patient selection was determined by stages that were defined by the International Federation of Gynecology and Obstetrics as follows: Stage I-carcinoma strictly confined to the cervix (early stage) Stage IA-cases of early stromal invasion Stage IB-all other cases of stage I Stage IIA-the carcinoma extends beyond the cervix but has not extended onto the pelvic wall; the carcinoma involves the vagina except for the lower third; no parametrial involvement Stage IIB-the carcinoma extends beyond the cervix but has not extended onto the pelvic wall; the carcinoma involves the vagina except for the lower third; parametrial involvement is noted Stage 111-the carcinoma has extended onto the pelvic wall; on rectal examination there is no cancer-free space between the tumor and the pelvic wall; the tumor involves the lower third of the vagina Stage Iv-the carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum Patients were treated with shark liver oil-derived alkylglycerol containing 100 mg of alkylglycerol, given as two capsules three times a day for a total dose of 600 mg/day. The treated group received 600 mg/day for 7 days before irradiation and for 1 to 3 months after radiation therapy. The study covered three time periods: period 1, from September 1, 1964, to February 15, 1964, comprising 458 patients; period 2, from 1970 to 1973, comprising 137 patients in a double-blind study; and period 3, from late 1973 to 1975, comprising 245 patients who were treated with alkylglycerols on as “every second patient.” The control group consisted of all patients who received radiation therapy for cervical cancer but did not receive alkylglycerols. The control group in this study consisted of 4404 patients treated during the same periods, while the total treated group was 841 patients. The mortality after 5 years was 31% for the group treated with alkylglycerols and 39.6%for the control group. The difference is statistically significant (p < 0.001).45

Protection Against Radiation Injuries Studies of patients treated from 1963-1966 and 1970-1972 by Brohult and colleagues46were aimed at evaluating

Pharmacology of Natural Medicines further the protective effects of ether lipids against irradiation injuries in patients with uterine cervix cancer. Alkylglycemls derived from Greenland shark liver oil were administered to one group of patients at a level of 600 mg/day during the radiation treatment and 300 mg/day for 1 to 3 months after treatment. Another group of patients was treated the same way during and after radiation but was also treated prophylactically 8 days before radiation with 600 mg/day of alkylglycerols. The patients receiving alkylglycerols during and after radiation treatment are referred to as the nonprophylactic group, and the patients also given alkylglycerols before the radiation as the prophylactic group. The system proposed by Kottmeier and Grap7 was used to evaluate radiation injuries that had occurred in the bladder, rectum, uterus, and intestine. Radiation injuries of grade I, with minimal objective changes in the mucosa, were excluded. Patients with radiation injuries of grades 11to IV were treated as a single group: "patients with radiation injuries." Grade II was characterized by moderate to severe changes such as necroses, ulcerations, moderate stenoses, and reactions with lengthy bleeding. Radiation complications of grade 111included injuries to the bladder, radiation fistulas from the ureters, and rectal and intestinal stenoses of such severity that colostomy or resection was needed. Grade IV was characterized by rectal and intestinal fistulas. Complications included patients with clinical features of radiation injury in whom the symptoms were found to be caused by tumor growth or a combination of tumor growth and radiation injury. These complications were termed complex injuries and represented a serious situation. AU patients with complex injuries were dead after 5 years. The incidence of radiation injuries varies with the spread of the cancer and radiation technique. The incidence is higher in the more advanced tumor stages than in the less advanced ones. It is also higher after ' T o three-beam treatment of combined high-voltage and x-ray treatment than after conventional radiographs or radium alone. When comparing the groups statistically, standardized proportions have been used in order to cancel out differences with regard to stage distribution and radiation technique. The total incidence of injuries was lower in the groups that had received alkylglycerols (18.1Y0in the prophylactic group and 24.4% in the nonprophylactic group) than in the controls (37.1%). The prophylactic group had a considerably lower incidence of complex injuries and multiple injuries than both the controls and the nonprophylactic groups. The differences were highly sigruficant (p < 0.001). Analysis of the patients divided into groups according to tumor stage or radiation technique showed that the incidence of complex injuries was lower in all subgroups of prophylactically treated patients than in the corresponding control groups. A double-blind study

from 1970-1972showed a pronounced protective effect of prophylactic treatment against injuries after radiation therapy.&The use of increased doses of radium in intracavitary irradiation was followed by a high incidence of radiation injuries, which was considerably reduced by treatment with alkylglycerols, especially when these compounds were administered prophylactically.48

Alkylglycerols in Other Medical Conditions Although few studies support the use of natural alkylglycerols in disease states other than cancer, it s e e m appropriate to consider these agents in any condition that would benefit from stimulation of an immune component. Currently the alkylglycerols are viewed as adjunct therapy rather than primary therapeutic agents, except for the methoxy-substituted alkylglycerols. Newer forms of the alkylglycerols have been synthesized and are being tested successfully with a wide range of tumor types. Conditions that are characterized by a hyperproliferative state may benefit from treatment with alkylglycerol. Considering that one possible effect of the alkylglycerols is competitive inhibition of diacylglycerol, it is plausible that protein kinase C would also be inhibited by this same action, since diacylglycerol is a stimulator of protein kinase C. Protein kinase C is essential to the oxidative burst in neutrophils, and agents that inhibit protein kinase C inhibit this acti0n.4~By inhibition (TPAFmediated of 12-0-tetradecanoylphorbol-13-acetate arachidonic acid release, studies examining the effects of synthetic alkylglycerols on the release of arachidonic acid and arachidonate metabolites from Madin Darby canine kidney cells in response to P A have suggested this same mechanism of protein kinase C inhibition.5O The work by Yamamoto and colleagues37supports the role of ether analogs as activators of macrophages and as primary cytotoxic agents. This dual role would suggest a wider application of alkylglycerol as adjunct therapy. 0 t h and JadhavS1observed that alkylglycerols given to lactating mice increase the peripheral granulocyte count, as well as the serum immunoglobulins in the pups. This action suggests the possible use of alkylglycerols in most infectious disorders.

Male Infertility In the near future, alkylglycerols may also be known to help in cases of poor sperm motility and fertility. Alkylglycerols are known to ampllfy platelet-activating The factor (PAF) biosynthesis in monocyte cell PAF produced by mammalian sperm is an important activator of sperm motility. In one in vitro study of boar spermatozoa, alkylglycerol treatment improved percentage of motility, as well as velocity parameters after 24 hours and number of boars produced. Those boars treated with PAF receptor antagonist did not show these effe~ts.5~

Alkylglycerols

Antiangiogenesis Although more clinical and in vitro studies are necessary to fully examine the usefulness of alkylglycerols, a strong body of research is being gathered. In one research project, the antitumor effects of shark liver oil and more refined alkylglycerols were analyzed in mice with Lewis lung carcinoma tumors. Purified alkylglycerols were found to sigrhcantly decrease plasmalogen content in tumors, although the shark liver oil had no such effect. In alkylglycerol-treated mice, metastasis dissemination was reduced by 64 f 8%, whereas the shark liver oil demonstrated a 30 f 9% effect below control. Lastly, after a 5-day treatment with alkylglycerols there was an attenuated presence in tumors of von Willebrand factor, a marker of endothelial cellsM The authors of this study believe these data may suggest an antiangiogenic effect of alkylglycerols. Another study of shark liver oil, as a standardized concentration of alkylglycerols and their methoxyderivates, found that prostate cancer cells demonstrated a marked colony inhibition following relatively small doses of 0.5 and 0.1 mg/ml of medium. Using flow cytometry to elucidate the mode of cell death, ovarian and prostate carcinoma exhibited an increased percentage of apoptotic cells. Interestingly, mammary carcinoma cells showed a predominantly necrotic effe~t.5~

Blood-Brain Barrier Permeability The treatment of central nervous system cancer with chemotherapeutic drugs is fraught with difficulty because low-toxicity methods that effectively traverse the blood-brain barrier are not well characterized. Alkylglycerols have demonstrated multiple biologic activities with a prominent effect on blood-brain barrier permeability56 including increasing the permeability of tight j~nctions.5~ Clinically, this effect may prove useful to improve the brain uptake of cancerostatic agents. Testing the ability to transfer methotrexate in normal rats, intracarotid short-chain alkylglycerols were shown to constitute an effective and low-toxic strategy for transient opening of the blood-brain barrier.%Another study employing intracarotid coadministration of methotrexate and 1-0-pentylglycerol in nude mice resulted in a significant increase in delivery of small and large compounds to normal brain and brain tumors, including methotrexate concentrations. These increases were found in the ipsilateral brain, compared with controls without 1-0-pentylglycerol (p < 0.005).5’

Experimental Antitumor Activity with Methoxy-Substituted Alkylglycerol About 3% of the alkylglycerols in Greenland shark liver oil consists of methoxy-substituted alkylglycerols,which have been found to inhibit tumor growth in cultured cells. Two cell lines were used, a methylcholanthrene-induced

murine sarcoma (MCGI-SS) and a juvenile osteogenic sarcoma (2T). Marked growth inhibition was noted for the mixture of 2-methoxyalkylglycerolsfrom Greenland shark liver oil, different single components derived from this oil (2-methoxyhexadecylglycerol,2-methoxyhexadecenylglycerol, and 2-methoxyoctadecenylglycerol), and various synthetic compounds including, for example, 2-ethoxyhexadecylglycerol,2-methoxyhexadecenylglycerol, and 3-methoxyhexadecylglycerol.59 In several tumor-host systems including solid tumors, leukemias, and lymphomas, the methoxy-substituted alkylglycerols were incorporated into the feed in different concentrations(0.1%to 2%, w/w). Growth inhibition was noted for melanoma B16, for a methylcholanthreneinduced sarcoma (MCG101) and Lewis lung tumor (LLT) in C57BL/6J mice, for lymphoma LAA in A/Sn mice with synthetic 2-methoxyhexadecylglycerol, and for a spontaneous mammary carcinoma in C3H mice with methoxy-substituted alkylglycerols from Greenland shark liver oil. The survival time of DBA/2J mice transplanted with lymphatic leukemia P1534 was increased by synthetic 2-methoxyhexedecylglycero1.59~aMetastases induced by the injection of MCG1-SS cells into a tail vein or into the portal vein were inhibited in the liver by methoxy-substituted alkylglycerols from Greenland shark liver Spontaneous metastasis formation from a methylcholanthrene-induced sarcoma (MCG1SS) in lymph nodes and lungs of CBA mice was inhibited by methoxy-substituted alkylglycerols derived from Greenland shark liver oil, as well as by synthetic 2-methoxyhexadecylglycerol.59Spontaneous metastasis formation from melanoma B16 was inhibited by synthetic 2-methoxyhexadecylglycerol.60 Worth noting is that the same substance can both stimulate the immune system and inhibit tumors. This has also been proven for akyllysophospholipids synthesized with a methoxy group in the 2-position of the glycerol part of the molecule. These substances have been studied at the Max-Planck Institute for Immunobiology at Freiburg and at the Department of Haematology and Oncology of the University of Munich. The German research groups have shown that even alkyllysophospholipidswithout the 2-methoxy group in the glycerol part can activate macrophages in the bone marrow. This shows that ordinary glycerol ethers, after incorporation into phospholipids, can activate the body’s immune defense system. These investigators think that the macrophage-stimulating effects of alkyllysophospholipids explain the effects of these substances on tumors and tumor spread. Tumor cells have only a low activity of enzymes that can break down ethers. This means that alkyl ethers are incorporated into the cell membrane’s phospholipids, which are then recognized and attacked by macrophages, which have a high activity of ether catabolic enzymes.

Pharmacology of Natural Medicines In experiments performed at the University of Stockholm,61 it has been shown that both types of methoxy-substituted alkylglycerols (methoxy group in the 1-position and methoxy group in the 2-position of the glycerol part of the molecule) inhibit growth of two tumor cell lines (neuroblastoma from mice and glioma cells from rats), while alkylglycerols without methoxy groups did not have any growth-inhibitingeffects on the tumor cell line studied. Interactions between different types of alkylglycerols and human neutrophil granulocytes have been studied by Palmblad and colleagues.62Platelet-activating factor (PAF) was the most potent with regard to the ability to produce an oxidative response, followed by the methoxysubstituted alkylglycerols. The study shows that there is a dissociation between the ability of an alkylglycerol to initiate oxidative and calcium responses, indicating strict structure-activity relationships for the different alkylglycerols studied.

batyl alcohol in rats at levels of 5 to 10 mg/kg of body weight had no effect on the thymus gland or on the production of adenosine triphosphate.

Toxicity in Humans BrohulP2observed that a healthy human being consumes about 10 to 100 mg/day of alkylglycerols in an average diet. Sandler'O gave healthy adult males 45 mg/day of batyl alcohol for 10 days with no ill effects. This was a relatively low dose compared with that consumed by people who eat shark meat and shark byproducts. Only the consumption of shark liver has been reported to produce ill effects, mainly diarrhea, due to the high squalene content. Alkylglycerols from the Greenland shark have been used for more than 30 years without undesirable side effects.

CONCLUSIONS

Ether lipids are well known as a new class of tumoricidal compounds, producing strong biologic signals. INDICATIONS AND DOSAGE Although many new compounds have been syntheCurrently, shark liver oil-derived alkylglycerols are not sized, natural compounds have been known for a long used as specific therapy for any medical condition. time, beginning with the work of Hanahan on plateletHowever, they may be used as ancillary, auxiliary, or activating factor, a 1-0-alkyl glycerol. This class of augmentative agents in many disorders. In cancer compound, know as plasmalogens, is known to inhibit chemotherapy or irradiation therapy, they are not only phosphorylation reactions, particularly those catalyzed protective but also additive in the overall therapeutic by protein kinase C. The dual action of alkylglycerolson effect. Any disorder that has a proliferative component, both the physical structure of the cell, such as the cell which includes most inflammatory disorders, responds membrane, and the complex biochemical pathways to alkylglycerols. Immune disorders in particular can be makes them extremely interesting as modulators of cell treated effectively with alkylglycerols. In the prevention functions. of infection or neoplastic diseases, 50 mg of alkylglycerol The biologic action of the alkylglycerols suggests they three times a day is suggested. For aggressively treated may have both prophylactic and inhibitory properties disorders, 300 mg/day or more may be necessary. The against tumors. This action is highly selective and appears use of the methoxy-derived alkylglycerols must await to be related mainly to the chemical structure of the alkylfurther research and availability of this powerful glycerol. Most clinical trials with alkylglycerolshave been with advanced cases, but these results are encouraging. alkylglycerol. The mechanisms involved in antitumor activity are many and include macrophage activation, immune cytotoxiaty, TOXICOLOGY OF THE ALKYLGLYCEROLS natural killer cell activation, enzyme inhibition and actiToxicity in Animals vation, and cell membrane disturbances. Other actions Oral toxicity studies with alkylglycerols have been include the antiinfective properties, as well as the radiaconducted on rats, mice, and dogs. Alexander and coltion protective properties of these agents. leaguesa reported that mice given a diet containing 18% Two areas that hold promise with the use of alkylglycalkyldiacylglycerolsshowed no ill effects after 2 years. erols are the suppression of autoimmune disorders and Work by Brohult,32Peifer and Carls0n,6~ the selective destruction of leukemic cells. Much of this Berger? and Bandis on oral feeding of alkylglycerols to work is covered in a report of the First International rats has shown that they are relatively nontoxic. Symposium on Ether Lipids in Oncology published Carlson6 tested dogs with chimyl, batyl, and selachyl by the American Oil Chemist Society in 1987.67Also, alcohols by feeding levels of 2.4 g/kg of body weight research in male fertility and the use of alkylglycerols and found no ill effects. in order to effectively traverse the blood-brain barrier Subcutaneous injections of batyl alcohol in mice by are other up-and-coming probabilities of employment. Bergergfound that a dose of 3 g/kg was necessary to The outlook for the use of alkylglycerols in medical obtain a subcutaneous LDm. Peritoneal injections of treatment and in the maintenance of health is optimistic.

Alkylglycerols

1.Feulgen R, Voit K. Gesamte Physiol. Menschen Xere. Pfluegers Arch 1924;206:389. 2. Kossel A, Edbacher S. Hoppe-Seyler’s. Z Physiol Chem 191594277. 3. Bergman W, Stanbury HA. Contributions to the study of marine products. J Org Chem 1943;8:283. 4.Tsujimoto M, Toyama Y. Uber die unverseifbaren Bestandteile (hoheren Alkohole) der Haifisch und Rochenleberole. Chem Umschau 1922;29:35-43. 5. Toyama Y. Chem Umsch. Geb Fette, Oele, Wachse, Harze 192491:13. 6. Heilbron IM,Owens WM. The unsaponifiable matter from the oils of the elasmobranch fish. Part Iv.The establishment of the structure of selachyl and batyl alcohols as monoglycerol ethers. J Chem Soc (Lond) 1928;942. 7. Giffin HZ,Watkins C. Treatment of secondary anemia. J Am Med Assoc 1930;95:587. 8. Marberg CM, Wiles HO. Yellow bone marrow extracts in grandocytopenia. J Am Med Assoc 1937;109:1965. 9. Berger FM. The relationship between chemical structure and central depressant action of a-substituted ethers of glycerol. J Pharmacol Exp Ther 1948;93470. 10. Sandler OE. Some experimental studies on the erythropoietic effect of yellow bone marrow extracts and batyl alcohol. Acta Med Scand 1949;22572. 11. Emmerie A, Engel C, U p W. The tuberdostatic action in vitro of the unsaponifiable fraction of cod-liver oil. J Sci Food Agr 19529:264. The a-glyceryl ethers. Clin Chim Acta 12.Bodman J, Haisin JH. 1958;3253-74. 13. Brohult A. Alkylglycerolsas growth stimulating substances. Nature (London) 1960;188:591-592. 14. Tsujimoto M. The liver oils of Elasmobranch fish. J Soc Chem Ind Japan 1932;51:317-323. 15. Holmberg J, Mysen G, Persson G. Component lipids of some food raw materials. Sixth Congress of the International Society for Fat Research, London, 1962. 16. Hallgren 8, Larsson S. The glyceryl ethers in the liver oils of elasmobranch fish. Lipid Res 1962;3:31-38. 17. Mangold HK, Paltauf F, eds. Ether lipids: biochemical and biomedical aspects. New York Academic Press, 1983Ch. 11. 18.Mangold HR, Weber N. Biosynthesis and biotransformation of ether lipids. Lipids 1987;22:789-799. 19. Bergstrom S, Blomstrand R. The intestinal absorption and metabolism of chimyl alcoholin the rat. Ada Physiol Scand 1956;38:166172. 20. Blomstrand R, Ahrens EH Jr. Absorption of chimyl alcohol in man. Proc Soc Exp Biol Med 1959;100:802-805. 21.Brissette JL, Cabacungan EA, Pieringex RA. Studies on the antibacterial activity of dodecylglycerol. Its limited metabolism and inhibition of glycerolipid and lipoteichoic acid biosynthesis in Streptococcus mutans BHT. J Biol Chem 1986;261:6338-6346. 22. Hugo WB, Stretton RJ. The role of cellular lipid in the resistance of some Gram-positive bacteria to penicillins. J Gen Microbiol 1966; 42133-138. 23. Brohult A, Holmberg J. Alkylglycerols in the treatment of leukopenia caused by irradiation. Nature 1954;1741102-1103. Hemopoietic effects of batyl alcohol. J Clin Invest 24.Linman JW. 1958;37913. 25. Osmond DG, Roylance PJ, Webb AJ, et al. The action of batyl alcohol and selachyl alcohol on the bone marrow of the guinea pig. Acta Haematol1963;29180-186. 26. Suki WN, Grollman A. The effect of batyl alcohol and related alkylglycerols on hemopoiesis in the rat. Tex Rep Biol Med 1960;18:662. 27. Alexander P, Connel DI, Brohult A, et al. Reduction of radiation induced shortening of life span by a diet augmented with alkoxy glycerol esters and essential fatty acids. Gerontologia 1959;3:147.

28. Ghys H. Effets des alkoxyglycerols (Kaby 700) sur la leucopenie consecutive a la radiotherapie. Lava1 Med 1962;33:331. 29. Snyder F, Piantadosi C, Malone B. The participation of 1- and 2isomers of Oalkylglycerolw as acyl acceptors in cell-free systems. Biochim Biophys Acta 1970;202:244-249. 30. Lorenze E, Congdon C, Uphoff D. Modification of acute irradiation injury in mice and guinea pigs by bone marrow injections. Radiology 1952;8863-877. 31. Arturson G, Lindback M. Experiments on the effect of batyl alcohol on the number of erythrocytes and reticulocytes in white mice. Acta Soc Med Upsal1951;5619. 32. Brohult A. Alkylglycerolsand their use in radiation treatment. Ada Radio1 1963;223(suppl):7-99. 33. Cohn ZA. The macrophageversatile element of inflammation. Harvey Lect 1981;77:63-80. 34. Elsbach P. Cell surface changes in phagocytosis. In Nicolson GL, Poste G, eds. Cell surface reviews, vol 4. Amsterdam: NorthHolland Publishing, 1977:363. 35. Ngwenya BZ, Yamamoto N. Activation of peritoneal macrophages by lysophosphatidylcholine.Biochim Biophs Acta 1985;839:9-15. 36. Ngwenya BZ, Yamamoto N. Effects of inflammation products on immune systems: lysophosphatidylcholine stimulates macrophages. Cancer Immunol Immunother 1986;21:174182. 37. Yamamoto N, St Clair DA Jr, Homma S, et al.Activation of mouse macrophages by alkylglycerols, inflammation products of cancerous tissues. Cancer Res 1988;48:6044-6049. 38. Adams DO, Hamilton TA. The cell biology of macrophage activation. Annu Rev Immunol1984;2283-318. 39. Hallgren 8,Niklasson A, Stallberg G, et al. On the occurrence of 1-0-alkylglycerols and lO(2-methoxyalkyl) glycerols in human colostrum, human milk, cow’s milk, sheep’s milk, human red bone marrow, red cells, blood plasma and a uterine carcinoma. Acta Chem Scand B 1974;281029-1034. 40. Das AK, Holmes RD, Wilson GN, et al. Dietary ether lipid incorporation in tissue plasmalogens of humans and rodents. Lipids 1992;27401-405. 41. Hallgren B, Larsson S. The glyceryl ethers in man and cow. J Lipid Res 19623:39-43. 42. Orga SS, Weintraub D, Orga PL. Immunologic aspects of human colostrum and milk. J Inununol1977;119245-248. 43. Quie PG.Antimicrobial defenses in the neonate. Semin Perinatol 1990;14:2-9. 44.Migliore-Samour D, Jolles P. Casein, a prohormone with an immunomodulating role for the newborn? Experientia 1988;44: 188-193. 45. Brohult A, Brohult J, Brohult S, et al. Reduced mortality in cancer patients after administration of alkoxyglycerols. Acta Obstet Gynecol Scand 1986;65:779-785. 46. Brohult A, Brohult J, Brohult S, et al. Effect of akyoxyglycerols on the frequency of fistulas following radiation therapy for carcinoma of the uterine cervix. Acta Obs Gynecol Scand 1979;58:203-207. 47. Kottmier HL, Gray MJ. Rectal and bladder injuries in relation to radiation dosage in carcinoma of the cervix. Am J Obs Gynecol 1961;827482. 48. Brohult A, Brohult J, Brohult S, et al. Effect of alkyoxyglycerols on the frequency of injuries following radiation therapy for carcinoma of the uterine cervix. Acta Obs Gynecol Scand 1977;56441-448. 49. Wilson E, Olcott MC, Bell RM, et al. Inhibition of the oxidative burst in human neutrophils by sphingoid long-chain bases. Role of protein kinase C in activation of the burst. J Biol Chem 1986;261:12616-12623. 50. Robinson M, Burdine R, Wame TR.Inhibition of phorbol ester-stimulated arachidonic acid release by alkylglycerols.Biochem Biophys Acta 1995;1254.361-367.

Pharmacology of Natural Medicines 51. Oh SY, Jadhav Ls.Effects of dietary alkylglcyerols in lactating rats on immune response in pups. Pediatr Res 1994;36:300-305. 52. P6drono F, Cheminade C, Legrand AB. Natural 1-0-alkylglycerols reduce platelet-activating factor-induced release of [3H]-serotonin in rabbit platelets. Prostaglandins Leukot Essent Fatty Acids 2004;71:19-23. 53. Cheminade C, Gautier V, Hichami A. 1-Oalkylglycerols improve boar sperm motility and fertility. Biol Reprod 2002;66:421-428. 54. Pkdrono F, Martin B, Leduc C, et al. Natural alkylglycerols restrain growth and metastasis of grafted tumors in mice. Nutr Cancer 2004;48364-69. 55. KrotkiewskiM, PrzybyszewskaM, Janik P.Cytostatic and cytotoxic effects of alkylglycerols(Ecomer).Med Sci Monit 2003;9:PI131-35. 56. Gopinath D, Ravi D, Rao BR, et al. 1-0-Alkylglycerol vesicles (Algmmes): their formation and characterization. Int J Pharm 2002;246:187-197. 57. Erdlenbruch B, Alipour M, Fricker G, et al. Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries. Br J Pharmacol2003;140.1201-1210. 58. Erdlenbruch B, Schinkhof C, Kugler W, et al. Intracarotid administration of shortchain alkylglycerols for increased delivery of methotrexate to the rat brain. Br J Pharmacol2003;139:685-694. 59. Hallgren B, Stallberg G. Occurrence,synthesis and biologicaleffects of substituted glycerol ethers. Prog Chem Fats Other Lipids 1978;164158.

60.Boeryd B, Hallgren B. The influence of the lipid composition of the feed given to mice on the immunocompetenceand tumor resistance of the progeny. Int J Cancer 1980;26241-246. 61. Brohult J. Personal communication. 62. Palmblad J, Samuelsson J, BrohultJ. Interactionsbetween alkylglycerols and human neutrophil granulocytes. %and J Clin Lab Invest 1990;50:363-370. 63. Alexander P, Connell DI, Brohult A, et al. Reduction of radiation induced shortening of life span by a diet augmented with alkyl glycerol esters and essential fatty acids. Gerontologia 1959;3: 147-152. 64.Peifer JJ, Lundberg WO, Ishio S, et al. Studies of the distributions of lipids in hypercholesteremicrats. 3. Changes in hypercholesteremia and tissue fatty acids induced by dietary fats and marine oil fractions. Arch Biochem Biophys 1965;110270. 65. Carlson WE. MSc thesis. Vancouver, Canada: University of British Columbia, 1966. 66. Bandi ZL, Mangold HK, Holmer G, et al. The alkyl and alk-1-enyl glycerols in the liver of rats fed long-chain alcohols or alkyl glycerols. FEBS Lett 1971;12217-220. 67. Baumann WJ, ed. First International Symposiumon Ether Lipids in Oncology, Gottingen, Germany, 1986. Lipids 1987;22:775-980.

Allium cepa (Onion) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 725 Chemical Composition 725

Antiasthmatic Action 726 Antitumor Effects 727 Hair Tonic Effects 727

History and Folk Use 725

Dosage 727

Pharmacology 726 Antimicrobial Activity 726 Cardiovascular Effects 726 Diabetes 726

Toxicology 727

Allium cepu (family:Amaryllidaceous or Liliaceous) Common name: onion

GENERAL DESCRIPTION Numerous forms and varieties of onion exist, as this perennial or biennial herb is cultivated worldwide. The part used is the fleshy bulb. Common varieties are white globe, yellow globe, and red globe. Onions range in size, color, and taste depending on their variety. The two general types of large, globe-shaped onions are classified as spring/summer or storage onions. The former class includes those grown in warm weather climates and mild or sweet in flavor. Included in this group are the Walla Walla, Vidalia, and Maui Sweet onion. Storage onions are grown in colder weather climates. After harvesting, they are dried out for several months to attain dry, crisp skins. They generally have a more pungent flavor and are usually named by their color: white, yellow, or red. Spanish onions fall into this classification. In addition to these large onions, there are smaller varieties such as the green onion, or scallion, and the pearl onion.

CHEMICAL COMPOSITION Onions, like garlic, contain various organic sulfur compounds: Smethylcysteine sulfoxide Trans-S(1-propenyl)cysteine sulfoxide

Summary 727

Spropylcysteine sulfoxide Dipropyl disulfide Onions also contain the enzyme alinase, which is released when the onion is cut or crushed, causing conversion of trans-S(1-propenyl) cysteine sulfoxide to the so-called lacrimatory factor (propanethialSoxide).Other constituents include the following1? Flavonoids (primarilyquercetin) Phenolic acids (e.g., caffeic, sinapic, and p-coumaric) Sterols Saponins Pectin Volatile oils

HISTORY AND FOLK USE Although not as valued a medicinal agent as garlic, onion has been used almost as widely. Like garlic (AZZium sutivum),onion has been used as an antispasmodic, carminative, dimtic, expectorant, stomachic, anthelmintic, and antiinfective agent. Externally it has been used as a rubefacient and poultice, giving relief in skin diseases and insect Onions originated in the central part of Asia, from Iran to Pakistan, and northward into the southern part of Russia. Onions have been revered throughout time not only for their culinary use but also for their therapeutic properties.As early as the sixth century, onions were used as medicine in India. Although they were popular with 725

Pharmacology of Natural Medicines

the ancient Greeks and Romans, they were often dressed with extra seasonings, since many people did not find them spicy enough. Yet it was their pungency that made onions popular among poor people throughout the world because this inexpensivevegetable could spark up meals. Onions were an indispensable vegetable in the cuisines of many European countries during the Middle Ages and later even served as a classic healthy breakfast food. Christopher Columbus brought onions to the West Indies, and then their cultivation spread throughout the Western hemisphere. Today China, India, the United States, Russia, and Spain are among the leading producers of onions. World onion production has increased dramatically, with current production around 44 million tons per year, making onions the second most important horticultural crop after tomatoes. Because of their storage characteristics and durability for shipping, onions have always been traded more widely than most vegetables. Onions are versatile, often used in many dishes, and accepted by almost all traditions and cultures?

PHARMACOLOGY Onions and garlic, due to their similar constituents, have many of the same pharmacologic effects. However, significant differences make one more advantageous than the other in certain conditions. One of the key nutritional qualities of onions is their high content of quercetin. To determine uptake as well as in vivo antioxidant effects of quercetin from onions, six healthy nonobese normocholesterolemic female volunteers participated in a randomized two-phase crossover supplementation trial to compare the antioxidant effects associated with (a) a meal of fried onions and (b) a meal of fried onions and fresh cherry tomatoes? Plasma flavonoids, lymphocyte DNA damage, plasma ascorbic acid, tocopherols and carotenoids, urinary malondialdehyde, and &hydroxy-2'deoxyguanosine were determined to assess flavonoid absorption and antioxidant efficacy. The results indicated that the flavonoid glucosides (quercetin-3-glucoside and isorhamnetin-4-glucoside) were sigruficantly elevated in plasma following ingestion of the onion meal, and the increases were associated with an increased resistance of lymphocyte DNA to DNA strand breakage. A significant decrease in the level of urinary 8-hydroxy-2'-deoxyguanosinewas evident 4 hours after ingestion of the onion meal. After the combined tomato and onion meal, only quercetin was detected in plasma. Endogenous base oxidation was decreased, but resistance to strand breakage was unchanged. No sigruficant change in the excretion of urinary malondialdehyde occurred following either meal. The conclusions from the study were that both meals-onions and onions

with tomatoes-led to transient decreases in biomarkers of oxidative stress, although the particular biomarkers affected differed. It is possible that the differences in patterns of response reflect the different uptakes of flavonoids, but the underlying mechanism is not yet understood.

Antimicrobial Activity Although onions exhibit antibacterial, antifungal, and anthelmintic activity, it is not nearly as potent as that of garlic. This suggests that garlic may be better indicated in cases of infection,23S6but onion can usually be consumed in larger quantities than garlic, which may increase the concentration of antimicrobial constituents in vivo to approximate those of garlic.

Cardiovascular Effects Like garlic, onions and onion extracts have been shown to decrease blood lipid levels, increase fibrinolysis, decrease platelet aggregation, and lower blood pressure in several clinical Onion oil, compared with garlic oil, is a stronger inhibitor of the enzymes cyclo-oxygenase and lipoxygenase, which mediate eicosanoid metabolism (prostaglandins, thromboxanes, and leukotrienes).1° This suggests that onions would also have a greater effect on inhibition of platelet aggregation and other events mediated by eicosanoids. Garlic and onion consumption is associated with lower levels of cholesterol and triglycerides, as well as an increase in fibrinolytic activity" (see Chapter 65 for details). As the quantity of onion consumed in the study cited was so much larger than that of garlic (600 g of onion/week compared with 50 g of garlic), an argument could be made that onion consumption was the major determinant.

Diabetes Onions have been shown to have sigruficant oral hypoglycemic action, comparableto that of the prescriptionoral hypoglycemic agents tolbutamide and phenf~rmin.'~J~ The active hypoglycemic principle in onions is believed to be ally1 propyl disulphide (APDS), although other constituents such as quercetin and anthocyanidin, may play a sighcant role as well. Experimental and clinical evidence suggests that APDS lowers glucose by competing with insulin (also a disulfide) for degradation sites, thereby increasing the half-life of insulin.Other mechanisms such as increased hepatic metabolism of glucose or increased insulin secretion have been proposed.

Antiasthmatic Action Onions have historically been used as antiasthmatic agents.2J Their action in asthma, as well as in other conditions associated with increased lipoxygenase derivatives (leukotrienes), such as psoriasis and atopic dermatitis, appears to be greater than that of garlic.

Allium cepa (Onion) 8 weeks of treatment with no sex difference. These results (As mentioned previously, onion oil is a much greater indicate that crude onion juice can be an effective topical inhibitor of cyclo-oxygenase and lipoxygenase.)’O The net effect is similar to that of cortisol, which inhibits all therapy for patchy alopecia areata. eicosanoid metabolism via inhibition of phospholipase. Lnhibition of leukotriene formation and onion’s quercetin DOSAGE and isothiocyanate content are probably the primary facOnions can be eaten liberally as part of a nutritious diet. tors responsible for onion’s antiasthmatic effects. These effects have been confirmed in experimental ~ t u d i e s . ’ ~ J ~Therapeutic dosages in the various forms are typically 50 to 150 g/day.

Antitumor Effects

An onion extract was found to be cytotoxic to tumor cells in vitro and to arrest tumor growth when tumor cells were implanted in rats.I6 The onion extract was shown to be unusually nontoxic, since a dose as high as 40 times that of the cytotoxic dose for the tumor cells had no adverse effect on the host. Another species, Allium ascalonicum (shallots), has been shown to exhibit significant antileukemic activity in mice.17 One human study evaluated onion consumption and stomach cancer in more than 120,000 men and women between 55 and 69 years of age. After a 3.3-year follow-up, 139 stomach cancers were diagnosed. The researchers found a strong inverse association between onion consumption and stomach cancer incidence but no association with the use of leeks or garlic.18

Hair Tonic Effects Topical application of onions has been shown to help alopecia areata-a patchy, nonscarring hair loss condition. Any hair-bearing surface may be involved in alopecia areata, and different modalities of treatment have been used to induce hair regrowth. One study compared the effectiveness of topical crude onion juice in the treatment of patchy alopecia areata in comparison with tap water.5 The patients were divided into two groups. The onion juice-treated group consisted of 23 patients, 16 males and 7 females ranging in age from 5 to 42 years old with a mean of 22.7 years. The control group consisted of 15patients, 8 males and 7 females ranging in age from 3 to 35 years old with a mean of 18.3 years. The two groups were advised to apply the treatment twice daily for two months. Regrowth of terminal coarse hairs started after 2 weeks of treatment with crude onion juice. At 4 weeks, hair regrowth was seen in 17patients (73.9%).At 6 weeks, hair regrowth was observed in a total of 20 patients (86.9%)and was sigruficantlyhigher among males (93.7”/0) compared with females (71.4%). In contrast, with tap water, hair regrowth was apparent in only 2 patients at

TOXICOLOGY Virtually no reports of toxicity have been reported. However, people with heartburn may note an aggravation of symptoms. One study evaluated symptoms of acid reflux in 16 normal subjects and 16 heartburn patients. Subjects were studied with an esophageal pH probe for 2 hours after eating a plain hamburger and a glass of ice water, then on another day after an identical meal plus a slice of raw onion. In the normal patients, ingestion of onions did not increase any of the variables measured (number of reflux episodes, pH allicin > ally1 methyl thiosulfinate > methyl ally1 thiosulfinate

Ajoene was found in oil macerates of garlic but not in fresh garlic extracts. No antiviral activity was found for alliin, deoxyalliin, diallyl disulfide, or diallyl trisulfide. Fresh garlic extract was viruadal against all viruses tested. Virucidal activity of commercial products was dependent on their preparation processes. Those producing the highest level of allicin and other thiosulfinates had the best virucidal activity." The antiviral activity of an allicin-containing garlic supplement was investigated in 146 subjects randomized to receive a placebo or an allicincontaining garlic supplement, one capsule daily, over a 12-week period.= The garlic-treatment group had significantly fewer colds than the placebo group (24 vs. 65). The placebo group, in contrast, recorded sigruficantlymore days challenged virally (366 vs. 111)and a sigruficantly longer duration of symptoms (5.01 vs. 1.52 days). This study indicates that allicin-containing garlic supplements can prevent the common cold virus.

Cardiovascular Effects Garlic appears to be an important protective factor against heart disease and strokes via its ability to affect the process of atherosclerosis at many steps. As there is substantial clinical information on garlic's beneficial effects on the cardiovascular system, the pharmacology is discussed later in the section on clinical applications.

Other Effects Antiinflammatory Effects Garlic extract has demonstrated sigruficant antiinflammatory activity in experimental models of inflammation.2J2 This activity is probably a result of garlic's inhibition of the formation of inflammatory compounds.

Immune-Enhancing Effects

Hypoglycemic Action

Extensive research has shown that garlic has many immune-potentiating properties, most of which are thought to be due to volatile factors composed of sulfurcontaining compounds: allicin, diallyl disulfide, diallyl trisulfide, and others. For example, in vitro studies with allicin have shown it to stimulate enhanced cell-mediated cytotoxicity in human peripheral mononuclear cells. In animal models, multiple administration of allicin elicits marked antitumor effects via immune-stimulatory mechanisms.26Fresh garlic, commercial products containing allicin, and aged garlic preparations have all shown these immune-enhancing properties. Garlic has been shown to enhance the pathogen-attacking activity of T cells, neutrophils, and macrophages to increase the secretion of interleukin and increase natural killer

Garlic and onions have often been used in the treatment of diabetes. Allicin has been shown to have significant hypoglycemic action. This effect is thought to be due to increased hepatic metabolism, increased release of insulin,and insulin-sparing effect.50The latter mechanism appears to be the major factor, as allicin and other sulfhydryl compounds in garlic and onions compete with insulin (also a disulfide protein) for insulin-inactivating compounds, which results in an increase in free insulin. Interestingly, when allicin was administered to groups of rats fed a high-fructose diet, the control group that was fed a diet enriched by fructose alone continued to gain weight, whereas the groups fed allicin did not.51 This study indicates that garlic may have some practical use in weight control.

Pharmacology of Natural Medicines

Miscellaneous Effects Garlic possesses diuretic, diaphoretic, emmenagogue, and expectorant action.'JO It is also a carminative, antispasmodic, and digestant, making it useful in cases of flatulence, nausea, vomiting, colic, and indigestion.'252

COMMERCIAL PREPARATIONS The modern use of garlic features primarily the use of commercial preparations designed to offer the benefits of garlic without the odor. The marketplace is swamped with garlic products, and each manufacturer claims its product is the best. However, there are vital considerations when choosing a garlic product to prescribe. First, if the primary goal is to lower cholesterol or blood pressure, as well as exert immune-enhancing or antimicrobial effect, it is important to ensure that the product provides a sufficient level of allicin. Since allicin is not actually in the product at significant levels, manufacturers often refer to the a k i n potential or allicin yield. These terms signify the amount of allicin produced when allinase is activated in the garlic tablet or powder. The next issue is not so simple to tell from a label. It involves the quality and character of the enteric coating of the tablet. In order for the allicin to be liberated within the intestinal tract, the tablet must not only be resistant to the stomach's acid, it must disintegrate rapidly when it reaches the small intestine. According to research conducted by the renowned garlic expert Dr.Larry D. Lawson and ~olleagues?~ when 24 brands of entericcoated garlic were analyzed for tablet dissolution using an approved method (U.S. Pharmacopoeia [USP] dissolution method 724A), only one brand released the amount of allicjn claimed on the label. The second-best brand released only 44% of its label claim, and 75% of the brands released less than 10%of their label claim. Failure to deliver an effective dosage of allicin most assuredly does not lower cholesterol or blood pressure. Why so many garlic products fail to deliver allicin is basically due to two major problems. First, many of the garlic products contained little allinase activity. Alliin was plentiful, but since the activity of allinase was low, the level of allicin formed was also low. Next, many tablets contained excipients (e.g., binders and fillers) that actually inhibit allinase activity. The allinase activity in 63% of the brands was less than 10% of the expected activity. The inability to release an effective dose of allicin would explain why so many studies on garlic supplements fail to show benefits in lowering cholesterol or blood pressure.54For example, studies done on one particular garlic supplement before 1993 were mostly positive. In fact, the results from these positive studies were the main reason garlic supplements have been allowed to refer to cholesterol-lowering activity in Germany and in the United States. However, most studies published since

1995 have failed to show a consistent effect in lowering cholester01.~~-~' Although the authors of the negative studies on garlic believed that the underlying reason for the results was a better-designed study, a more likely explanation is that they are due to a poorer-quality tablet. Specifically, research conducted by Lawson has shown that tablets manufactured before 1993were twice as resistant to disintegration in acid as tablets manufactured after 1993 and that the older tablets released three times the amount of allicin as the more recently manufactured tablets.53Examination of the package labels shows several changes in tablet excipients between the pre-1993 and post-1993 tablets. Again, these excipients are believed to block allinase activity. Importantly, most studies that show a positive effect of garlic and garlic preparations in reducing cholesterol and blood pressure are those using products that deliver a sufficient dosage of allicin, other garlic components such as Sallylcysteine,and garlic extracts (e.g., aged garlic extract) protect against atherosclerosis via additional mechanisms including protecting against low-density lipoprotein (LDL) oxidation and improving endothelial cell function.

CLINICAL APPLICATIONS Although garlic has long been used in infectious conditions, a use supported by its antimicrobial and immuneenhancing properties, the primary clinical use of garlic has focused on its role in cardiovascular disease. Specifically, garlic is recommended primarily for its ability to lower cholesterol and blood pressure in the attempt to reduce the risk of dying prematurely from a heart attack or stroke. In addition to the use of garlic preparations, garlic consumption as a food should be encouraged, despite its odor, in patients with high cholesterol levels and high blood pressure. Garlic and garlic preparations should also be encouraged in patients with diabetes, candidiasis, asthma, infections (particularly respiratory tract infections), and gastrointestinal complaints.

Cholesterol-Lowering Activity One of the major areas of focus in garlic's ability to offer sigruficantprotection against heart disease and strokes has been the evaluation of its ability to lower blood cholesterol levels, even in apparently healthy individual~.l,~&~~ According to the results from numerous double-blind, placebocontrolled studies in patients with initial cholesterol levels greater than 200, supplementation with commercial preparations providing a daily dose of at least 10 mg alliin or a total allicin potential of 4000 pg can lower total serum cholesterol levels by about 10% to 12Y0.In addition, LDL cholesterol decreases by about 15%,

high-density lipoprotein (HDL) cholesterol levels usually increase by about lo%, and triglyceride levels typically drop by 15%.1,53,54,6246 However, most trials not using products that can deliver this dosage of allicin fail to produce a lipid-lowering e f f e ~ t . ~ ~ - ~ ~ Although the effects of supplemental garlic preparations on cholesterol levels are modest, the combination of lowering LDL and raising HDL can greatly improve the HDL-to-LDL ratio, a sigruficant goal in the prevention of heart disease and strokes. Garlic preparations standardized for alliin content exert several other beneficial effects in preventing heart disease and strokes (discussed later). In addition to taking a garlic supplement, individuals with high cholesterol levels should eat more garlic and onions, as increased dietary intake of garlic and onion can also lower cholesterol level^.^^,^^ In a 1979 population study, researchers studied three populations of vegetarians in the Jain community in India who consumed differing amounts of garlic and o n i ~ n s . ~ Numerous ,~~ favorable effects on blood lipids, as shown in Table 65-1, were observed in the group that consumed the largest amount. Blood fibrinogen (discussed later) levels were highest in the group eating no onions or garlic. The study is quite significant because the subjects had nearly identical diets, except in garlic and onion ingestion.

Hypertension Garlic has demonstrated hypotensive action in both experimental animal models and humans with hypertension.5861*70-74 An early meta-analysis of published and unpublished randomized controlled trials of garlic preparations was conducted to determine the effect of garlic on blood pressure relative to placebo.70Eight trials (seven double-blind, one single-blind)were identified as meeting analytic criteria. A total of 415 subjects were included in the analysis. All trials used a dried garlic powder standardized to contain 1.3% alliin at a dosage of 600 to 900 mg daily (corresponding to 7.8 and 11.7 mg of alliin or the equivalent of approximately 1.8 to 2.7 g of fresh garlic daily).The meta-analysis concluded that garlic preparations designed to yield allicin can lower systolic and diastolic blood pressures over a 1-to 3-month period. The typical drop from pooled data was 11mmHg in the systolic and 5 mmHg in the diastolic.This degree of blood

Effects of garlic and onion consumption on serum lipids under carefully matched diets Garlidonion

Cholesterol

Triglyceride

None

208 mg/dl

109 mg/dl

10/200g/wk

172 mg/dl

75 mudl

501600 glwk

159 mg/dl

52 rng/dl

pressure reduction in hypertensives can be quite significant. If blood pressure-lowering effects of garlic can be maintained, the risk of stroke may be reduced by an estimated 30% to 40% and the risk of heart attack by 20% to 25%.

Platelet Aggregation Inhibition Excessive platelet aggregation is strongly linked to atherosclerosis, heart disease, and strokes. Garlic preparations standardized for alliin content, as well as garlic oil and aged-garlic extract, have all demonstrated sigruficant inhibition of platelet a g g r e g a t i ~ n . ~In~ one ~,~~-~ study, 120 patients with increased platelet aggregation were given either 900 mg/day of a dried garlic preparation containing 1.3% alliin or a placebo for 4 weeks.75 In the garlic group, spontaneous platelet aggregation disappeared, the microcirculation of the skin increased by 47.6%, plasma viscosity decreased by 3.2%, diastolic blood pressure dropped from an average of 74 to 67 mmHg, and fasting blood glucose concentration dropped from an average of 90 to 79 mg/dl. In a double-blind study of aged garlic extract (Kyolic) in normal healthy individuals, dosages between 2.4 and 7.2 g per day were shown to product a dose-dependent selective inhibition on platelet aggregation and adhesion.76 S-allylcysteineis thought to be the component responsible for this effect in aged garlic extract.78

Fibrinolytic Activity Epidemiologic studies have suggested that excessive fibrinogen formation is a major primary risk factor for cardiovascular disease.79Garlic preparations standardized for alliin content and garlic oil and both fried and raw garlic have been shown to significantly increase serum fibrinolytic activity in humans.80,81This increase occurs within the first 6 hours after ingestion and continues for up to 12 hours.

Prevention of Low-Density Lipoprotein Oxidation Growing evidence indicates that LDL oxidation plays a significant role in the development of atherosclerosis. Accordingly, substances that prevent oxidation of LDL may slow down atherosclerosis. Garlic is known to exert antioxidant activity and has recently been shown to exert sigruficant effects on preventing LDL oXidation.82m-86 In one study, healthy human volunteers given 600 mg/day of a garlic preparation providing 7.8 mg alliin for 2 weeks had a 34% lower susceptibility to lipoprotein oxidation compared with controls.82These results are significant given the short amount of time in which they were produced, coupled with the importance of reducing lipoprotein oxidation. Another study was a placebo-controlled double-blind trial of 23 subjects with coronary artery disease who had

Pharmacology of Natural Medicines

one to three major comnary arteries that were 75%blocked or higher. After the subjects ingested 300 mg of garlic powder, 2 and 4 hours after a single dose, the atherogenicity of their sera was markedly decreased. Less cholesterol accumulated and there were lower levels of oxidized LDL in human aortic smooth muscle cells cultured with patients’ sera after treatment compared with those cultured with sera obtained before administration of garlic. After 3 weeks of therapy at 300 mg, three times daily, blood serum atherogenicity was decreased twofold compared with initial levels.87 As aged garlic extract has also shown an ability to prevent LDL oxidation% it is likely that Sallylcysteine and other non-allicin components of garlic play a major role in the protection against LDL oxidation.

Other Vascular Effects Studies have also shown garlic or garlic components to exert positive effects on endothelial function, vascular reactivity, and peripheral blood

DOSAGE On the basis of extensive clinical research, a commercial garlic product should provide a daily dose equal to at least 4000 mg of fresh garlic. This dosage translates to at least 10 mg alliin or a total allicin potential of 4000 pg (Figure 65-1).

0 CH-CH-

CH2-

NH2

I1

S-

CH2-

0 CH2= CH-

CH2-

I1

I

0

I

I

CH - C - OH

Alliinase

-CH2-

NH2

I

CH - CH = CH2

Figure 65-1 Conversion of alliin to allicin.

Others are apparently unable to effectively detoxify allicin and other sulfur-containingcomponents.Prolonged feeding of large amounts of raw garlic to rats results in anemia, weight loss, and failure to grow?l Although the exact toxicity of garlic has yet to be definitively determined, side effects are rare at the dosage recommended earlier. Garlic is thought to be safe during pregnancy and breastfeeding. In fact, two studies have shown that babies like breast milk better from mothers who eat garli~?~,~~

DRUG INTERACTIONS

For the vast majority of individuals, garlic is nontoxic at the dosages commonly used. For some, however, it can irritate the digestive tract and cause heartburn.

Generally, garlic supplements should not be used in patients taking anticoagulant drugs (e.g., Coumadin) or in those scheduled for an elective surgery because of garlic’s effects on platelet aggregation. Though garlic components have shown an ability to affect cytochrome P450 enzymes, they do not appear to interfere with drug metabolism

1. Koch H, Lawson L, eds. Garlic: the science and therapeutic application of Allium sativum L. and related species, ed 2. Baltimore: Williams & Wilkins, 1996. 2. Raj KF’, Parmar RM. Garlic-condiment and medicine. Indian Drugs 1977;15:205-210. 3. Block E. The chemistry of garlic and onions. Sci Am 1985;252:114119. 4. Adetumbi MA, Lau BH. Allium sativunl (garlicha natural antibiotic. Med Hypotheses 1983;12:227-237. 5. Koch HP. Garlicin-fact or fiction? Phytother Res 1993;7278-280. 6. Hughes BG, Lawson L. Antimicrobial effects of Alliunr sativirrn L. (garlic), Allium ampeloprasum L. (elephant garlic, and Allium cepa L. (onion), garlic compounds and commercial garlic supplement products. Phytother Res 1991;5:154-158. 7. Harris JC, Cottrell SL, Plummer S, et al. Antimicrobial properties of Allium sativum (garlic). Appl Microbiol Biotechnol2001;57282-286. 8. Huddleston IF, DuFrain J, Barrons K,et al. Antibacterial substances in plants. J Am Vet Med Assoc 1944;105:394-397.

9. Cavallito CJ, Bailey JH. Allicin, the antibacterial principle of Alliiim sativiini. I. Isolation, physical properties and antibacterial action. J Am Chem Soc 1944;66:1950-1951. 10. Sharma VD, Sethi MS, Kumar A, et al. Antibacterial property of AIIiuni sativiinr Linn: in vivo and in vitro studies. Indian J Exp Biol 1977;15:466-468. 11. Elnima EI, Ahmed SA, Mekkawi AG, et al.The antimicrobial activity of garlic and onion extracts. Pharmazie 1983;38:747-748. 12. Vohora SB, W a n M, Khan JA. Medicinal uses of common Indian vegetables. Planta Med 1973;23:381-393. 13.Salih BA, Abasiyanik FM. Does regular garlic intake affect the prevalence of Helicobacter pylori in asymptomatic subjects? Saudi Med J 2003;24:842-845. 14. h e r M, Taha M, Tosson Z. The effect of aqueous garlic extract on the growth of dermatophytes. Int J Dermatol 1980;19:285-287. 15. Venugopal PV, Venugopal Tv.Antidermatophytic activity of garlic (Alliumsativum) in vitro. Int J Dermatol 1995;34:278-279.

TOXICITY

.y43y5

Allium sativum (Garlic) 16. Sandhu DK, Warraich MK, Singh S. Sensitivity of yeasts isolated from cases of vaginitis to aqueous extracts of garlic, Mykosen 1980;23:691-698. 17. Prasad G, Sharma VD. Efficacy of garlic (Alliurn sutivum) treatment against experimental candidiasis in chicks. Br Vet J 1980;136:448-451. 18. [No authors listed]. Garlic in cryptococcal meningitis: a preliminary report of 21 cases. Chin Med J 1980;93:123-126. 19. Fromtling RA, Bulmer GS. In vitro effect of aqueous extract of garlic (Allium sativum) on the growth and viability of Cryptococcus neoformans. Mycologia 1978;70:397-405. 20. Lemar KM, Turner MP, Lloyd D. Garlic (Alliurn sativurn) as an antiCandida agent: A comparison of the efficacy of fresh garlic and freeze-dried extracts. J Appl MiCrobiol2002;93:398405. 21. Kim JW, Kim YS, Kyung KH. Inhibitory activity of essential oils of garlic and onion against bacteria and yeasts. J Food Prot 2004;67 499-504. 22. Bastidas GJ. Effect of ingested garlic on Necator americanus and Ancylostorna caninurn. Am J Trop Med Hyg 1969;18:920-923. 23. Nagai K. Experimental studies on the preventive effect of garlic extract against infection with influenza virus. Jpn J Infect Dis 1973;47321-325. 24. Weber ND,Andersen DO, North JA, et al. In vitro virucidal effects of Allium sativurn (garlic) extract and compounds. Planta Med 1992;58:417-423. 25. Josling P. Preventing the common cold with a garlic supplement: a double-blind, placebo-controlled survey. Adv Ther 2001;18:189-193. 26. Patya M, Zahalka MA, Vanichkin A, et al. Allicin stimulates lymphocytes and elicits an antitumor effect: a possible role of p2lras. Int Immunol2004;16:275-281. 27. Morioka N, Sze LL, Morton DL, et al. A protein fraction from aged garlic extract enhances cytotoxicity and proliferation of human lymphocytes mediated by interleukin-2 and concanavalin A. Cancer Immunol Immunother 1993;37316-322. 28.Lau BH, Yamasaki T, Gridley DS. Garlic compounds modulate macrophage and T-lymphocyte functions. Mol Biother 1991;3 103-107. 29. Kandil OM, Abdullah TH,Elkadi A. Garlic and the immune system in humans. Its effect on natural killer cells. Fed F'roc 1987;46:441. 30. Hirao Y, Sumioka I, Nakagami S, et al. Activation of immunoresponder cells by the protein fraction from aged garlic extract. Phytother Res 1987;1:161-164. 31. Lau BH, Tadi P, Tosk J. Allium sativurn (garlic) and cancer prevention. Nutr Res 1990;10937-948. 32. Dorant E, van den Brandt PA, Goldbohm RA, et al. Garlic and its significance for the prevention of cancer in humans: a critical review. Br J Cancer 1993;67:424-429. 33. Dausch JG, Nixon DW. Garlic: a review of its relationship to malignant disease. Prev Med 1990;19346-361. 34. Thomson M, Ali M. Garlic [Alliurn sativurnl: a review of its potential use as an anti-cancer agent. Curr Cancer Drug Targets 2003;3: 67-81. 35.Khanum F, Anilakumar KR, Viswanathan KR. Anticarcinogenic properties of garlic: a review. Crit Rev Food Sci Nutr 2004;44: 479-488. 36. Choy YM, Kwok TT,Fund KP, et al. Effect of garlic, Chinese medicinal drugs and amino acids on growth of Erlich ascites tumor cells in mice. Am J Chin Med 1983;11:69-73. 37. Lin X, Liu J, Milner J. Dietary garlic powder suppresses in vivo formation of DNA adducts induced by N-nitroso compounds in liver and mammary tissues. FASEB J 1992;6A1392. 38. Nagabhushan M, Line D, Polverini F'J, et al. Anticarcinogenic action of diallyl sulfide in hamster buccal pouch and forestomach. Cancer Lett 1992;66:207-216. 39. Meng CL, Shyu KW. Inhibition of experimental carcinogenesis by painting with garlic extract. Nutr Cancer 1990;14207-217.

40. Niukian K, Schwartz J, Shklar G. Effects of onion extract on the development of hamster buccal pouch carcinomas as expressed in tumor burden. Nutr Cancer 1987;9:171-176. 41. Wargovich MJ. Diallyl sulfide, a flavor component of garlic (Allicrrn sativum), inhibits dimethylhydrazine-induced colon cancer. Carcinogenesis 1987;3487-489. 42. Belman S . Onion and garlic oils inhibit tumor promotion. Carcinogenesis 1983;41063-1065. 43. Weisberger AS, Pensky J. Tumor inhibition by a sulfhydryl-blocking agent related to an adive principle of garlic fANium sativum). Cancer Res 1958;18:1301-1308. 44. Kroening F. Garlic as an inhibitor for spontaneous tumors in mice. Acta Unio Int Contra Can1964;20855-856. 45. Mei X, Lin X, Liu JZ, et al. The blocking effect of garlic on the formation of N-nitrosoproline in the human body. Acta Nutrimenta Sinica 1989;11:144-145. 46. Xing M, Wang ML, Xu HX, et al. Garlic and gastric cancer-the effect of garlic on nitrite and nitrate in gastric juice. Acta Nutrimenta S i i c a 1982;453-55. 47. Sundaresan S, Subramanian P. Sallylcystehe inhibits circulatory lipid peroxidation and promotes antioxidants in N-nitrosodiethylamine-induced carcinogenesis. Pol J Pharmacol 2003;55: 37-42. 48. Ledezma E, Apitz-Castro R, Cardier J. Apoptotic and anti-adhesion effect of ajoene, a garlic derived compound, on the murine melanoma B16F10 cells: possible role of caspase-3 and the alpha(4)beta(l) integrin. Cancer Lett 2004;206:35-41. 49. Munday R, Munday CM. Induction of phase II enzymes by aliphatic sulfides derived from garlic and onions: an overview. Methods Enzymol2004;382449-456. 50. Bever BO, Zahnd GR. Plants with oral hypoglycemic action. Q J Crude Drug Res 1979;17139-196. 51. Elkayam A, Mirelman D, Peleg E, et al. The effects of allicin on weight in fructose-induced hyperinsulinemic, hyperlipidemic, hypertensive rats. Am J Hypertens 2003;161053-1056. 52. Barowsky H, Boyd LJ. The use of garlic (Allistan) in gastrointestinal disturbances. Rev Gastroenterol1944;11:22-26. 53. Lawson LD, Wang ZJ, Papadimitriou D. Allicin release under simulated gastrointestinalconditions from garlic powder tablets employed in clinical trials on serum cholesterol. Planta Medica 2001;6713-18. 54. Lawson LD, Wang ZJ. Tablet quality: a major problem in clinical trials with garlic supplements. Forsch Komplementarmed Klass Naturheilkd 2000;745. 55. Banerjee SK, Maulik SK. Effect of garlic on cardiovascular disorders: a review. Nutr J 2002;1:4. 56. Alder R, Lookinland S, Berry JA, et al. A systematic review of the effectiveness of garlic as an anti-hyperlipidemic agent. J Am Acad Nurse Pract 2003;15120-129. 57. Stevinson C, Pittler MH, Emst E. Garlic for treating hypercholesterolemia: a meta-analysis of randomized clinical trials. Ann Intern Med 2000;133:420-429. 58. Ali M, Thomson M. Consumption of a garlic clove a day could be beneficial in preventing thrombosis. Prostaglandins Leukot Essent Fatty Acids 199553211-212. 59. Lau BH, Adetumbi MA, Sanchez A. Alliurn sativum (garlic) and atherosclerosis. A review. Nutr Res 19833:119-128. 60. Kendler BS. Garlic (Alliurn sativurn) and onion (Allium cepd: a review of their relationship to cardiovascular disease. Prev Med 1987;16670-685. 61. Ernst E. Cardiovascular effects of garlic (Alliurn sativum): a review. Pharmatherapeutica 1987;583-89. 62. Kleijnen J, Knipschild P, ter Riet G. Garlic, onions and cardiovascular risk factors. A review of the evidence from human experiments with emphasis on commercially available preparations. Br J Clin Pharmacol1989;28535-544.

Pharmacology of Natural Medicines 63. Warshafsky S, Kamer RS, Sivak SL. Effect of garlic on total serum cholesterol. A meta-analysis. Ann Intern Med 1993;119599-605. 64. Jain AK, Vargas R, Gotzkowsky S, et al. Can garlic reduce levels of serum lipids? A controlled clinical study. Am J Med 1993;94 632-635. 65. Rotzsch W, Richter V, Rassoul F, et al. [Postprandial lipemia under treatment with AIIiurn sativurn. Controlled double-blind study of subjects with reduced HDLZ-cholesterol.] Arzneimittelforschung 1992;42:1223-1227. 66. Mader FH. Treatment of hyperlipidaemia with garlic-powder tablets. Evidence from the German Association of General Practitioners’ multicentric placebo-controlled double-blind study. Arzneimittelforschunng1990;40:1111-1116. 67. Bordia A. Effect of garlic on blood lipids in patients with coronary heart disease. Am J Clin Nutr 1981;34:2100-2103. 68. Sainani GS, Desai DB, Gorhe NH, et al. Effect of dietary garlic and onion on serum lipid profile in Jain community. Indian J Med Res 1979;69:776-780. 69. Sainani GS, Desai DB, Gorhe NH, et al. Dietary garlic, onion and some coagulation parameters in Jain community. J Assoc Physicians India 1979;27707-712. 70. Silagy CA, Neil HA. A meta-analysis of the effect of garlic on blood pressure. J Hypertens 1994;12:463-468. 71. Petkov V. Plants and hypotensive, antiatheromatous and coronarodilatating action. Am J Chin Med 1979;7197-236. 72. Foushee DB, Ruffin J, Banerjee U. Garlic as a natural agent for the treatment of hypertension: a preliminary report. Cytobios 1982;

34:145-152. 73. Al-Qattan KK, Khan I, Alnaqeeb MA, et al. Mechanism of garlic (Allium sativum) induced reduction of hypertension in 2K-1C rats: a possible mediation of Na/H exchanger isoform-1. Prostaglandins Leukot Essent Fatty Acids 2003;69:217-222. 74. Sharifi AM, Darabi R, Akbarloo N. Investigation of antihypertensive mechanism of garlic in 2K1C hypertensive rat.

J Ethnopharmacol2003;86.219-224. 75. f i e w e t t e r H, Jung F, Pindur G, et al. Effect of garlic on thrombocyte aggregation, microcirculation, and other risk factors. Int J Clin Pharmacol Ther Toxicol 1991;29:151-155. 76. Steiner M, Li W. Aged garlic extract, a modulator of cardiovascular risk factors: a dose-finding study on the effects of AGE on platelet functions. J Nutr 2001;131:98OS984S. 77. Rahman K, Billington D. Dietary supplementation with aged garlic extract inhibits ADP-induced platelet aggregation in humans. J Nutr 2000;1302662-2665. 78. Kodera Y, Suzuki A, Imada 0,et al. Physical, chemical, and biological properties of s-allylcysteine, an amino acid derived from garlic. J Agric Food Chem 200250622-632. 79. Emst E. Fibrinogen: an important risk factor for atherothrombotic diseases. Ann Med 1994;26:15-22.

80. Chutani SK, Bordia A. The effect of fried versus raw garlic on fibrinolytic activity in man. Atherosclerosis 1981;38:417-421. 81. Legnani C, Frascaro M, Guazzaloca G, et al. Effects of dried garlic preparation on fibrinolysis and platelet aggregation in healthy subjects. Arzneimittelforschung 1993;43119-122. 82. Phelps S, Harris WS. Garlic supplementation and lipoprotein oxidation susceptibility. Lipids 1993;28:475-477. 83. Huang CN, Horng JS, Yin MC. Antioxidative and antiglycative effects of six organosulfur compounds in low-density lipoprotein and plasma. J Agric Food Chem 2004;52:36743678. 84. Durak I, Kavutcu M, Aytac 8, et al. Effects of garlic extract consumption on blood lipid and oxidant/antioxidant parameters in humans with high blood cholesterol. J Nutr Biochem 2004;15 373-377. 85. Banerjee SK, Mukherjee PK, Maulik SK. Garlic as an antioxidant: the good, the bad and the ugly. Phytother Res 2003;1797-106. 86. Dillon SA, Burmi RS, Lowe GM, Billington D, et al. Antioxidant properties of aged garlic extract: an in vitro study incorporating human low density lipoprotein. Life Sci 2003;72:1583-1594. 87. Orekhov AN, Tertov W, Sobenin IA, et al. Garlic powder tablets reduce atherogenicity of low density lipoprotein: a placebocontrolled double-blind study. Nutr Metab Cardiovasc Dis 1996; 6 21-31. 88. Ganado P, Sanz M, Padilla E, Tejerina T. An in vitro study of different extracts and fractions of Alliurn sativum (garlic): vascular reactivity. J Pharmacol Sci 2004;94:434-442. 89. Anim-Nyame N, Sooranna SR, Johnson MR, et al. Garlic supplementation increases peripheral blood flow: a role for interleukin-6? J Nutr Biochem 2004;15:30-36. 90. Baluchnejadmojarad T, Roghani M. Endothelium-dependent and -independent effect of aqueous extract of garlic on vascular reactivity on diabetic rats. Fitoterapia 2003;74630-637. 91. Nakagawa S, Masamoto K, Sumiyoshi H, et al. [Effect of raw and extracted-aged garlic juice on growth of young rats and their organs after peroral administration (author’s trans).] J Toxicol Sci 1980;5:91-112. 92. Menneua JA, Beauchamp GK. Maternal diet alters the sensory qualities of human milk and the nursling‘s behavior. Pediatrics 1991;88:737-44. 93. Mennella JA, Beauchamp GK. The effects of repeated exposure to garlic-flavored milk on the nursling’s behavior. Pediatr Res 1993; 342305-808. 94. Gallicano K, Foster 8, Choudhri S. Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers. Br J Clin Pharmacol2003;55:199-202. 95. Markowitz JS, Devane CL, Chavin KD, et al. Effects of garlic (Alliurn sutivurn L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers. Clin Pharmacol Ther 2003; 7 4 170-177.

Aloe Vera (Cape Aloe) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 737 Aloe Vera Terminology 737 Chemical Composition 738 Anthraquinones 738 Saccharides 738 Prostanoids 738 Superoxide Dismutase 738 Other Constituents 738

Clinical Applications 741 Burns, Frostbite, and Other Tissue Damage 741 Radiation Burns 742 Psoriasis 743 Gastric Ulcers 743 Acquired immunodeficiency Syndrome 743 Asthma 744 Diabetes 744 Contraception 745 Cancer Prevention 745

History and Folk Use 738 Dosage 745 Pharmacology 739 Gastrointestinal Effects 739 Immune-Enhancing and Antimicrobial Activity 740 immunologic Effects 740 Antiinflammatory Activity 741 Other Effects 741

Aloe veru (family: Lilaceous) Common name: cape aloe

GENERAL DESCRIPTION More than 300 species of aloe plants exist, but the most popular medicinal variety is currently Aloe veru. The nomenclature of A. veru has been somewhat confused, as the plant has been known by various names, most notably Aloe burbudensis and Aloe vulguri. The geographic origination of the plant is unclear. Historical records indicate that it may have originated from Egypt or the Middle East. Aloe has been introduced and naturalized throughout most of the tropics and warmer regions of the world including the Caribbean, southern United States, Mexico, Latin America, the Middle East, India, and Asia.' A. veru is a perennial plant with yellow flowers and tough fleshy triangular or spearlike leaves arising in a rosette configuration. The leaves are up to 20 inches long and 5 inches across at the base, tapering to a point. There may be as many as 30 leaves per plant. The margins of the

Toxicology 745 Drug Interactions 745

leaf are characterized by sawlike teeth. Inside, the meaty leaf is filled with gel that arises from a clear, central mucilaginous pulp. Mature aloe measures 1.5to 4 feet long and has a base of 3 inches or greater in diameter. The leaf is composed of three distinct layers: an outer layer of tough tissue; a corrugated lining just beneath the outer layer; and the major portion of the leaf, the inner layer consisting of parenchymal cells containing large vacuoles of a semisolid, gelatinous, transparent gel. The bitter latex of the corrugated layer protects the plants from predators. Should an animal bite the leaf, the sap causes irritation. The dried latex (juice) derived from the corrugated layer is the source of the laxative properties of aloe. The parenchymal tissue or gel is the portion of the aloe used in other applications.*

Aloe Vera Terminology A. veru gel-naturally occurring, undiluted parenchymal tissue obtained from the decorticated leaves of A. Vera 737

A. veru concentrate-A. veru gel from which the water has been removed A. veru juice-an ingestible product containing a minimum of 50% A. v e r ~gel A. veru latex-the bitter yellow liquid derived from the pericyclic tubules of the rind of A. vmu, the primary constituent of which is aloin

CHEMICAL COMPOSITION The main feature of all aloe plant portions is a high water content. Aloe gel contains 99% water, while the skin and fillet fractions contain 90% and 98% water, respectively. A. veru contains numerous compounds possessing biologic activity. Although many botanical medicines suffer from substantial geographic variation in content, commercial aloe is quite consistent. One study found that the composition of the major compounds is remarkably invariable, with aloeresin A, aloesin, and aloin (both epimers A and B) contributing between 70% and 97%of total dry weight in a ratio of approximately 4:3:2,respectively. Minor compounds were less evenly distributed, with aloinoside A and aloinoside B found in higher concentrations in Western countries. The aloin content of the exudate did vary, but there were no distinct geographic discontin~ities.~

Anthraquinones In 1851the cathartic action of aloe was discovered to be due to aloin, a lemon yellow powder formed from drying of the bitter latex (Figure 66-1). From this material several anthracenes have been isolated, the major anthraquinone being barbaloin. Barbaloin and aloin are often referred to synonymously. Although aloe contains other anthraquinone derivatives, including the anthracene known as aloe-emodin, barbaloin is considered the most potent cathartic. As a whole, the anthraquinone compounds are water-soluble glycosides easily separated from the water-insoluble resinous

Saccharides Recent research on A. veru has focused on the glycoprotein, mucopolysaccharide, and polysaccharide constituents. Aloe contains the polysaccharides galactose, xylose, arabinose, and acetylated mannose. The latter, similar to guar and locust bean, has received considerable clinical research attention as an antiviral and immunopotentiating agent, especially in the treatment of acquired immunodeficiency syndrome (AIDS). Acemannan, a water-soluble, long-chain polydispersoid beta-(1,4)linked mannan polymer interspersed with 0-acetyl groups found mainly in aloe gel, is discussed later?

Prostanoids Several prostanoid compounds have been discovered in A. veru extracts? The conversion of essential fatty acids to prostanoids by the enzyme cyclooxygenase in a plant such as A. veru is rare. The major unsaturated fatty acid in the plant is gamma-linolenic acid (C18:3), which can be converted to icosatrienoic acid, the precursor to prostaglandins of the 1series. The 1series prostaglandins are known to exert more favorable effects on inflammation, allergy, platelet aggregation, and wound healing. The presence of gamma-linoleic acid or prostaglandins, or both, in a stable medium, along with inhibitors of thromboxane synthesis, may be another important chemical characteristic of aloe responsible for its antiinflammatory and wound-healing effects.

Superoxide Dismutase Extracts from the parenchymatous leaf gel and the rind of aloe (A. burbadensis Miller) have been shown to contain seven electrophoretically identifiable superoxide dismutases (SODs). Two of these seven are mangano SODs, while the other five activities are cupro-zinc SODS.~

Other Constituents Other biologic active compounds found in A. ueru include the following:

A serine carboxypeptidase Salicylates Minerals Vitamins Sterols Amino acids Box 66-1 provides a partial listing of the remarkably diverse range of compounds isolated from A. ~eru.2-~

HISTORY AND FOLK USE H

OH

Figure 66-1

Aloin and aloe-erncdin.

A. Vera has a storied history of use. Mesopotamian clay tablets dated 1750 EKindicate that A. veru was being used for medicinal purposes. Egyptian records from 550 BC

Aloe Vera (Cape Aloe)

Anthraquinones:Aloin, barbaloin, isobarbaloin, anthranol, aloetic acid, anthracene, ester of cinnamic acid, aloe-emodin, emodin, chrysophanic acid, ethereal oil, resistannol Saccharides: Cellulose, glucose, mannose, L-rhamnose, aldopentose Prostanoids:Gamma-linolenic acid Enzymes: Oxidase, amylase, catalase, lipase, alkaline phosphatase Amino acids: Lysine, threonine, valine, methionine, leucine, isoleucine, phenylalanine Vitamins: Vitamins B,, BPIB6, C, and E,folic acid, choline, betacarotene Minerals: Calcium, sodium, manganese, magnesium, zinc, copper, chromium Miscellaneous:Cholesterol, triglycerides, steroids, uric acid, lignins, beta-sitosterol. gibberellin, salicylic acid Modified from Shelton RM. Int J Dermatol 1991;30:679-683

also mentioned aloe for infections of the skin. The ancient Greeks were also aware of aloe's medicinal effects, as both Pliny (23-79 AD) and Dioscorides (first century AD) wrote of aloe's ability to treat wounds and heal infections of the skin.A. veru is still widely used in many traditional systems of medicine. In India, for example, in addition to external applications, aloe (whole leaves, the exudate, and the fresh gel) is used as a cathartic, stomachic, and anthelmintic. A. veru has been adopted into the materia medicas by many cultures of the world.' In the United States, the history of aloe can be traced as far back as the United States Phmcopot?iu of 1820, where a number of aloe preparations were described. Most of these preparations were designed to take advantage of aloe's laxative effects. By the early 1900s, more than 27 different aloe preparations were in popular use. In 1920 aloe began being cultivated for pharmaceutic use? A major development in the modern use of aloe occurred in 1935 when a group of physicians successfully used the fresh juice to treat a patient suffering from facial bums due to radiographs? The relief offered by aloe in the topical treatment of burns, minor irritations, skin ulcers, and other skin disorders is a major reason why companies supplying dematologic and cosmetic products have incorporated aloe into many of their formulations. Although more and more of aloe's medicinal effects are being confirmed, it is still predominantly administered without direct medical supervision. Therefore the history and folk use of aloe are continuing to evolve.

PHARMACOLOGY The pharmacology of aloe is surprisingly d i v e r s e laxative, immune potentiation, antimicrobial and wound-healing activities help explain its wide-ranging folk and clinical applications.

Gastrointestinal Effects Laxative Effects Although physicians have prescribed the whole aloe leaf as a cathartic for more than 2000 years, it was not until 1851 that the active principle aloin was discovered.' In small doses, aloin acts as a tonic to the digestive system, giving tone to the intestinal muscle. At higher dosages, it becomes a strong purgative. Its actions are most obvious on the large intestine, where it increases colonic secretions and peristaltic contractions. In combination with strychnine and belladonna, aloin became one of the most popular laxativesfor chronic constipation for many years. Since aloin often causes painful contractions, other anthraquinone laxatives like cascara and senna are now much more popular.'OJ1 A substantial amount of research activity continues in an effort to understand the laxative effects of aloe. Research using the rat large intestine shows that the increase in water content of the large intestine induced by barbaloin precedes the stimulation of peristalsis, attended by diarrhea. Therefore it is suggested that the increase in water content is a more important factor than the stimulation of peristalsis in the diarrhea induced by barbaloin.I2 Further studies by the same researchers suggest that aloe-emodin-9-anthrone (AE:anthrone) produced from barbaloin in the rat large intestine may be the actual chemical mediator of this effect. AE-anthrone not only caused an increase in the intestinal water content but also stimulated mucus ~ecreti0n.l~

Bowel Detoxification In 1985 Bland14 reported the effect of orally consumed A. oeru juice on urinary indican, gastrointestinal pH, stool culture, and stool specific gravity in a semicontrolled study of 10 (5 men and 5 women) healthy human subjects.14Urinary indican (see Chapter 32) is used as an indicator of the degree to which either dietary protein is malabsorbed or intestinal bacteria are engaged in putrefactive processes. After a full week of drinking 6 oz. of A. veru juice three times daily, urinary indican levels decreased one full unit. This suggests that regular A. veru juice consumption can lead to improved protein digestion and assimilation or reduced bacterial putrefaction, or both.

Inhibition of Gastric Acid Secretion With Heidelberg gastric analysis, A. vem juice was shown to increase gastric pH by an average of 1.88 units. This supports the findings of other researchers that A. veru gel can inhibit the secretion of hydrochloric acid. The Heidelberg test also demonstrated that A. veru juice can slow down gastric emptying, possibly leading to improved digestion. Six of the 10 subjects showed marked alterations in stool cultures after the week-long study. This implies that

Pharmacology of Natural Medicines

A. vma juice may exert some bacteriostatic or fungistatic activity.In the four subjectswith positive cultures for yeast, theR was a reduction in the number of yeast colonies. Stool specific gravity was reduced after the week of drinking A. Vera juice. This implies improved water retention, yet none of the subjects complained of diarrhea or loose stools.

IMMUNE-ENHANCING AND ANTIMICROBIAL ACTIVITY Immunologic Effects Antibacterial and Antifungal Activity Aloe has demonstrated activity against many common bacteria and fungiin several studies. In a detailed review of these studies, the researchers assayed the antimicrobial properties of an A. uera extract and reviewed the work of others.16-18Both mean inhibitory and mean lethal concentrationswere determined and compared with silver sulfadiazine, a potent antiseptic used in the treatment of extensive bums. As shown in Table 66-1,15 the antimicrobial effects of A. Vera compare quite favorably with those of silver sulfadiazine. A 60% A. Vera extract was found to be bactericidal against Pseudomonas aeruginosa, Klebsiella pneurnoniae, Serra tia marcescens, Citrobacter spp., Enterobacter cloacae, Streptococcus pyogenes, and Streptococcus ugaluctiae. Concentrations of 70% aloe were bactericidal for Staphylococcus uureus, 80% for E . coli, and 90% for Streptococcus faecalis and Candida albicans. Organisms inhibited in other studies include Mycobacferiurn tuberculosis, Trichophyton spp., and Bacillus s ~ b t i l i s . * ,The ~ , ~ antimicrobial activity against common

Organism

Gram-Negative Escherichia coli Enterobacter cloacae Klebsiella pneumoniae Pseudomonas aeruginosa Gram-Positive Staphylocmcus aureus Streptococcus pyogenes Streptococcus agalactiae Streptococcus faecalis Bacillus subtilis

Aloe Vera

AaSD

16

12

14

12

14

6

17

12

18

12

16

12

16

12

6

11

19

14

Modiied from Robson MC, Heggers JP, Hagstrom WJ. J Burn Care Rehabil1982; 3:157-162. Inhibition zones measured in millimeters.

skin pathogens of A. Vera gel in a cream base was shown to be slightly better than silver sulfadiazine in agar well diffusion studies.lS

Antiviral Effects Acemannan (acetylated mannose) in injectable form has been approved for veterinary use in fibrosarcomas and feline leukemia. Its action in feline leukemia is quite impressive. Feline leukemia, like AIDS, is caused by a retrovirus (feline leukemia virus, or FeLV). The virus is so lethal that once cats develop clinical symptoms, they are usually euthanized. Typically more than 70% of cats die within 8 weeks of the onset of clinical signs. In a study of 44 cats with clinically confirmed feline leukemia, acemannan was injected (2 mg/kg) weekly for 6 weeks and the cats reexamined 6 weeks after termination of i~eatment.'~ At the end of the 12-week study, 71% of the cats were alive and in good health. Acemannan has demonstrated significant antiviral activity against several viruses including feline AIDS, influenza human immunodeficiency virus type 1(W-l), virus, and measles virus.2°-z2

Immune Enhancement Acemannan is a potent i m m u n o s t i m ~ l a n t . ~Among ~,~-~ the effects noted for acemannan are the enhancement of macrophage release of interleukin (1L)-1-alpha,cytokines, tumor necrosis factor, and nitric oxide release, as well as phagocytosis and nonspecific cytotoxicity. Acemannan also enhances T-cell function and interferon production, although these actions may also be due to enhanced macrophage function. Macrophage production of cytokines IL-6 and tumor necrosis factor alpha were dependent on the dose of acemannan provided. These effects can be substantial. For example, in one study, acemannan has been shown to enhance the macrophage respiratory burst (twofold increase above the media controls), phagocytosis (45% compared with 25% in controls), and killing of C . albicuns (38% killing of C . albicans compared with 0% to 5% killing in

Hematopoietic Effects Several complex carbohydrates have been found to significantly stimulate hematopoiesis. CARN 750, a polydispersed beta-(1,4)-linked acetylated mannan isolated from the A. Vera plant, has been shown to have hemato-augmenting properties. Subcutaneous injections of 1 mg/mouse of CARN 750 optimally increased hematopoietic progenitors, measured as IL-3-supported colony-forming units, culture (CFU-C) and high proliferative potential colony-forming cell (HPP-CFC) assays in the spleen. Providing 2 mg/animal of CARN 750 optimally increased bone marrow cellularity, frequency, and absolute number of HPP-CFCs and CFU-Cs. The hematopoietic activity of CARN 750 increased with

Aloe Vera (Cape Aloe) ~

the frequency of administration. The greatest increase in activity in mice myelosuppressed with radiati~n.~'

Antiinflammatory Activity A. veru has been shown to exert a number of antiinflammatory actions, including blocking of the generation of inflammatory mediators like thromboxanes and bradykinin, reducing neutrophil infiltration during inflammation, and reducing edema.2,45J5*2831 Several compounds in aloe are responsible for these actions. The most important are glycoproteins, which inhibit and actually break down bradykinin, a major mediator of pain and inflammation; various anthraquinones; and salicylates. These antiinflammatory substances may be of significance in both topical (discussed later) and oral applications. One comprehensive study evaluated the effects of aqueous, chloroform, and ethanol extracts of A. veru gel on carrageenan-induced edema in the rat paw and neutrophil migration into the peritoneal cavity stimulated by carrageenan. Also evaluated was the capacity of the aqueous extract to inhibit cyclooxygenase activity. The aqueous and chloroform extracts decreased the edema induced in the hind paw and the number of neutrophils migrating into the peritoneal cavity, whereas the ethanol extract only decreased the number of neutrophils. The aqueous extract was also found to inhibit prostaglandin E2 production from arachidonic acid, demonstrating an inhibitory action on cyclooxygenase.The aqueous extract contained anthraglycosides, reductor sugars, and cardiotonic glycosides, while the ethanol extract contained saponins, carbohydrates, naphthoquinone, sterols, triterpenoids, and anthraquinones. The chloroform extract contained sterols and anthraquinones?2 Another useful aspect of aloe is its ability to inhibit lipid peroxidation and scavenge free radicals. One study measured the activity of seven anthraquinones and four anthrones against nonenzymatic and enzymatic lipid peroxidation in vitro and their ability to scavenge free radicals. Using rat hepatocytes exposed to strong oxidizing agents, dithranol and anthrone provided the strongest inhibition of nonenzymatic peroxidation. Rhein anthrone and aloe-emodin showed the highest inhibitory activity against peroxidation of linoleic acid catalyzed by lipoxygenase. Anthrone, dithranol, and rhein anthrone were the most effective free radical

scavenger^.^^

Other Effects Wound Healing The topical effects of A. vmu appear to be due to a combination of enhancement of wound healing along with antiinflammatory, moisturizing, emollient, and antimicrobial acti0ns?,~5J~- A. veru contains a number of compounds necessary for wound healing, including

vitamin C, vitamin E, and zinc. Unlike many other antiinflammatory substances, A. vera has been shown to stimulate fibroblast and connective tissue formation, thereby promoting wound repair. Finally, aloe appears to stimulate the epidermal growth and repair process including increasing the manufacture of supportive glycosaminoglycans, presumably due to its polysaccharides.4l Mannose-6-phosphate, the major sugar in the A. veru gel, may be its most active growth substance." Another interesting effect of aloe in wound healing is its ability to counteract the wound healing suppression effects of cortisone. In one study, A. veru at doses of 100 and 300 mg/kg daily for 4 days blocked the wound healing suppression of hydrocortisone acetate up to 100% using the wound tensile strength assay. The authors suggested this response was because of the growth factors present in A. vern masking the wound-healing inhibitors.43

Alcohol Detoxification Oral administration of aloin (300 mg/kg) given 12 hours before administration of alcohol (3 g/kg) significantly decreases the blood alcohol area under the curve by a remarkable 40%. This suggests an increase in the rate of blood alcohol elimination from the body of 45% to 50%. Analysis of hepatic triglyceride (TG) levels revealed that both ethanol and aloin given alone significantly increased the TG levels in a comparable manner. However, the level obtained by the combined treatment of aloin and ethanol was not statistically different from that produced by either treatment alone. The levels of serum L-aspartate:2-oxoglutarate aminotransferase (AST) and L-alanine:2-oxoglutarateaminotransferase (ALT) activities were not increased by acute alcohol intoxication, aloin alone, or the combined treatment of alcohol and a l o h U

CLINICAL APPLICATIONS Burns, Frostbite, and Other Tissue Damage Despite growing consumer awareness of A. veru's soothing effects on burns and wound healing during the past 40 years, few human studies have been conducted. Virtually all of the studies support the topical use of A. veru gel, especially in minor bums or skin inflammation? Recent research has supported its use for even more severe tissue damage. Although limited, the human research has been promising. For example, one study found A. veru gel quite successful in three patients with chronic leg ulcers of 5,7, and 15 years' duration." The gel was applied to the ulcers on gauze bandages. Rapid reduction in ulcer size was noted in all three subjects, and complete resolution occurred in two. Encouraging results were also reported for acne and seborrhea.

Pharmacology of Natural Medicines

In a study of 27 patients with a partial-thickness bum wound, treatment with A. veru gel was compared with Vaseline gauze. The average time of healing in the aloe gel area was a statistically sigruficant and dramatic 1 week shorter: 11.9 days compared with 18.2 days for the Vaseline gauze-treated wound. Histologic evaluation showed early epithelialization in the A. veru geltreated area.& Another study compared the therapeutic effects of systemic pentoxlfylline with topical A. veru cream in the treatment of frostbite. The frostbitten ears of 10 New Zealand white rabbits were assigned to one of four treatment groups: untreated controls, those treated with A. veru cream, those treated with pentoxifylline, and those treated with A. veru cream and pentoxifylline. The control group had a 6% tissue survival. Tissue survival was notably improved with pentoxlfylline (20%),better with A. uem cream (24%), and best with the combination therapy (30%)!’ Aloe appears to be effective even in particularly severe tissue injuries, such as those seen in necrotizing fasciitis. Necrotizing fasciitis usually manifests as a lowgrade cellulitis that quickly deteriorates to a limb- and life-threatening soft tissue infection. Immediate surgical debridement is essential, followed by aggressive wound management. An interesting report describes excellent results in two cases. Case 1 was a 72-year-old female who, upon presenting to the emergency department with a “sore bottom,” was diagnosed with five problems:

Radiation Burns

Research into the topical applications of A. veru gel began in the 1930s in the treatment of radiation burns. During the 1930s, radiographs were used therapeutically for cancer, eczema and other skin complaints, and as a depilatory agent. In 1935 Collins and Collins9 reported the success of A. veru gel in a single case, a woman with a patch of severe x-ray dermatitis on her forehead. The woman had tried various medical treatments for 8 months, only to have her condition worsen. The Collinses were going to perform a skin graft, but as a temporary measure applied a preparation of fresh whole A. veru leaves to reduce the itching. The result was that “Twenty-four hours later she reported that the sensation of itching and burning had entirely subsided,” and by 5 weeks “there was complete regeneration of the skin of the forehead and scalp, new hair growth, complete restoration of sensation, and absence of scar.” Five months after treatment was started there was complete healing. Following case reports, although not as positive as this initial study clearly indicated that A. veru was effective in some cases. Until the 1940s most of the studies on aloe were reported case histories? In order to substantiate these case studies, animal studies began to appear in the literature. Rowe and colleagues39performed several studies in rats with radiation-induced ulcers and determined that fresh aloe pulp was effective, while dried aloe powder was Anal-rectal abscess In 1953 Lushbaugh and Hale,@working for the U.S. Foumier’s gangrene Atomic Energy Commission, produced one of the most Ulcerative enterocolitis convincing studies of the efficacy of A. vera gel. Twenty Chronic blood loss/anemia albino rats were exposed to beta-radiation, and different Protein caloric malnutrition treatments were used on quadrants of the affected area of each animal. The treatments used were fresh A. veru After debridement, her anal-rectal wound extended leaf, a commercial A. veru ointment, application of a dry from the labia to the left buttock. Care was multidiscipligauze bandage, and an untreated control. Both fresh nary and included applying a water-based aloe gel and A. veru and the A. veru ointment produced clear improvesaline-soaked gauze twice a day. After 45 days, the ments. At the end of 2 months, the A. veru-treated areas wound exhibited a pink base with granulation tissue were completely healed, while the other two areas had and contraction of the wound edges. not yet healed at the end of 4 months. Case 2 was a 48-year-old male with seroma of the left Recently, a large, placebo-controlled, double-blind leg secondary to a crush injury. Within 3 days he develstudy cast doubt on the efficacy of aloe for severe radiaoped deep vein thrombosis in that leg, as well as two tion bums. Three phase III randomized trials were large seroma cavities on either side of the thigh. Care reported in this study. The first one was double-blind, included packing with aloe gel and saline-soaked used a placebo gel, and involved 194 women receiving sponges. Two weeks after admission, the anterior breast or chest wall irradiation. The second trial randomwound was covered with a split-thickness skin graft, ized 108 such patients to A. veru gel versus no treatment. while partial closure of the lateral cavity was attempted Skin dermatitis was scored weekly during both trials unsuccessfully with retention sutures. After 5 weeks, healing was complete for the anterior wound and 95% both by patients and by health care providers. Skin dermatitis scores were virtually identical on both treatment complete for the posterior wound.@ arms during both trialsw The aim of the study was to see A double-blind study showed that patients with presif topical A. veru gel would be beneficial in reducing the sure sores responded equally to an acemannan hydrogel wound dressing or a moist saline gauze wound dre~ing!~ identified skin side effects of radiation therapy including

erythema, pain, itching, dry desquamation, and moist desquamation when compared with aqueous cream. The secondary aim was to assess the effect of other factors known to predict severity of radiation skin reaction (i.e., breast size, smoking habit, and one or more drainages of lymphocele after surgery) on other skin side effects. The third study involved more than 225 patients with breast cancer after lumpectomy or partial mastectomy who required a course of radiation therapy using tangential fields. Like the other two studies, A. veru gel did not significantly reduce radiation-induced skin side effects.5l These surprising results might be explained by another recent study that compared the efficacy of commercially available gels with an acemannan-rich extract from aloe leaves in the treatment of irradiated mice. Male C3H mice received graded single doses of gamma radiation ranging from 30 to 47.5 Gy to the right leg. In most experiments the gel was applied daily, beginning immediately after irradiation. To determine the timing of application for the best effect, gel was applied beginning on days -7,0, or +7 relative to the day of irradiation (day 0) and continuing for 1, 2, 3, 4, or 5 weeks. The right inner thigh of each mouse was scored on a scale of 0 to 3.5 for severity of radiation reaction from the seventh to thirty-fifth day after irradiation. Dose-response curves were obtained by plotting the percentage of mice that reached or exceeded a given peak skin reaction as a function of dose. The researchers found that while the acemannan-rich extract gel was highly effective, the commercially available gel showed no improvement over the control. They also found that the aloe gel had to be applied immediately after irradiation and continued for at least 2 weeks. There was no effect if the aloe gel was applied only before irradiation or beginning 1 week after irradiation. Clearly, the quality and concentration of aloe constituents are crucial if clinical results are to be obtained.52

Psoriasis A recent double-blind, placebo-controlled study evaluated the clinical efficacy and tolerability of topical A. vera extract 0.5% in a hydrophilic cream and obtained impressive results. Sixty patients (36 male/24 female) aged 18 to 50 years (mean 25.6) with slight to moderate chronic plaquetype psoriasis and psoriasis area and severity index (PASI) scores between 4.8 and 16.7 (mean 9.3) were enrolled and randomized to two groups. The mean duration of the disease before enrollment was 8.5 years (range 1 to 21). Patients self-administered trial medication topically at home three times daily for 5 consecutive days/week (maximum 4 weeks active treatment). Patients were examined on a weekly basis, and those showing a progressive reduction of lesions, desquamation followed by decreased erythema, infiltration, and lowered PASI score were considered healed.

The study was scheduled for 16 weeks with 12 months of follow-up on a monthly basis. The treatment was well tolerated by all the patients, with no adverse drugrelated symptoms and no dropouts. By the end of the study, the A. vmu extract cream had cured 25 of 30 patients (83.3%)compared with the placebo cure rate of only 2 of 30 (6.6%),resulting in significant clearing of the psoriatic plaques (328 of 396, or 82.8%) versus placebo (28 of 366, or 7.7%), and a decreased PASI score to a mean of 2.2.53

Gastric Ulcers Internal use of A. veru gel to treat peptic ulcers was studied in 1963.%Twelve patients with x-ray-confirmed duodenal ulcers were given 1 tablespoon of an emulsion of A. veru gel in mineral oil once daily. At the end of 1 year, all patients demonstrated complete recovery and no recurrence. On the basis of experimental evidence, the following factors were considered responsible for the effectiveness:

A. veru gel inactivates pepsin in a reversible fashion. When the stomach is devoid of food, pepsin is inhibited by A. veru gel; however, in the presence of food, pepsin is released and allowed to digest the food. The gel inhibits the release of hydrochloric acid via interference with histamine binding to the parietal cells. A. Vera gel is an extremely good demulcent that heals and prevents aggravating irritants from reaching the sensitive ulcer.

Acquired Immunodeficiency Syndrome Although acemannan has demonstrated some direct antiviral activity against HIV-1 by inhibiting glycosylation of viral glycoproteins, its main promise in treating AIDS and HIV may be to enhance the action of azidothymidine (AZT), the antiviral drug used in AIDS. In vitro studies have shown that acemannan combined with suboptimal noncytotoxic concentrations of AZT or acyclovir acts synergistically to inhibit the replication of HIV and herpes simplex type 1 (HSV-1).2*On the basis of these studies, as well as preliminary human studies, researchers believe that the use of acemannan may reduce the amount of AZT required by as much as 90Y0,5~ which is significant. In addition to AZT being extremely expensive, its use is often associated with severe side effects including anemia and granulocytopenia due to bone marrow suppression. Preliminary clinical studies suggest that acemannan and A. veru may be beneficial when administered orally in HIV-positive individuals.5657In one study, 14 HIV patients prescribed oral acemannan (800 mg/day) demonstrated sigruficant increases in circulating monocytes/macrophages. In particular, there were significant increases in the number of large circulating monocytes,

Pharmacology of Natural Medicines

indicating improvement in phagocytizing, processing, and presenting cells in the blood.57In another study of 15 AIDS patients receiving an oral dose of acemannan (800 mg/day), the average scores of Modified Walter Reed (MWR) Clinical Evaluation scoring, absolute T-4, absolute T-8, and p24 core antigen levels all improved in those surviving (Table 66-2) at the end of 900 days. Two patients died of AIDS, and another committed suicide. From this study, as well as others, it has been suggested that prognostic criteria to determine the most responsive patients are those with an absolute T-4 count greater than 150/mm3 and p24 levels less than 300.% In another study A. vera juice (0.6 L/day) was used in conjunction with essential fatty acids and a multiple vitamin, mineral, and amino acid supplement to treat 30 patients. The 15 AIDS, 12 AIDS-related comlpex, and two I-IlV-seropositive patients continued with regular medication, including AZT.After 180 days, all patients showed clinical improvement according to modified Kamofsky Quality of Life Assessment scores and the MWR Clinical Evaluation; 25% of those positive for the p24 core antigen converted to nonreactive; anemia induced by AZT showed improvement in all patients; and the patients gained an average of 7%. Unfortunately, a follow-up study did not reproduce these early, promising results. A comprehensive study assessed the safety and efficacy of acemannan as an adjunctive to antiretroviral therapy among 63 male patients (mean age, 39 years) with advanced HIV disease receiving zidovudine (ZDV) or didanosine (ddI).% The randomized, double-blind, placebo-controlled trial provided a large dose of acemannan (400 mg orally four times daily). Eligible patients had CD4 counts of 50 to 3OO/pl twice within 1 month of study entry and had received 26 months of antiretroviral treatment (ZDV or ddI) at a stable dose for the month before entry. CD4 counts were made every 4 weeks for 48 weeks. p24 Antigen was measured at entry and every 12 weeks thereafter. Sequential quantitative lymphocyte cultures for I-IlV and ZDV pharmacokinetics were performed in a subset of patients.

of acquired immunodeficiency syndrome Test

Pretreatment

After 900 days

Modified Walter Reed Clinical Evaluation

65

2

Absolute T-4

322/mm3

324/mm3

Absolute T-8

469/mm3

660/mm3

p24 Core antigen

5115

4112

Modified from McDaniel HR. Carpenter RH, Kernp M, et al. Antiviral Res 1990; 13(suppl 1):117.

The mean baseline CD4 counts were 165 and 147/p1 in the placebo and acemannan groups, respectively; 90% of the patients were receiving ZDV at entry. Six patients in the acemannan group and five in the placebo group developed AIDSdefining illnesses. There was no statistically significant difference between the groups at 48 weeks with regard to the absolute change or rate of decline at CD4 count. Among ZDV-treated patients, the median rates of CD4 change (ACD4) in the initial 16 weeks were -121 and -120 cells/year in the placebo and acemannan groups, respectively; ACD4 decline from week 16 to 48 was 0 and -61 cells/year in the acemannan and placebo groups (p = O.ll), respectively. No statistical difference between groups occurred with regard to adverse events, p24 antigen, quantitative virology, or pharmacokinetics. Twenty-four patients, 11receiving placebo and 13receiving acemannan, discontinued study therapy prema-ly, none due to serious adverse reactions. The decreased, but not statistically significant, rate of loss of CD4 cells in the acemannan group from weeks 16 to 48 provides a possible ray of hope that long-term use, such as reported earlier, may be of value and should be investigated.

Asthma Oral administration of an extract of A. veru for 6 months was shown to produce good results in the treatment of asthma in some individuals of various age~i.5~ The exception was the fact that the A. vera extract was not effective in patients dependent on corticosteroids. The mechanism of action is thought to be via restoration of protective mechanisms followed by augmentation of the immune system. The extract used in the study was produced from the supernatant of fresh leaves stored in the dark for 7 days at 4" C. The dosage was 5 ml of a 20% solution of the aloe extract in saline twice daily for 24 weeks. Eleven of 27 patients (40%) without corticosteroid dependence reported significant improvement at the study's conclusion. Studies indicate that subjecting the leaves to dark and cold results in an increase in the polysaccharide fraction. One gram of the crude extract obtained from leaves stored in the cold and dark produced 400 mg of neutral polysaccharide, compared with only 30 mg produced from leaves not subjected to cold or dark.

Diabetes A. vera also exhibits a hypoglycemic effect in both normal and alloxan-induced diabetic mice.60 A small human study showed benefit in diabetics. Five patients with non-insulin-dependent diabetes ingested half a teaspoonful of aloe four times daily for 14 weeks. Fasting blood sugar in each patient fell from a mean of 273 to 151 mg/dl with no change in body weight. The authors concluded that aloe lowers blood glucose levels by an

Aloe Vera (Cape Aloe)

A more recent and larger study unknown (49 men and 23 women) now provides more support for the efficacy of aloe in combination with glibenclamide in diabetes. Although there was no response to glibenclamide alone, the combination was effective.62 The patients were provided with 1 tablespoon of aloe gel and 5 mg of glibenclamide twice daily, with 5 mg twice daily of glibenclamide serving as the control. After 2 weeks, fasting blood sugar decreased sigfuficantlyin the treated group, and by day 42 had decreased from an average of 289 mg% to a remarkable 148 mg%. Although the drop in serum cholesterol was insignificant, serum triglycerides decreased from 223 mg% to (again remarkable) 128 mg% by day 42. No adverse effects were noted using standard blood chemistries.

Contraception An interesting new application of aloe is as a spermicide. Twenty samples of fresh ejaculate from healthy human volunteers between 20 and 30 years of age were treated in vitro with a 1%concentration of zinc acetate combined with lyophilized A. burbudensis (at concentrations of 7.5%to 10%). The combination of zinc acetate with lyophilized A. barbudensis was shown to possess powerful spermicidal and antiviral effects. This was attributed to their concentration of minerals (boron, barium, calcium, chromium, copper, iron, potassium, magnesium, manganese, phosphorus, and zinc), which were toxic to the sperm tail, causing instant immobilization. Studies with rabbit vaginal epithelium showed no irritation. This is important because nonoxynol-9, the active spermicidal ingredient used in vaginal contraception for more than 30 years, appears to cause cell membrane damage in vaginal and cervical epithelium and may possibly have teratogenic effects.@

Cancer Prevention The antigenotoxic and chemopreventive effect of A. barbudensis on benzo[u]pyrene (B[u]P)-DNA adducts was investigated in vitro and in vivo in an animal model. Aloe showed a time-course and dose-dependent inhibition of [3H]B[u]P-DNAadduct formation in primary rat hepatocytes, inhibited cellular uptake of [3H]B[u]P in a dose-dependent manner, and significantly inhibited adduct formation in various organs (liver, kidney, forestomach and lung). When mice were pretreated with aloe for 16 days before B[u]P treatment, inhibition of BPDE-I-DNA adduct formation and persistence was enhanced. Phase I1 glutathione-S-transferaseactivity was slightly increased in the liver, but phase I cytochrome P450 activity was not affected.@ This translates into animal cancer studies as protection from Norman murine sarcoma in mice6 and efficacy in treatment of spontaneous neoplasms in dogs and cats.&

A. veru may also play a role in cancer therapy. One clinical study sought to evaluate whether the concomitant administration of aloe may enhance the therapeutic results of melatonin in patients with advanced solid tumors for whom no effective standard anticancer therapies are available. The study included 50 patients suffering from lung cancer, gastrointestinal tract tumors, breast cancer, or brain glioblastoma who were treated with melatonin alone (20 mg/day orally in the dark period) or melatonin plus A. vem tincture (1 ml twice daily). A partial response was achieved in 2 of 24 patients treated with melatonin plus aloe and in none of the patients treated with melatonin alone. Stable disease was achieved in 12 of 24 and in 7 of 26 patients treated with melatonin plus aloe or melatonin alone, respectively. Therefore the percentage of nonprogressing patients was significantly higher in the group treated with melatonin plus aloe than in the melatonin group (14 of 24 vs. 7 of 26, p < 0.05). The percentage of 1-year survival was also significantly higher in patients treated with melatonin plus aloe (9 of 24 vs. 4 of 26, p < 0.05).67

DOSAGE A. veru gel can be applied liberally for topical applications. A wide range of products are available on the market; however, simple pure A. veru gel is sufficient. A. veru juice can be consumed orally as a beverage or tonic. Although detailed information is currently lacking as to the optimal dose for these types of products, it is recommended that no more than 1 quart be consumed daily. The dose of acemannan being used in HIV/AIDS patients is 800 to 1600 mg/day. This corresponds to a dose of approximately 0.5 to 1 L/day for most A. veru juice products. However, there may be great variation in the amount of acemannan in various products.

TOXIC0LOGY Although rare, hypersensitivity reactions manifesting as generalized, nummular, eczematous, and papular dermatitis have been reported as a result of topically applied A. veru preparations. A. veru gel has been shown to delay wound healing in cases of surgical wounds such as those produced during laparotomy or cesarean deliveryM Therefore topical aloe preparations are not useful for treating deep vertical wounds.

DRUG INTERACTIONS Excessive use of aloe dried juice/latex may interact with several d r u g ~ . 6Large ~ - ~ dosages of aloe may increase the risk of toxicity of antiarrhythmic drugs. Theoretically, overuse of aloe dried juice/latex may increase the risk of

Pharmacology of Natural Medicines cardiac glycoside toxicity. Potential for adverse effects exists when aloe dried juice/latex is used excessively along with herbs containing cardiac glycosides (e.g., black hellebore, Canadian hemp roots, digitalis leaf, pheasant's eye plant, pleurisy root, squill bulb leaf scales, Strophanthus seeds) or with cardiac glycoside drugs (eg., digoxin). Overuse of aloe dried juice/latex can exacerbate the potassium loss caused by corticosteroids, diuretics, horsetail, and licorice root. Due to the hypoglycemic effects of internally consumed A. veru gel, persons using glyburide drugs to control blood sugar (e.g., DiaBeta, Micronase, Glynase) should monitor blood glucose levels closely.

Aloe dried juice/latex causes shorter gastrointestinal transit time, so it may reduce the absorption of some drugs. Theoretically, concomitantuse of aloe with other stimulant laxative herbs might increase the risk of potassium depletion. In addition to senna leaves and pods and cascara bark, the two herbs most widely used for this purpose, stimulant laxative herbs also include wild cucumber fruit (Ecboliurn eluteriurn), blue flag rhizome, alder buckthorn, European buckthorn, butternut bark, castor oil, colocynth fruit pulp, gamboge bark exudate, jalap root, black root, manna bark exudate, podophyllum root, rhubarb root, and yellow dock root.

1.Haller JS Jr. A drug for all seasons, medical and pharmacological history of aloe. Bull N Y Acad Sci 1990;66:647-659. 2. Klein AD, Penneys NS. Aloe Vera. J Am Acad Dermatol 1988;18: 714-720. 3.van Wyk BE, van Rheede, van Oudtshoom MC, Smith GF. Geographical variation in the major compounds of Aloe ferox leaf exudate. Planta Med 1995;61:250-253. 4. Grindlay D, Reynolds T. The Aloe veru phenomena: a review of the properties and modem use of the leaf parenchyma gel. J Ethnopharrnacol1986;16117-151. 5. Shelton RM. Aloe veru. Its chemical and therapeutic properties. Int J Dermatol 1991;30:679-683. 6. West DP, Zhu YE Evaluation of aloe Vera gel gloves in the treatment of dry skin associated with occupational exposure. Am J Infect Control 2003;31:40-42. 7.Afzal M, Ali M, Hassan RAH, et al. Identification of some prostanoids in Aloe Vera extracts. Planta Med 1991;5738-40. 8. Sabeh F, Wright T, Norton SJ. Isozymes of superoxide dismutase from Aloe Vera. Enzyme Protein 1996;49:212-221. 9. Collins CE, Collins C. Roentgen dermatitis treated with fresh whole leaf Aloe Vera. Am J Roentenol1935d3:396-397. 10. Godding EW. Therapeutics of laxative agents with special reference to anthraquinones. Pharmacol 1976;14(suppl 1):78-101. 11. Anton R, Haag-Berrurier MH. Therapeutic use of natural anthraquinones for other than laxative actions. Pharmacol 1976;ZO (suppl1):104-112. 12. Ishii Y, Tanizawa H, Takino Y. Studies of aloe. IV. Mechanism of cathartic effect. Biol Pharm Bull 1994;17495-497. 13. Ishii Y, Tanizawa H, Takino Y. Studies of aloe. V. Mechanism of cathartic effect. Biol Pharm Bull 1994;17:651-653. 14. Bland J. Effect of orallyconsumed Aloe veru juice on human gastrointestinal function. Natural Foods Net News1 1985;August. 15. Robson MC, Heggers JP, Hagstrom WJ. Myth, magic, witchcraft, or fact? Aloe Vera revisited. J Bum Care Rehabil1982;3:157-162. 16. Fly LB, Keim I. Tests of Aloe Vera for antibiotic activity. Econ Bot 1963;17H. 17. LJ, W b u r g R, Bed J, Baldwin JN. Bacteriostaticproperty of Aloe Vera. J Pharm Sci 1964;531287. 18. Heggers JP, Pineless GR, Robson MC. Dermaide Aloe/Aloe Vera g e l comparison of the antimicrobial effects. J A m Med Techno1 1979;41:293-294. IR. Studies of 19.Sheets MA, Unger BA, Giggleman GF, T'ard the effect of acemannan on retrovirus infections: clinical stabilization of feline leukemia virus-infected cats. Mol Biother 1991; 341-45.

20. Kemp MC, Kahlon JB, Chinnah AD, et al. In-vitro evaluation of the antiviral effects of acemannan on the replication and pathogenesis of HIV-1 and other enveloped viruses: modificationof the processing of glycoprotein precursors. Antiviral Res 1990;13(suppl 1):83. 21. Kahlon JB, Kemp MC, Carpenter RH et al. Inhibition of AIDS virus replication by acemannan in vitro. Mol Biother 1991;3:127-135. 22. Kahlon JB, Kemp MC, Yawei N, et al. In vitro evaluation of the synergistic antiviral effects of acemannan in combination with azidothymidine and acyclovir. Mol Biother 1991;3214-223. 23. 't Hart LA, Nibbering PH, van den Barselaar MT, et al. Effects of low molecular constituents from Aloe Vera gel on oxidative metabolism and cytotoxic and bactericidal activities of human neutrophils. Int J Immunolpharmac 1990;12427-434. 24. Womble D, Helderman JH. Enhancement of allo-responsiveness of human lymphocytes by acemannan (Carrisyn). Int J Immunopharmacol1988;10:967-974. 25. Zhang L, T i r d IR. Activation of a mouse macrophage cell line by acemannan: the major carbohydrate fraction from Aloe Vera gel. Immunopharmacology 1996;35119-128. 26. Stuart RW, Lefkowitz DL, Lincoln JA, et al. Upregulation of phagocytosis and candidicidal activity of macrophages exposed to the immunostimulant acemannan. Int J Immunopharmacol 1997; 19:75-82. 27. Egger SF, Brown GS, Kelsey LS, et al. Studies on optimal dose and administration schedule of a hematopoietic stimulatory beta-(l,4)linked mannan. Int J Immunopharmacol1996;18113-126. 28. Davis RH, Shapiro E, Agnew PS.Topical effect of aloe with ribonudeic acid and vitamin C on adjuvant arthritis. J Am Pod Med Assoc 1985;75:229-237. 29. Yagi A, Harada N, Yamada H, et al. Antibradykinin active material in Aloe suponaria. J Pharm Sci 1982;71:1172-1174. 30.Davis RH, Parker WL, Samson RT, Murdoch DP. Isolation of a stimulatory system in an Aloe extract. J Am Podiatr Med Assoc 1991;81:473-478. 31. Davis RH, Leiher MG, Russo JM, Byme ME. Anti-inflammatory activity of AIoe Vera against a spectrum of irritants. J Am Podiatr Med Assoc 1989;79:263-276. 32.Vazquez B, Avila G, Segura D, Escalante B. Anti-inflammatory activity of extracts from Aloe veru gel. J Ethnopharmacol 1996; 55:69-75. 33.Malterud KE, Farbrot TL, Huse AE, Sund RB. Antioxidant and radical scavenging effects of anthraquinones and anthrones. Pharmacology 1993;47(suppl 1):77-85. 34.Henry R. An updated review of Aloe veru. Cosmet Toilet 1979; 94:42-50.

~~~

Aloe Vera (Cape Aloe) 35. Shida T, Yagi A, Nishimura H, Nishioka I. Effect of Aloe extract on peripheral phagocytosis in adult bronchial asthma. Planta Med 1985;51:273-275. 36. Davis RH, Kabbani JM, Mar0 NP.Aloe Vera and wound healing. J Am Podiatr Med Assoc 1987;77%5-169. 37. Davis RH, Leitner MG, Russo JM. Aloe Vera.A natural approach for treating wounds, edema, and pain in diabetes. J Am Podiatr Med ASSN 1988;78:60-68. 38. Rowe TD. Effect of fresh Aloe Vera gel in the treatment of thirddegree Roentgen reactions on white rats. J Am Pharm Assoc 1940;29:348-350. 39. Rowe TD, Love11 BK, Parks LM. Further observations on the use of Aloe Vera leaf in the treatment of third-degree X-ray reactions. J Am Pharm Assoc 1941;30:266-269. 40. Lushbaugh CC, Hale DB. Experimental acute radiodermatitis following beta irradiation. V. Histopathological study of the mode of action of therapy with Aloe Vera.Cancer 1953;6:690-698. 41. Chithra P, Sajithlal GB, Chandrakasan G. Influence of Aloe Vera on the glycosaminoglycans in the matrix of healing dermal wounds in rats. J Ethnopharmacol1998;59:179-186. 42. Davis RH, Donato JJ, Hartman GM, Haas RC. Anti-inflammatory and wound healing activity of a growth substance in Aloe Vera.J Am Podiatr Med Assoc 1994;84:77-81. 43. Davis RH, DiDonato JJ, Johnson RW, Stewart CB. Aloe Vera,hydrocortisone, and sterol influence on wound tensile strength and antiinflammation. J Am Podiatr Med Assoc 1994;84:614-621. 44.Chung JH, Cheong JC, Lee JY, et al. Acceleration of the alcohol oxidation rate in rats with aloin, a quinone derivative of Aloe.Biochem Pharmacol1996;521461-1468. 45. ZawahryM, Hegazy MR, Helal M. Use of aloe in treating leg ulcers and dermatoses. Int J Dermatol1973;126&73. 46. Visuthikosol V, Chowchuen B, Sukwanarat Y, et al. Effect of Aloe Vera gel to healing of burn wound. A clinical and histologic study. J Med Assoc Thai 1995;78:403409. 47. Miller MB, Koltai PJ. Treatment of experimental frostbite with pentoxifylline and aloe Vera cream. Arch Otolaryngol Head Neck Surg 1995;121:678-680. 48. Ardire L. Necrotizing fasciitis. case study of a nursing dilemma. Ostomy Wound Manage 1997;43:30-4,36,38-40. 49.Thomas DR, Goode PS, LaMaster K, Tennyson T. Acemannan hydrogel dressing versus saline dressing for pressure ulcers. A randomized, controlled trial. Adv Wound Care 1998;11:273-276. 50. Williams MS, Burk M, Loprinzi CL, et al. Phase Ill double-blind evaluation of an Aloe Vera gel as a prophylactic agent for radiationinduced skin toxicity. Int J Radiat Oncol Biol Phys 1996;36:345-349. 51. Heggie S, Bryant GP, Tripcony L, et al. A phase III study on the efficacy of topical aloe Vera gel on irradiated breast tissue. Cancer Nurs 2002;25:442451. 52. Roberts DB, Travis EL. Acemannan-containing wound dressing gel reduces radiation-induced skin reactions in C3H mice. Int J Radiat Oncol Biol Phys 1995;321047-1052.

53. Syed TA, Ahmad SA, Holt AH, et al. Management of psoriasis with Aloe Vera extract in a hydrophilic cream: a placebo-controlled, double-blind study. Trop Med Int Health 1996;1:505-509. Gerard JR. Aloe vera gel in peptic ulcer therapy: 54. Blitz JJ, Smith JW, preliminary report. J Am Osteopath Assoc 1963;62731-735. 55. Anonymous. Aloe Vera may boost AZT. Med Tribune 1991;224. 56. McDaniel HR, Carpenter RH, Kemp M, et al. Extended survival and prognostic criteria for acemannan (ACE-M) treated HIV-1 patients. Antiviral Res 1990;13(suppll):117. 57. McDaniel HR, Combs C, McDaniel R, et al. An increase in circulating monocyte/macrophages (MM) is induced by oral acemannan (ACE-M) in HN-1 patients. Am J Clin Pathol 1990;94516-517. 58. Montaner JS, Gill J, Singer J, et al. Double-blind placebo-controlled pilot trial of acemannan in advanced human immunodeficiency virus disease. J Acquir Immune Defic Syndr Hum Retroviroll996; 12:153-157. 59. Shida T, Yagi A, Nishimura H, Nishioka I. Effect of Aloe extract on peripheral phagocytosis in adult bronchial asthma. Planta Medica 1985;51:273-275. 60. Ajabnoor MA. Effect of aloes on blood glucose levels in normal and alloxan diabetic mice. J Ethnopharmacol1990;28:215-220. 61. Gnhannam N, Kingston M, Al-Meshaal IA,et al. The antidiabetic activity of Aloes. Horm Res 1986;2428&294. 62. Bunyapraphatsara N, Yongchaiyudha A, Rungpitarang S, Chokechaijaroenporn 0. Antidiabetic activity of Aloe veru juice 11. Clinical trial in diabetes mellitus patients in combination with glibenclamide. Phytomedicine 1996;3:245-248. 63. Fahim MS, Wang M. Zinc acetate and lyophilized Aloe barbadensis as vaginal contraceptive. Contraception 1996;53:231-236. 64.Kim HS, Lee BM. Inhibition of benzo[a]pyrene-DNA adduct formation by Aloe barbadensis Miller. Carcinogenesis 1997;18771-6. 65. Peng SY, Norman J, Curtin G, et al. Decreased mortality of Norman murine sarcoma in mice treated with the immunomodulator, acemannan. Mol Biother 1991;3:79-87. 66. Hams C, Pierce K, King G, et al. Efficacy of acemannan in treatment of canine and feline spontaneous neoplasms. Mol Biother 1991;3 207-213. 67. Lissoni P, Giani L, Zerbini S, et al. Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus aloe Vera in untreatable advanced solid neoplasms. Nat Immun 1998;16:27-33. 68. Schmidt JM, Greenspoon JS. Aloe Vera dermal wound gel is associated with a delay in wound healing. Obstet Gynecol1991;78:115-117. 69. Brinker F. Herb contraindications and drug interactions, ed 2. Sandy, OR Eclectic Medical Publications, 1998. 70. Klein AD, Penneys NS. Aloe Vera. J Am Acad Dermatol 1988;18: 714-720. 71. Brinker F. Herb contraindications and drug interactions. Sandy, OR Eclectic Medical Publications, 1997. 72. Blumenthal M. Herb and conventional possible interactions with drugs. Austin, Tx:American Botanical Council, 1997.

Angelica Species Michael T. Murray, ND Joseph E. Pizzorno Jr, ND C: H A P T E R C: 0 N T E N T S General Description 749 Angelica sinensis and Angelica acutiloba 749 Angelica archangelica and Angelica atropurpurea 750 Chemical Composition 750 Angelica sinensis and Angelica acutiloba 750 Angelica archangelica 750 History and Folk Use 750 Angelica sinensis and Angelica acutiloba 750 Angelica archangelica 750 Angelica atropurpurea 750

Pharmacology 750 Phytoestrogen Effects 750 Cardiovascular Effects 751 Smooth Muscle-Relaxing Activity 751 Analgesic Activity 751 Antiallergic, Immunomodulating, and Direct Antitumor Activity 751 Antimicrobial Activity 751 Clinical Application 752 Menopause 752 Dosage 752 Toxicology

Angelica sinensis or polyrnorpha (family: Umbelliferae or Apiaceae) Common names: Chinese angelica, tang-kuei (dong-quai) Angelica acutiloba (family: Umbelliferae or Apiaceae) Common name: Japanese angelica Angelica archangelica (family: Umbelliferae or Apiaceae) Common name: European angelica Angelica atropurpurea (family: Umbelliferae or Apiaceae) Common name: American angelica Angelica silves tris (family: Umbelliferae or Apiaceae) Common name: wild angelica

GENERAL DESCRIPTION Angelica spp. are biennial or perennial plants with hollow fluted stems that rise to a height of 3 to 7 feet. The umbels, or clusters, of greenish-whiteflowers bloom from May to August. The plants are found in damp mountain ravines and meadows, on river banks, and in coastal areas; angelica is also a widely cultivated species. In Asia it is grown primarily for its medicinal action, while in the United States and Europe it is cultivated for use as a flavoring agent in most major categories of food products including alcohol (e.g., bitters, liqueurs, vermouths) and nonalcoholic beverages, ice cream,

752

candy, gelatins, and puddings. With all species, the roots and rhizomes are the most extensively used portions of the plant.

Angelica sinensis and Angelica acutiloba In Asia the authentic and original medicinal angelica is Angelica sinensis (dong-quai), native to China. Although at least nine other angelica species are used in China, dong-quai is by far the most highly regarded. For several thousand years, dong-quai has been cultivated for medicinal use in the treatment of a wide variety of disorders, particularly "female" disorders. Several hundred years ago, when the supply of Chinese angelica was scarce, the Japanese began to cultivate Angelica acutiloba, an angelica species indigenous to Japan, as a substitute.' The two species appear to have similar therapeutic effects despite the following opinions: In China the Japanese angelica is thought to have no therapeutic value, while in Japan, Chinese angelica is thought to have no effect. Experimentally, both species exhibit similar therapeutic effects, so each country's claim to produce a superior dong-quai is apparently based more on emotion than scientific investigation. 749

Pharmacology of Natural Medicines

Angelica archangelica and Angelica atropurpurea Historical usage suggests that European angelica (Angelica archangelica) and American angelica (Angelica afropurpurea) have properties different from the Asian species. However, this difference has not been evaluated by chemical analysis.

CHEMICAL COMPOSITION Angelica sinensis and Angelica acutiloba Although it has been assumed that Chinese and Japanese angelica are similarly composed of various coumarins and flavonoids that are responsible for their medicinal actions, a recent analysis showed that A. sinensis contained approximately 10-fold higher levels of the key components ferulic acid and Z-ligustilide compared with roots of A. acutiloba.* Many medicinal compounds are believed to be present in the essential oil, including the following? 3n-Butylphthalide Cadinene Carvacrol n-Dodecanal Isosafrole Linoleic acid Palmitic acid Safrole Sequiterpene n-Tetradecanoyl

Angelica archangelica A. archangelica is also rich in coumarins and particularly phototoxic. Coumarins including osthole, angelicin, osthenol, umbelliferone, archangelicine, bergapten, and ostruthol are found in significant concentrations, with osthole composing nearly 0.2% of the root. The root is also a good source of flavonoids including archangelenone and caffeic acids. The root contains 0.3% to 1% volatile oil composed mainly of beta-phellandrene, alpha-pinene, bomeol, limonene, and four macrocyclic lac tone^.^,^

HISTORY AND FOLK USE Angelica sinensis and Angelica acutiloba In Asia angelica‘s reputation is perhaps second only to ginseng. Predominantly regarded as a “female” remedy, angelica has been used to treat dysmenorrhea, amenorrhea, metrorrhagia, and menopausal symptoms and to assure a healthy pregnancy and easy delivery. Angelica is also used in the treatment of abdominal pain, anemia,

injuries, arthritis, migraine headache, and many other

Angelica archangelica One of the most highly praised herbs in old herbal texts, A. archangelica was used by all Northern European countries as the following: a protection against contagion, for purrfylng the blood, and for curing every conceivable malady: it was held a sovereign remedy for poisons, a p e s and all infectious maladies.

According to one legend, A. archangelica was revealed in a dream as a cure for the plague. One explanation for the name is related to its blooming near May 8, the feast day of Michael the Archangel. It was therefore seen as a “protector against evil spirits and witchcraft.”6 A. archangelica has been used for a wide variety of conditions including flatulent dyspepsia, pleurisy, respiratory catarrh, and bronchitis. The plant was believed to possess carminative, spasmolytic, diaphoretic, expectorant, and diuretic activity.6

Angelica atropurpurea American angelica’s therapeutic use mirrors that of European angelica. Its most common use is for heartburn and flatulent colic.’

PHARMACOLOGY The pharmacology of Angelica spp. primarily relates to high coumarin content. However, unlike other scientific investigations of botanical medicines, most research on Angelica spp. has been done on plant extracts, rather than isolated constituents. The overwhelming majority of studies have been done on the Asian species. Some of the pharmacologic activities demonstrated include the following: Phytoestrogen activity Analgesic activity Cardiovascular effects Smooth muscle-relaxing effects Antiallergic, immunomodulating, and direct antitumor activity Antimicrobial activity

Phytoestrogen Effects Plant estrogenic substances or phytoestrogens are components of many medicinal herbs with a historic use in conditions that are now treated by synthetic estrogens. Chinese and Japaneseangelica contain weakly active phytoestrogens, much lower in activity than other phytoestrogens and approximately no more than 1:400 as active as estrogen? This helps to explain why angelica was used in both excessive and deficient estrogen conditions.

Angelica Species Phytoestrogens demonstrate an alterative effect by competing with estrogen for binding sites. When estrogen levels are low, they can exert some weak estrogenic activity; when estrogen levels are high, they reduce overall estrogenic activity by occupying estrogen receptor sites. This alterative action of angelica's phytoestrogens is probably the basis of much of the plant's use in amenorrhea and menopause. Japanese angelica has demonstrated uterine tonic activity, causing an initial increase in uterine contraction followed by relaxation?JOIn addition, administration of Japanese angelica to mice resulted in an increase of uterine weight, increase of the DNA content of the uterus and liver, and increase of glucose use by the liver and uterus.lt9Because of these and other effects, angelica has been referred to as a uterine tonic.

Cardiovascular Effects Although not used historically for these purposes, angelica does possess significant hypotensive a~ti0n.l.~ This is largely due to its vasodilator activity. Dihydropyranocoumarins and dihydro-furanocoumarins from Umbelliferousplants have been shown to possess significant coronary vasodilatory, spasmolytic, and cyclicAMP-phosphodiesterase inhibitory properties." The mechanism of action appears to be largely a result of calcium channel antagonism. Agents that interact with calcium channels (calcium channel blockers) are quickly coming into prominence in the treatment of wideranging conditions including hypertension and angina. Umbelliferous plants such as angelica may offer similar effects. Other cardiovascular effects noted for angelica are negative inotropic and antiarrhythmic action.'

Smooth Muscle-Relaxing Activity Calcium channel blocking compounds are also capable of relaxing the smooth muscles of visceral organs. Angelica (essential oil) has demonstrated relaxing action on the smooth muscles of the intestines and uterus, while the water extract produces an initial contraction This confirms its and then prolonged rela~ation.',~J~ historical use in the treatment of intestinal spasm and uterine cramps. Its action on other smooth muscles could explain its hypotensive action (vascular smooth muscle) and historical use in asthma (bronchial smooth muscle).

Analgesic Activity Both Chinese and Japanese angelica have demonstrated pain-relieving and mild tranquilizing effects in experimental studies in animals.19J2J3Angelica's analgesic action was 1.7 times that of aspirin in one study.13 Its analgesic activity, combined with its smooth muscle-relaxing activity, supports its historical use in

such conditions as uterine cramps, trauma, headaches, and arthritis.

Antiallergic, lmmunomodulating, and Direct Antitumor Activity Angelica has a long history of use by Chinese and Japanese herbalists in the prevention and treatment of allergic symptoms in individuals who are sensitive to various substances (e.g., pollen, dust, animal dander, food).lJ4Its action is related to its ability to inhibit the production of IgE in a selective manner. Since IgE levels in patients with atopic conditions are typically 3 to 10 times greater than the upper limit of normal, angelica may offer some benefit by reducing these elevated antibodies. Coumarin compounds have demonstrated immuneenhancing activity in both healthy and cancer patients.15J6 Coumarins have been shown to stimulate macrophages and increase phag~cytosis.'~ Such activity is thought to offer significant protection against metastasis and growth of tumor cells. Upon coumarin administration, macrophages are said to be "activated" and thus capable of entering the tumor, where a specific destruction of the tumor cells may o c c ~ r . ~ ~ J ~ Coumarin compounds of angelica and the polysaccharides of the water extract of Japanese angelica have demonstrated immune-modulating and antitumor activity. They have been shown to possess mitogenic activity to B-lymphocytes, interferon-producing activity, antitumor activity, and complement-activating (both the classical and alternative pathway) a ~ t i v i t y . ' ~ Chinese -~~,~~ angelica has been shown to increase murine IL-2 production, stimulate the reticuloendothelial system, and increase tumor necrosis factor p r o d u ~ t i o n . ~ The , ~anti~,~~ tumor effects of angelica appear to be mainly due to the polysaccharide components, as these compounds have been shown to exert antitumor effects on experimental tumor models in vivo and inhibitory effects on invasion and metastasis of cancer cells in ~itro.~~~*~Altogether these effects by coumarins, polysaccharides, and extracts of Angelica sp. would seem to support the historical use of angelica as an adjunct in cancer therapy.

Antimicrobial Activity Extracts of Chinese angelica have been shown to possess antibacterial activity against both gram-negative and gram-positive bacteria, while extracts of Japanese angelica exhibited no antibacterial action.6The inconsistency could be due to different essential oil concentrations of the extracts used in the studies. The oil of A . archangelica has also exhibited significant antifungal and anthelmintic properties but virtually no antibacterial a ~ t i v i t y . ~As, ~ ~ , ~ other herbs have much greater antimicrobial activity, Angelica spp. would be considered a less than optimum agent if this effect is desired.

Pharmacology of Natural Medicines

CLINICAL A PPLICAT10N Angelica spp. have been used worldwide to treat wide-ranging conditions. At present it appears that A. archungelicu and A. atropurpureu are most indicated as expectorants, antispasmodics, and carminatives in the treatment of respiratory ailments, gas, and abdominal spasm. Chinese angelica (A. sinensis or polymorpha) and Japanese angelica (A. acutiloba) appear most useful in the treatment of disorders of menstruation, menopause (especially hot flashes), atopic conditions, smooth muscle spasm (e.g., uterine cramps, migraines, abdominal spasm), and possibly as an immunostimulatory adjunct in cancer therapy.

Menopause By far the most popular use of Angelica spp. has been the use of A. sinensis in the treatment of menopausal complaints. Although a double-blind, placebo-controlled study in women showed no significant benefit, the traditional use of angelica has been in combination with other plants. The preparation used (a dried aqueous extract) was clearly lacking some of the important volatile compounds, though it was standardized for ferulic acid c0ntent.2~A study conducted in China showed that a combination of A. sinensis, Paeonia lactifora, Ligusticum monnieri, Atractylodes chinensis, Sclerotium poriae, and Alisma orientalis was effective in roughly 70°/"of women experiencing menopausal symptoms.30 Though not

1. Hikino H. Recent research on Oriental medicinal plants. Econ Med Plant Res 1985;1:53-85. 2. Zhao KJ, Dong IT,Tu PF, et al. Molecular genetic and chemical assessment of radix Angelica (Danggui) in China. J Agric Food Chem 2003;51:2576-2583. 3. Duke JA. Handbook of medicinal herbs. Boca Raton, FL: CRC Press, 1985:43-44. 4. Leung AY. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. New York: Wiley, 1980:28-29. 5.Duke JA, Ayensu ES. Medicinal plants of China. Algonac, MI: Reference Publications, 1985:74-77. 6.Grieve M. A modern herbal. New York Dover Publications, 1971:35-40. 7. Lust J. The herb book. New York Bantam Books, 1974:97-99. 8. Liu J, Burdette JE, Xu H, et al. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem 2001;492472-2479. 9. Yoshiro K. The physiological actions of tang-kuei and conidium. Bull Oriental Healing Arts lnst USA 1985;10:269-278. 10.Harada M, Suzuki M, Ozaki Y. Effect of Japanese angelica root and peony root on uterine contraction in the rabbit in situ. J Phannacobiodyn 1984;7304-311. 11. Thastrup 0, Fjalland B, Lemmich J. Coronary vasodilatory, spasmolytic and CAMP-phosphodiesterase inhibitory properties of dihydropyranocoumarins and dihydrofuranocoumarins. Acta Pharmacol Toxic01 (Copenh) 1983;52:246-253.

double-blind, this study shows promise for using angelica in the management of menopausal symptoms. Interestingly, in an in vitro study with human bone, the aqueous extract of A. sinensis was found to directly stimulate the proliferation, alkaline phosphatase activity, protein secretion, and type I collagen synthesis in a dosedependent manner.31 Also, in a double-blind study, the combination of 100 mg angelica, 60 mg soy isoflavones, and 50 mg of black cohosh extract sigruficantlyreduced menstrual

DOSAGE Dried root or rhizome: 1 to 2 g orally, or by infusion, three times daily Tincture (1:5):3 to 5 ml, three times daily Fluid extract (1:l):0.5 to 2 ml, three times daily

TOXICOLOGY Angelica is generally considered to be of low toxicity. However, it contains many photoreactive substances that may induce photosensitivity.This should be kept in mind when using any Umbelliferous plant. This photoreactive activity can be used therapeutically in the treatment of vitiligo and psoriasis. Use of Angelica spp., particularly A. sinensis, in men may lead to gyne~omastia.~~

12. Tanaka S, Ikeshiro Y, Tabata M, Konoshima M. Anti-nociceptive substances from the roots of Angelica acutiloba. Arzneimittelforschung 1977;272039-2045. 13. Tanaka S, Kano Y, Tabata M, Konoshima M. [Effects of "Toki" (Angelica acutiloba Kitawaga) extracts on writhing and capillary permeability in mice (analgesic and anti-inflammatory effects).] Yakugaku Zasshi 1971;91:1098-1104. 14. Sung CP, Baker AP,Holden DA, et al. Effect of extracts of Angelica polymorpha on reaginic antibody production. J Nat Prod 1982;45:398406. 15.Casley-Smith JR. The actions of benzopyrenes on the blood-tissuelymph system. Folia Angiol 1976;247-22. 16.Berkarda B, Bouffard-Eyuboglu H, Derman U. The effect of coumarin derivatives on the immunological system of man. Agents Actions 1983;13:50-52. 17. Ohno N, Matsumoto S, Suzuki I, et al. Biochemical and physicochemical characterization of a mitogen obtained from an oriental crude drug, Tohki (Angelica actiloba Kitagawa). J Pharmacobiodyn 1983;6:903-912. 18. Yamada H, Kiyohara H, Cyong JC, et al. Studies on polysaccharides from Angelica acufiloba. Part 1. Fractionation and biological properties of polysaccharides. Planta Med 1984;50:163-167. 19. Yamada H, Kiyohara H, Cyong JC, Otsuka Y. Studies on polysaccharides from Angelica ncutiloba-IV, Characterization of an anti-complementary arabinogalactan from the roots of Angelica acutiloba Kitagawa. Mol Immunol 1985;22:295-304.

Angelica Species 20. Kumazawa Y, Mizunoe K, Otsuka Y. Immunostimdating polysaccharide separated from hot water extract of Angelica acutiloba Kitagawa (Yamato Tohki). Immunology 1982;4775-83. 21. Lu S, Huang H, Wu S. [The regulation effects of Angelica sinensis on the erythrocytic immune function and IL-2 in mice.] Zhong Yao Cai 1997;20:301-303. 22. Weng XC, Zhang P, Gong SS, Xiai SW. Effect of immuno-modulating agents on murine IL-2 production. Immunol Invest 1987167946. 23. Haranaka K, Satomi N, Sakurai A, et al. Antitumor activities and tumor necrosis factor producibility of traditional Chinese medicines and crude drugs. Cancer Immunol Immunother 1985;201-5. 24.Shan JJ, Wang Y, Wang SC, et al. [Effect of Angelica sinensis polysaccharides on lymphocyte proliferation and induction of IFNgamma.] Yao Xue Xue Bao 2002;37497-500. 25. Shang P, Qian AR,Yang TH, et al. Experimental study of anti-tumor effects of polysaccharides from Angelica sinensis. World J Gastroenterol2003;9:1963-1967. 26.Zheng M, Wang YI? [Experimental study on effect of Angelica polysaccharide in inhibitory proliferation and inducing

differentiation of K562 cells.] Zhongguo Zhong Xi Yi Jie He Za Zhi 2002;22:54-57. 27. Rhee JK, Woo KJ, Baek BK, Ahn BJ. Screening of the wormicidal Chinese raw drugs on Clonorchis sinensis. Am J Chin Med 1981;9277-284. 28. Opdyke DL. Angelica root oil. Food Cosmet Toxic01 1975;13713-714. 29. Hirata JD, Swiersz LM, Zell 8, et al. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebocontrolled trial. F e d Steril1997;68981-986. 30.Chang HM, But PPH, eds. Pharmacology and applications of Chinese Materia Medica, vol 1. Singapore: World Scientific, 1987489-505. 31. Yang Q, Populo SM, Zhang J, et al. Effect of Angelica sinensis on the proliferation of human bone cells. Clin Chim Acta 2002;32489-97. 32. Burke BE, Olson RD, Cusack BJ. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomed Pharmacother 2002;56283-288. 33. Goh SY, Loh KC. Gynaecomastia and the herbal tonic “Dong Quai.” Singapore Med J 2001;42:115-116.

Artemsia absinthium (Wormwood)

CHAPTER CONTENTS General Description 755

Antiparasitic Effects 757 Neurologic Effects 757

Chemical Composition 755 Clinical Applications 757 History and Folk Use 755 Dosage 757 Pharmacology 756 Digestive Effects 756 Hepatic Effects 756

Toxicity 757 Drug Interactions 758

Arfemisia absinfhium (family:Asteraceae) Common names: wormwood

are absinthin, artabsin, matricin, and anabsinthin (Figures 68-1 through 68-3).

GENERAL DESCRIPTION

HISTORY AND FOLK USE

Arfemisia absinfhium generally occurs as a semiwoody, perennial subshrub reaching up to 1 m tall, particularly in its native Mediterranean habitat. The opposite, pinnatifid leaves are silvery gray and quite aromatic. The leaves and flowers are used as medicine. The stems and leaves are covered by fine, silky hairs. Tiny, dull yellowgreen flowers bloom in drooping clusters from July to September.

Wormwood was used historically as a digestive bitter in traditional herbal systems of various societies around its native Mediterranean habitat. The Ebers papyrus, an Egyptian medical treatise and one of the oldest extant pieces of writing (circa 1550 BC), mentions wormwood. Pliny the Elder discussed the use of wormwood to expel parasites, as reflected in the common name of the plant, in the first century AD. The medicinal aspects of most of the history of wormwood are unfortunately overshadowed by developments in the late eighteenth century-absinthe. The standard account of the rise of absinthe, a liqueur derived in part from wormwood, begins with French expatriate Pierre Ordinaire, who allegedly developed the first absinthe recipe in 1792 in Switzerland? Absinthe schnapps, absinthe-infused ale (known as "purl"), absinthe-infused wine, and other absinthe-containing beverages had been in use since Dioscorides' time and probably before. Absinthe was apparently made by infusing wormwood, Angelica archangelica (garden angelica) root, Pimpinella anisurn (anise) fruit, and Origanum rnaioriuna (marjoram) herb in ethanol; distilling them; and adding other flavorings including volatile The resulting product was bright green and intensely

CHEMICAL COMPOSITION The aboveground parts of wormwood contain two components considered most important to its medicinal activity: 0.15%to 0.4% volatile oil and 0.2% to 1.5%bitter sesquiterpenelactones.' The volatile oil is most notorious for its content of the terpenoids alpha- and beta-thujone, given the potential neurotoxicity of these compounds. Alpha-thujone is believed to be much more toxic and is present as 0.53%to 1.22%of the volatile oil compared with 17.5% to 42.3% for beta-thujone.2 Several chemotypes of wormwood depend on growing environment, and only certain ones contain thujon-thers have trans-sabinyl acetate, cis-epoxyocimen, or chrysanthenyl acetate instead.l Major sesquiterpene lactones present

755

Figure 681 Aipha-thujone.

.A Figure 682 Beta-thujone.

Figure 68-3 Absinthin.

The growing popularity of absinthe, combined with a fire at the Pernod Fils distillery in 1901, led to a surge of absinthelike products on the market. Unfortunately, these imitation products were often made as cheaply as possibly by simply mixing volatile oils with alcohol, adding various coloring agents to given the appropriate green hue (including copper sulfate) and antimony chloride to create the appearance of the white precipitate At the same time, a new pheformed in true ab~inthe.~ nomenon termed absinthisrn was becoming widely known. This syndrome was a result of chronic absinthe overindulgence and included bursts of violent aggressiveness followed by prolonged depression, trembling, hallucinations, seizures, and death? However, the presence of adulterated, low-quality, high-ethanol absinthe products on the market and the inability to distinguish the effects of ethanol abuse from those of other compounds in the mixture make it difficult to be certain exactly what was causing absinthism. The levels of the purported neurotoxin thujone in true absinthe were 2 to 4 mg per drink, far below the 10 mg/kg levels needed to induce neurologic damage in numerous animal experiments6 In the early twentieth century, absinthe was banned in most of Europe and the United States. It remains banned today. The Eclectics regarded wormwood as a digestive tonic useful in atonic dyspepsia, as a potential treatment for roundworms, and for topical application to sprains and bruise^.^ The dangers of absinthism were well known to these turn-of-the-century American natural physicians, but they did not seem clear on the various problematic elements in the history of absinthe discussed earlier.

bitter, formed a white precipitate, and had a high alcohol PHARMACOLOGY content (50%to 80%).4 Wormwood's actions have been studied in three major Henri Dubied and his son-in-law Henri Louis Pernod realms: digestive effects, antiparasitic effects, and effects purchased Ordinaire's formula and began producing on the central nervous system. Various reported effects large quantities of absinthe at the Pernod Fils distillery? of isolated alpha- and beta-thujone may also be relevant One client for their product was the French military, which invaded Algeria from 1844-1847 and issued to wormwood's effects. absinthe regularly to the troops to help prevent and treat Digestive Effects dysentery. These troops apparently returned to France In a controlled clinical trial, wormwood tincture and with a taste for absinthe and increased the popularity of thujone-free wormwood tincture were both shown to sigthe beverage. nificantly increase bile and pancreatic enzyme secretion Though originally absinthe was most popular with in humans compared with water.6The levels of secretion people in the lower classes, it caught on among the intelwere assessed intraduodenally. Investigations into the ligentsia in the 1860s and 1870s, a time of cultural ferment, particularly in Paris. Between 5 and 7 PM, Parisians mode of action of wormwood have not been published. These effects seem to be common to many bitter herbs would gather in cafes to sip absinthe, often diluted by that contain sesquiterpene lactones. pouring cold water over a sugar cube held in a perforated spoon into a glass containing a shot of ab~inthe.~ Hepatic Effects Numerous famous artists of the time drank absinthe regThe effect of methanol and water extracts of wormwood ularly, including Vincent van Gogh, whose insanity has on liver function in mice and rats were assessed in one been blamed on his absinthe habit.

Artemisia absinthium (Wormwood)

series of studies? Pretreatment of mice with 500 mg/kg of wormwood extract decreased the 100% lethality of 1g/kg acetaminophen to 20%. The toxicity of carbon tetrachloride was also reduced by pretreatment of rats with wormwood. Giving rats a toxic, sublethal dose of acetaminophen led to sigruficant hepatic damage; administering 500 mg/kg wormwood extract 6 hours after acetaminophen administration sigruficantly reduced this damage. Wormwood extract did not reduce the hepatotoxicity of carbon tetrachloride in this same model. Because acetaminophen and carbon tetrachloride are both converted to toxic intermediates by cytochrome P450 enzymes, and because wormwood had effects on the toxicity of both drugs, as well as lengthening pentobarbitalinduced sleep in mice (an effect possibly related to cyt P450 inhibition), it was hypothesized that the effects of wormwood may in part be mediated by inhibition of cyt P450 enzymes.

Antiparasitic Effects The effects of wormwood on various parasitic microorganisms has been assessed in vitro and in animals. These results have been of somewhat greater interest lately with the discovery of potent antimalarial compounds from Artmisiu annua (sweet Annie), a close relative of wormwood. Wormwood does not appear to contain the same active constituents as sweet Annie, which are artemisinin and related sesquiterpene lactones. Nonetheless, aqueous extracts of wormwood showed antimalarial effects in vitro.'" In mice, oral administration of extracts using 95% ethanol of wormwood was shown to have a potent schizonticidal effect against Plasmodium berghei, though not as potent as chloroquine." Although 74 mg/kg of wormwood extract suppressed 96% of schizonticide activity, chloroquine at 10 mg/kg suppressed 100% of schizonticide activity. The effects of wormwood and its constituents on various amebae have also been investigated. In vitro, aqueous and ethanolic extracts of wormwood strongly inhibited the growth of the ameba Naegleriafowleri.'2 The lowest concentration of a sesquiterpene lactone extract from wormwood that inhibited growth of the amebae to 50% or less than that of controls was 31.9 pg/ml, compared to 0.025 pg/ml for amphotericin B. Apparently research has shown an effect for wormwood against Entamoeba histolytica from India, but details of thispublication could not be ~btained.'~

Neurologic Effects Structural and biosynthetic similarities have long been noted among alpha- and beta-thujone and tetrahydrocannabinol (THC),the active hallucinogen from Cannabis sativa (marijuana).'* Though thujone does weakly bind cannabinoid receptors in animals and human receptors in vitro, it does not appear to activate these receptors to

any appreciable extent at reasonable c~ncentrations.'~ Wormwood oil also failed to have significant cannabinomimetic activity in this assay. Though thujone is widely considered to have hallucinogenic effects, these are not proven and do not appear to be mediated by cannabinoid receptors. For a discussion of the convulsant potential of thujone, refer to the toxicity section later. An 80% ethanol extract of wormwood was a strong muscarinic and nicotinic cholinergic receptor agonist in vitro.I6The effectswere due only slightly to the presence of choline in the plant, but other quaternary ammonium compounds appeared to largely account for the activity. Further research is necessary to determine if wormwood might have antidementia activity in humans.

CLINICAL APPLICATIONS Wormwood is officially approved by the German Commission E for treatment of patients with dyspepsia, loss of appetite, and biliary dy~kinesia.'~Published clinical trials were not located supporting the use of wormwood for any indication, with the exception of the paper discussed in the pharmacology section showing that wormwood could increase digestive secretions. That trial supports the use of wormwood for loss of appetite, though much more specific work is necessary for definitive proof of efficacy.

DOSAGE Wormwood is primarily used in three forms-tea, tincture, and capsule. The volatile oil is also occasionally encountered, though it is considered too toxic for use. A typical dose of tea is 1g (1tsp) dried leaf and flower per cup of water, steeped for 10 to 15 minutes.'8 The tea should be covered during steeping to retain as many volatile constituents as possible. A cup of tea is sipped before meals three times daily. Thujone is not water soluble, so aqueous extracts of the plant are generally low in thujone. A typical dose of tincture is 0.5 to 1ml threetimes daily mixed with 2 to 4 oz water, sipped before meals. A typical capsule dose is 2 to 3 g per day in divided doses.I9

TOXICITY Though much toxicity is ascribed to wormwood, details and confirmed reports are scarce. Any toxicity attributed to the use of various forms of the beverage absinthe must not be confused with use of teas or tinctures in medicinal doses. Symptoms and effects said to be caused by chronic absinthe overindulgence were discussed earlier. The toxicity of the volatile oil also cannot be easily translated to other dose forms (particularly teas) of wormwood, which contain much lower concentrations of terpenoids.

Pharmacology of Natural Medicines

Alpha-thujone is considered a neurotoxin and convulsant compound.2° Beta-thujone, present in much higher levels in wormwood, is generally considered much less In mice, alpha- and beta-thujoneboth antagonize gamma-aminobutyric acid-A (GABAA)receptors and induce seizures.22Alpha-thujone was a much stronger convulsant thanbeta-thujone in thisstudy. This study confirmed prior findings that thujone is rapidly metabolized by the liver and removed from the body in animals.23 A 31-year-old man who drank 10 ml of wormwood volatile oil, mistakenly believing it was identical to absinthe, became agitated, belligerent, and incoherent and developed tonic-clonic seizures.24 Haloperidol improved his mental function, but acute renal failure and rhabdomyolysis were discovered, becoming worse a day later. Congestive heart failure developed, in part due to aggressive alkalinization. Seventeen days after discharge from the hospital he had recovered completely. These effects have never been documented to occur in patients being treated with reasonable doses of medicinal extracts of or crude wormwood. In one naturopathic medical practice, nine patients over a 3-year period were identified who had been treated with a bitters formula including 11%tinof wormwood, generally as a treatment for dyspepsia or malabsorption.25Administered at a dose of 1 tsp (5 ml) three times daily, patients would have been exposed to approximately 500 pL wormwood tincture three times daily for weeks to months. For the eight patients with available laboratory data, there was no evidence of renal, hepatic, or other damage. One patient, in fact, showed improvement in serum liver

enzyme levels while taking the bitters formula. None of the patients developed seizures or other signs or symptoms of neurotoxicity from the use of this formula. Though retrospective, this study does support the notion that wormwood in this form and at this dose is safe for use in adults as a digestive aid, in accordance with German Commission E indications and long-standing traditional use. Controlled clinical trials on the efficacy of wormwood should also include thorough analysis of its safety at medicinal doses. Thujone stimulates 5-aminolevulinate synthase in vitro, leading to large increases in porphyrin levelsJ6 Though it seems likely that porphyrogenic levels of thujone could be achieved by drinking large volumes of absinthe, levels of intake of tincture of wormwood are far lower and unlikely to lead to such high levels. Porphyrogeniceffects have not been clearly documented to be induced by wormwood in humans, though thujone and thujone-containing herbs such as wormwood should be avoided by people with porphyria until more information is available.

1. Bisset NG, Wichtl M, eds. Herbal drugs and phytopharmaceuticals. Boca Raton, n:CRC Press, 199445-48. 2.Lawrence BM, ed. Perfumer and flavorist. Essential oils 1992-1994. Natural flavor and fragrance materials. Carol Stream, IL: Allured Publishing Corporation, 1995:ll-14. 3.Vogt DD. Absinthium: a nineteenth-century drug of abuse. J Ethnopharmacol1981;4:337-342. 4.Vogt DD, Montagne M. Absinthe: behind the emerald mask. Int J Addict 1982;171015-1029. 5. Haines JD.Absinthe-return of the green fairy. J Okla State Med Assac 1998;91:406-407. 6.Tiserand R, Balacs T. Essential oil safety: a guide for health care professionals. Edinburgh: Churchill Livingstone, 1995. 7.Felter HW. Eclectic materia medica, pharmacology and therapeutics. Sandy, OR Eclectic Medical Publications, 1922,reprinted 1998. 8.Baumann IC, Glatzel H, Muth HW.Studies on the effects of wormwood (Artemisia ubsinthium L.) on bile and pancreatic juice secretion in man. Z Allgemeinmed 1975;51:784-791. 9. Gilani AH, Janbaz KH. Preventive and curative effects of Artetnisia absinthium on acetaminophen and CCl&duced hepatotoxicity. Gen Ph~Col1995;26309-315.

10.Hernandez H,Mendiola J, Torres D, et al. Effect of aqueous extracts of Artemisia on the in vitro culture of Plasmodium falciparum. Fitoterapia 1990;61:540-541. 11.Zafar MM, Hamdard ME, Hameed A. Screening of Artemisia absinfhium for antimalarial effects on Plasmodium berghei in mice: a preliminary report. J Ethnopharmacol1990;30:223-226. 12.Mendiola J, Bosa M, Perez N, et al. Extracts of Artemisia abrotanum and Artemisin absinthium inhibit growth of Nuegleriafowleri in vitro. Trans R Soc Trop Med Hyg 1991;8578-79. 13.Tahir M, Khan AB, Siddiqui MMH. Effect of Artemisiu absinthium Linn in acute intestinal amebiasis. Conference of Pharmacology and Symposium on Herbal Drugs, New Delhi, India, 1991. 14.del Castillo J, Anderson M, Rubottom GM. Marijuana, absinthe and the central nervous system. Nature 1975;253:365-366. 15.Meschler JP,Howlett AC. Thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses. Pharmacol Biochem l3ehav 1999;62:473-480. 16.Wake G, Court J, Pickering A, et al. CNS acetylcholine receptor activity in European medicinal plants traditionally used to improve failing memory. J Ethnopharmacol2000;69105-114. 17. Blumenthal M, Busse WR, Goldberg A, et al, eds. The complete German Commission E monographs: therapeutic guide to

DRUG INTERACTIONS No confirmed drug interactions exist for wormwood. It should be avoided in combination with chronic ethanol abuse due to historical reports pertaining absinthe. Given the low doses of tinctures used, this should not represent any health threat related to ethanol ingestion. Wormwood may have synergistic porphyrogenic effects with other drugs that can induce porphyric attacks including barbiturates, hydantoins, and carbamazepine.

Arternisia absinthium (Wormwood) herbal medicines. Austin, Tx: American Botanical Council, 1998: 232-233. 18. Windholz M, Budavari S, Blumetti RF, Otterbein S, eds. The Merck index. Rahway, NJ:Merck & Co, 1983. 19. Duke JA. Handbook of medicinal herbs, ed 2. Boca Raton, FL.:CRC Press, 2002798-799. 20. Summary of data for chemical selection alpha-thujone 546-80-5. National Toxicology Program. Available online at http://ntp-server. niehs.nih.gov/htdocs/Chem-Background/ExecSumm/hujone. html [accessed October 20021. 21. Arnold WN. Vincent van Gogh and the thujone connection. JAMA 1988;260:3042-3044. 22. Hold Kh4, Sirisoma NS, Jkeda T, et al: Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification. Proc Natl Acad Sci U S A 2000;973826-3831.

23. Hold KM, Sirisoma NS, Casida JE. Detoxification of alpha- and beta-thujones (the active ingredients of absinthe): Site specificity and species differences in cytochrome p450 oxidation in vitro and in vivo. Chem Res Toxic01 2001;14589-595. 24. Weisbord SD, Soule JB, Kimmel PL. Poison on l i n e a c u t e renal failure caused by oil of wormwood purchased through the Internet. N Engl J Med 1997337825-827. 25. Heron S, Yamell E. Retrospective analysis of the safety of bitter herbs with an emphasis on Artemisin absinthium L (wormwood). J Naturopathic Med 2OOO;932-39. 26. Bonkovsky HL, Cable EE, Cable JW, et al. Porphyrogenic properties of the terpenes camphor, pinene, and thujone. Biochem Pharmacol 1992;432359-2368.

Artemsia annua (Sweet Wormwood) Eric L. Yarnell, N D , RH(AHG Kathy Abascal, BS, JII, RH(AHG CHAPTER CONTENTS General Description 761 Chemical Composition 761

Clinical Applications 763 Malaria 763 Schistosomiasis 763

History and Folk Use 761

Dosage 763

Pharmacology 762 Antimalarial Effects 762 Antiparasitic 762 Antineoplastic 762

Toxicity

Arfernisiu unnua (family: Asteraceae) Common names: sweet Annie, qing hao

GENERAL DESCRIPTION The genus Artemisia is named after the Greek goddess Artemis, who apparently used a plant in the genus and gave her name to it. Sweet wormwood is a large annual herb with woody stems that may attain 2 m in height. The fine leaves are dark green and have a strong, pleasant odor. The herb produces fragrant yellow flowers in late summer and early autumn. It grows as an invasive weed in many areas.

CHEMICAL COMPOSITION Sweet wormwood contains several sesquiterpene trioxane lactones, most notably artemisinin (also known as qinghaosu) but also deoxyartemisinin, artemisinic acid, and arteannuin-B.' These compounds give the plant a distinctive bitter taste. A peroxide bridge in artemisinin is vital in the antimalarial effects of the compound (Figure 69-1).2 Artemisinin is rapidly and readily reduced to dihydroartemisinin in the body. Dihydroartemisinin appears to be the active metabolite of artemisinin and all synthetic artemisinin derivatives developed to date (Figure 69-2).3

763

Drug Interactions 763

Sweet wormwood also containsa number of flavonoids.' In vitro research suggests these flavonoids potentiate the antimalarial activity of the sesquiterpene lactones.4 Three semisynthetic derivatives of artemisinin are widely available for use: artemether, artesunate, and arteether? Artemether is a lipophilic beta epimer of dihydroartemisinin and is administered intramuscularly. Artesunate is a hydrophilic hemisuccinate compound administered orally or by injection. Arteether is an ethyl ether derivative of dihydroartemisinin and is lipophilic (Figure 69-3).

HISTORY AND FOLK USE The herb, known to the ancient Chinese as qing hao, was recommended for treatment of fever as early as 341 AD, as written in the handbook for prescription for emergencies, Zhou Hou Bei Ji Fang by Ge Heng.3 Qing hao had been prescribed in traditional Chinese medicine for other problems for at least 500 years beforehand on the basis of extant written records. Qmghaosu, known as arfernisinin in the West, was isolated and identified in Sing hao in the 1970s in China.5 It was thoroughly investigated and determined to have excellent antimalarial activity. Several semisynthetic drugs have since been created as discussed above; along with artemisinin, they are used more and more in treating patients with malaria.

761

Pharmacology of Natural Medicines rapid death of all stages of malaria parasites.8 Because the presence of an oxidizing peroxide bridge appears essential to the activity of artemisinin compounds, the oxidative hypothesis is further supported. The importance of iron to this process is unclear. Some investigators suggest that iron chelators such as desferrioxamine actually increase the activity of artemisinin in vitro? Artemisinin compounds are synergistic with many other, but not all, antimalarial drugs. Low doses of mefloquine and artemisinin showed definite synergism in vitro against Plasmodiumfalciparum,while higher doses showed additive effects.'O Mefloquine, chloroquine, primaquine, and tetracycline were all potentiated by artemisinin in mice with malaria; the effects of pyrimethamine, cycloguanil, and sulphonamide antibiotics were all decreased."

Figure 69-1 Artemisinin.

Antiparasitic

I

OH Figure 69-2 Dihydroartemisinin.

Besides killing Plasmodium spp., artemisinin compounds have shown activity against Schistosoma spp. and Clonorchis sinensis. Numerous animal studies show that artemether and artesunate can prevent and cure infections by Schistosoma japonicum, Schistosoma mansoni, and Schistosoma haematobi~m.'*-'~It is not clear if artemisinin or dihydroartemisinin is effective. However, artemisinin and the various semisynthetic variants available were all effective at treating Clonorchis infections in rats with no sign of toxicity.16

Antineoplastic

Artemether: R=CH,

OR

Arteether: R=C,H, Artesunate sodium: R=COCH,CH,CO,Na Flgure 69-3

Artemisinin derivatives (artesunate,artemether, and arteether).

PHARMACOLOGY Antimalarial Effects Dihydroartemisinin preferentially accumulates in erythrocytes, and malaria-infected erythrocytes accumulate 300 times as much as uninfected erythrocytes.6 Since active artemisinin compounds all appear to be converted to dihydroartemisinin in vitro and then to act as mentioned earlier, all these compounds ultimately end up in erythrocytes. Artemisinin and related molecules appear to act in part by generation of free radicals, leading to damaging the membranes of several parasitic organisms7 This leads to

Mounting evidence suggests that artemisinin compounds have potent anticancer activity. Artemisinin and quercetagetin 6,7,3',4'-tetramethyl ether, a flavonoid found in sweet wormwood, both showed activity against several tumor types in ~ i h - 0 . Dihydroartemisinin '~ and artesunate have also been investigated and found to ~ ~presence ,~~ inhibit cancer cells sigruficantly in ~ i t r o .The of ferrous iron appears to be essential for this activity, and sufficient quantities of iron may be necessary to prevent cancer cells from becoming resistant to artemisinin compounds.'820 A combination of ferrous sulfate and dihydroartemisinin proved effective at limiting the growth of implanted fibrosarcomas in ratsz1 The combination did not appear to cause adverse effects. Ferrous sulfate or dihydroartemisinin administered alone were not effective in this model. Artemisinin inhibited human glutathione-Stransferase (GST) Al-1 in transgenic Escherichia coZi at concentrations readily achievable in humans.22This work suggests the possibility of using artemisinin to reduce drug resistance in cancer cells, which frequently protect themselves from chemotherapy agents by expressing various GST enzymes.

Arfemisiaannua (Sweet Wormwood)

CLINICAL APPLICATIONS Malaria A metaanalysis has confirmed that artemisinin; dihydroartemisinin; and the semisynthetic derivatives artemether, artesunate, and arteether are potent, effective, and safe in patients with uncomplicated malaria compared with other antimalarial agents.23In cases of severe or cerebral malaria, these agents appear to be at least as effective as quinine." No artemisinin compound has been shown to work better than any other, though there is a relative dearth of studies examining this question. It should be noted that most trials have been conducted in Southeast Asia, an area with a high incidence of multidrug-resistant malaria. Two uncontrolled trials have investigated the efficacy of an infusion of sweet wormwood leaves in patients against I? falciparurn or Plasmodium rnalariae malaria at two centers in the Democratic Republic of Congo.= The sweet wormwood was grown locally in both instances to try to determine the efficacy and cost effectiveness of this approach in Africa. In the first trial, 22 nonpregnantvolunteers older than the age of 11years with fevers higher than 38"C, evidence of parasitemia, and symptoms of malaria participated. Each received 1 L of an infusion of 5 g of sweet wormwood leaves in four divided doses for 5 days. Chromatographyshowed that thisprovided 12 mg of artemisinin total per day. Artemisinin has low water solubility, and this high degree of extraction can perhaps best be explained by the presence of nonartemisinin compounds improving artemisinin's water solubility or enhancing its efficacy.All but two patients reported complete elimination of symptoms. Five of these patients agreed to have blood smears checked daily during the trial. All five showed rapid decreases in parasite counts in the blood, and by day 4 all five patients showed complete elimination of parasitemia. In the second trial, 48 nonpregnant patients older than the age of 11 years, all with I? falcipururn and symptoms of malaria, volunteered for the study. The tea was prepared by boiling 5 g of sweet wormwood leaves in 1 L water for 5 minutes, resulting in a total of 7.2 mg of artemisinin being delivered daily for 4 days. In this group 92% had complete clearance of parasitemia by the end of the trial, and 77%were symptom free. Of the 11patients (23%)who still had parasites, only two showed evidence of parasitemia. Twelve patients complained of nausea or vomiting, or both, during the trial. The dose of artemisinin delivered in this study was substantially lower than the typical daily dose of artemisinin,which is 500 mg. This strongly suggests that compounds in sweet wormwood besides artemisinin have synergistic antimalarial activity, enhance absorption of artemisinin, or in other ways increase the effectiveness of artemisinin.

It is unknown if artemisinin would work the same way in people not chronically exposed to malaria. Artemisinin is also generally said to be ineffective at preventing malaria infection, though this does not appear to have been studied.

Schistosomiasis Several double-blind trials conducted in China and on the Ivory Coast have proven that artemether is effective at reducing the risk of developing schistosomiasis compared with placeb0.2~,~~ It is unclear if artemisinin or whole sweet wormwood would also be effective for this purpose, but trials are warranted.

DOSAGE The dose of sweet wormwood tea is 5 g/1 L water, drunk in three to four divided doses.2O The dose of a 1:5tincture of dried leaf is difficult to extrapolate from this dose because a higher ethanol concentration (60% to 70%) could be used, which would greatly improve the ability of the solvent to draw artemisinin into the final product. A rough estimate would be 1 to 3 ml three times a day for a healthy adult. The usual dose of isolated artemisinin as a prescription drug for uncomplicated malaria is 500 to 1000mg daily for 5 days.20,28 Food does not appear to significantly affect the absorption of artemi~inin.~~

TOXICITY The only common adverse effects from use of sweet wormwood are nausea, loss of appetite, and Vomiting is rare. Neurotoxic effects have been observed in experimentalanimals treated with artemisinin derivatives and in a small handful of humans.3oThese effects have not been observed during use of whole sweet wormwood or its extracts. Sweet wormwood should be avoided in pregnancy and lactation untiI more data are available regarding its safety in these situations. Artemisinin derivatives have frequently been used safely in children, particularly when administered by

DRUG INTERACTIONS Artemisinin compounds generally show more rapid parasite clearance and fever reduction when combined with mefloquine than either drug given by itself, according to a metaanalysis of clinical trials.18 Mefloquine's neurologic toxicity does not appear to be altered by combination with artemisinin compounds, though the tendency to induce severe vomiting may be slightly lessened. Artemisinin compounds can be combined safely with doxycycline and tetracycline, according to the results of

Pharmacology of Natural Medicines

two clinical trials, though at least one of these trials suggested the combination was less effective than artemether combined with m e f l o q ~ i n e . ~Another ~J~ double-blind trial found that the combination of artesunate and tetracycline is equally effective and much safer than quinine and tetracycline.34 Artemisinin may interfere slightly with sulfadoxinepyrimethamine (SP). In one trial, artemisinin by itself led to insigruficantlymore rapid parasite clearance than

artemisinin combined with SP.= Fever relief was achieved equally rapidly, and adverse effects were absent in both groups. Further research is necessary to determine for certain if there is any negative effect from combining these two agents. Grapefruit juice initially increases bioavailability of oral artemether, though it does not stop the inevitable decline in bioavailability of this compound that occurs with repeated dosing over a few days.%

1.Zheng GQ.Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 1994;60.54-57. 2. China Cooperative Research Group. Chemical studies on qinghaosu (artemisinine). On qinghaosu and its derivatives as antimalarials. J Tradit Chin Med 1982;2:3-8. 3. Hien TT,White NJ. Qinghaosu. Lancet 1993;341:603-608. 4. Elford K, Roberts MF, Phillipson JD,Wilson RJ. Potentiationof the antimalarial activity of qinghaosu by methoxylated flavones. Trans R Soc Trop Med Hyg 1987;81:434-436. 5. CoordinatingGroup for Research on the Structure of Qmghaosu. A new type of sesquiterpenelactone-qinghaosu. Kexue Tongbao 1977; 22142. 6. Gu HM,Warhurst DC, Peters W. Uptake of 3H-dihydroartemisinine by erythrocytes infected with Plasmodium fakiparum in vitro. Trans R Soc Trop Med Hyg 1984;7826.5-270. 7. Krungkrai SR,Yuthavong Y. The antimalarial action on Plasmodium falciparum of qinghaosu and artesunate in combination with agents which modulate oxidant stress. Trans R Soc Trop Med Hyg 198731: 710-714. 8. Meshnick SR. Artemisinin antimalarials:mechanisms of action and resistance. Med Trop (Mars) 1998;5813-17. 9. Sibmooh N,Pipitapom B, Wilairatana,'F et al. Effect of artemisinin on lipid peroxidation and fluidity of the erythrocyte membrane in malaria. Biol Pharm Bull 2000;23:1275-1280. 10. Bwijo B, Alin MH, Abbas N, et al. Efficacy of artemisinin and mefloquine combinations against Plasmodium falciparum. In vitro simulation of in vivo pharmacokinetics. Trop Med Int Health 19972: 461-467. 11. Chawira AN, Warhurst DC, Robinson BL, Peters W. The effect of combinations of qinghaosu (artemisinin)with standard antimalarial drugs in the suppressive treatment of malaria in mice. Trans R Soc Trop Med Hyg 1987;81:554-558. 12. Le WJ, You JQ,Yang YQ, et al. [Studies on the efficacy of artemether in experimental schistosomiasis.] Yao Xue Xue Bao 1982;17187-193. 13. Le WJ, You JQ Mei [Chemotherapeuticeffect of artesunate in experimental schistosomiasis.] Yao Xue Xue Bao 1983;18:619-621. 14.Xiao S, Tanner M, NGoran EK, et al. Recent investigations of artemether, a novel agent for the prevention of schistosomiasis japonica, mans0n.iand haematobia. Acta Trop 2002;82175181. 15. Yang Y, Xiao S, Tanner M, et al. Histopathologicalchanges in juvenile Schistosoma haematobium harboured in hamsters treated with artemether. Ada Trop 2001;79135-141. 16.Chen RX, Qu ZQ Zeng MA, Li JY. Effectof quinhaosu and its derivatives on CIonorchis sinensis in rats. Chin Pharm Bull 1983; 18410411. 17. Zheng GQ. Cytotoxic terpenoids and flavonoids from Artemisia annua. Planta Med 1994;60:54-57. 18.Singh NP, Lai H. Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci 2001; 7049-56.

19. Efferth T, Dunstan H, Sauerbrey A, et al. The anti-malarial artesunate is also active against cancer. Int J Oncol2001;18767-773. 20. Sadava D,Phillips T, Lin C, Kane SE. Transferrin overcomes drug resistance to artemisinin in human small-cell lung carcinoma cells. Cancer Lett 2002;179:151-156. 21.Moore JC, Lai H, Li JR, et al. Oral administration of dihydroartemisinin and ferrous sulfate retarded implanted fibrosarcoma growth in the rat. Cancer Lett 1995;9883-87. 22. Mukanganyama S, Widersten M, Naik YS, et al. Inhibition of glutathione Stransferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer 200297: 700-705. 23.McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria (Cochrane Review). In: The Cochrane Library, Issue 3,2002. Oxford, England: Update Software. 24. McIntosh HM, Olliaro P. Artemisinin derivatives for treating severe malaria (Cochrane Review). In:The Cochrane Library, Issue 3,2002. Oxford, England: Update Sohare. 25. Mueller Ms, Karhagomba IB, Hirt HM, Wemakor E. The potential of Artemisiu annua L. as a locally produced remedy for malaria in the tropics: Agricultural, chemical and clinical aspects. J Ethnopharmacol2OOO;73:487-493. 26. Xiao SH, Booth M, Tanner M. The prophylacticeffects of artemether against Schistosoma japonicum infections. Parasitol Today 2000;16: 122-126. 27. Utzinger J, NGoran EK, N'Dri A, et al. Oral artemether for prevention of Schistosoma mansoni infection: randomised controlled trial. Lancet 2000;355: 1320-1325. 28. B a h t GA. Artemisinin and its derivatives: an important new dass of antimalarial agents. Phannacol Ther 2001;90:261-265. 29. Dien TK,de Vries PJ, Khanh NX, et al. Effect of food intake on pharmacokinetics of oral artemisinin in healthy Vietnamese subjects. Antimicrob Agents Chemother 1997;41:1069-1072. 30.Miller LG, Panosian CB. Ataxia and slurred speech after artesunate treatment for fakiparum malaria. N Engl J Med 1997;336:1328. 31. Krishna S, Planche T, Agbenyega T, et al. Bioavailability and preliminary clinical efficacy of intrarectal artesunate in Ghanaian children with moderate malaria. Antimicrob Agents Chemother 2001;45509-516. 32. Looareesuwan S,Viravan C, Vanijanonta S, et al. Randomized trial of mefloquine-doxycycline, and artesunate-doxycycline for treatment of acute uncomplicated falciparum malaria. Am J Trop Med Hyg 1994;50:784-789. 33. Than M. Unpublished data obtained from the investigator, Defence Services General Hospital, Myanmar. Cited in McIntosh HM, Olliaro P. Artemisinin derivatives for treating uncomplicated malaria (CochraneReview). In:The Cochrane Library, Issue 3,2002. Oxford, England: Update Software. 34. Duarte EC, Fontes CJ,Gyorkos TW, Abrahamowicz M. Randomized controlled trial of artesunate plus tetracycline versus standard

v.

Artemisia annua (Sweet Wormwood) treatment (quinineplus tetracycline)for uncomplicated Plasmodium falciparum malaria in Brazil. Am J Trop Med Hyg 1996;54:197-202. 35. Tran TH, Arnold K, Nguyen TH, et al. Single dose artemisininmefloquine treatment for acute uncomplicated falciparum malaria. Trans R Soc Trop Med Hyg 1994;88:688-691.

36. van Aghnael MA, Gupta V, van der Graaf CA, van Boxtel CJ. The effect of grapefruit juice on the time-dependent decline of artemether plasma levels in healthy subjects. Clin Pharmacol Ther 1999;66:408414.

Bee Products-Pollen,

Propolis, and Royal Jelly Michael T. Murray, ND Joseph E. Pizzorno Jr, ND

C H A P T E I< C 0 N T E N T S General Description 767

Propolis 768 Royal Jelly 768

Chemical Composition 767 Dosage 768

History and Folk Use 767 Toxicity 768 Pharmacologyand Clinical Applications 768 Bee Pollen 768

GENERAL DESCRIPTION Historically, one of the most valued groups of natural medicines is that of bee pollen, propolis, and royal jelly. Bee pollen comes from the male germ cell of flowering plants. As the honeybee travels from flower to flower, it fertilizes the female germ cell. Honeybees enable the reproduction of more than 80%of the world’s grains, fruits, vegetables, and legumes. The pollen is collected and brought to the hive, where the bees add enzymes and nectar to the pollen. Propolis is the resinous substance collected by bees from the leaf buds and barks of trees, especially poplar and conifer trees. The bees use the propolis, along with beeswax, to construct the hive. Propolis has antimicrobial activities that help the hive block out viruses, bacteria, and other organisms. Royal jelly is a thick, milky substance produced by worker bees to feed the queen bee. The worker bees mix honey and bee pollen with enzymes in the glands of their throats to produce royal jelly. Royal jelly is believed to be a useful nutritional supplementbecause of the queen bee’s superior size, strength, stamina, and longevity compared with other bees.

CHEMICAL COMPOSITION Honey is composed primarily (roughly 70%) of simple sugars (mainly fructose, glucose, and maltose), but it also contains minerals including manganese, calcium, iron, and sodium; organic acids; amino acids; vitamins; and enzymes.

Drug Interactions 769

Although honey is a natural source of sugar, bee pollen is often referred to as “nature’s most perfect food” because it is a complete protein (typically containing 10% to 35% total protein), meaning it contains all eight essential amino acids. Bee pollen also provides B vitamins, vitamin C, carotenes, minerals, DNA, RNA, numerous flavonoid molecules, and plant hormones. Propolis and royal jelly have similar nutritional qualities to pollen but considerably higher levels of different biologically active compounds.’j2 Royal jelly contains approximately 12% protein, 5% to 6% lipids, and 12%to 15%carbohydrates.

HISTORY AND FOLK USE The use of bee products for medicinal purposes is as old as beekeeping itself. Chinese texts more than 2000 years old include many mentions of bee products. Hippocrates also wrote about them. Honey was so valued during Roman times that it was often used instead of gold to pay taxes. Of the bee products, propolis was the most valued as a medicinal agent. Hippocrates prescribed propolis to help heal sores, as well as external and internal ulcers. Propolis-making bees were also depicted on vases from ancient Egypt, where the sign of the bee was often interwoven with the titles of the kings and used as the motif on ornaments presented as rewards for valor. The ancient Egyptians looked upon bees and their propolis as the source of eternal health and life. In the seventeenth century, propolis was a major ingredient of healing ointments in the European pharmacopoeia.

-

767

PHARMACOLOGY AND CLINICAL APPLICATIONS The health benefits of bee products are much heralded but insufficiently researched. Some overlap exists in the clinical uses of pollen, propolis, and royal jelly. Following is a list of the principal uses for each of these bee p d ucts as shown in Box 70-1. This list is likely to grow with continued research.

Bee Pollen Little research has been done on bee pollen, probably because financial rewards to just@ such an investment are lacking. The research that does exist is limited but impressive. For example, studies in animals show that pollen can promote growth and development; protect against free radical and oxidative damage; and protect against the effects of harmful radiation, as well as toxic exposure to chemical solvents.55 A pollen extract has also been shown to produce sigruficant improvement in menopausal symptoms (headache, urinary incontinence, dry vagina, decreasing vitality) in double-blind studies? The improvements were achieved even though the pollen extract produces no estrogeniceffect, an important consideration for women who cannot take estrogens of any kind?

A key use of propolis is protection against and shortening the duration of the common cold. A preliminary human study reported that propolis extract reduced upper respiratory infections in children." In a doubleblind study of 50 patients with the common cold, the group taking propolis extract became symptom free far more quickly than the placebo group.lS Another possible application of propolis is in the treatment of inflammatory bowel diseases (IBDs) like Crohn's disease and ulcerative colitis. An anecdotal article described an interesting case of ulcerative colitis that responded to propolis therapy.19 The author suggested that the antimicrobial and antiinflammatory properties of propolis may be of value in the treatment of IBDs. The antimicrobial properties of propolis may also help protect against parasitic infections in the gastrointestinal tract. One preliminary study of children and adults with giardiasis showed a 52% rate of successful parasite elimination in children and a 60% rate in adults in those given propolis extract (amount not stated).20 However, these results are not as impressive as those achieved with conventional drugs used against giardiasis, so propolis should not be used alone for this condition without first consulting a physician about available medical treatment.

Propolis

Royal Jelly

The primary use of propolis has been in immune system enhancement and infections. Propolis has inherent antimicrobial activity that protects the hive block from viruses, bacteria, and other organisms. Propolis has shown considerable antimicrobial activity in in vitro studies.&1°Propolis also stimulates the immune system, according to preliminary human studies."J2 In vitro and animal studies have also shown that propolis exerts some antioxidant, liver protecting, antiinflammatory, and anticancer properties.1517

Some research on royal jelly has found a cholesterollowering effect. Specifically, 10 human studies have been published, 7 of which were double blind.2l Of the seven double-blind studies, only three used an oral preparation. An injectable form was used in the other four studies. Results of a detailed analysis of the double-blind studies indicate that with oral preparations, despite shortcomings in the design of the studies and lack of standardization with commercial preparations used, royal jelly can decrease total cholesterol levels by about 14%in patients with moderate to severe elevations in blood cholesterol levels (initial values ranging from 210 to 325 mg/dl). Even better results may be noted when using higherquality royal jelly products.

Bee pollen Allergies Antioxidant support Energy enhancement Menopausal symptoms Support for chemotherapy and radiation therapy Propolis Common cold Gastrointestinal infections Immune enhancement Topical antiinflammatory Upper respiratory tract infections Royal jelly Elevated cholesterol levels Energy enhancement

DOSAGE Bee pollen: usually 1to 3 tablespoons daily Propolis: 100 to 500 mg three times daily Royal jelly: 50 to 250 mg of royal jelly one to two times daily

TOXICITY Allergic reactions are the most common side effects. If there is a known allergy to conifer and poplar trees, use of bee products should be avoided. Allergic reactions

Bee Products-Pollen,

can range from mild (e.g.,mild gastrointestinal upset) to severe (e.g.,asthma, anaphylaxis [shock],intestinal bleeding, even death in people who are extremely allergic to bee products).22

1.Burdock GA. Review of the biological properties and toxicity of bee propolis (propolis).Food Chem Toxic01 1998;36347-363. 2. Hove SR, Dimick PS,Benton AW. Composition of freshly harvested and commercial royal jelly. J Apic Res 1985;2452-61. 3. Qian B, Zang X, Liu X. [Effectsof bee pollen on lipid peroxides and immune response in aging and malnourished mice.] Zhongguo Zhong Yao Za Zhi 1990;15:301-303,319. 4. Xie Y, Wan B, Li W. [Effect of bee pollen on maternal nutrition and fetal growth.] Hua Xi Yi Ke Da Xue Xue Bao 1994;25434-437. 5. Ceglecka M, Wojcicki J, Gonet B, et al. Effect of pollen extracts on prolonged poisoning of rats with organic solvents. Phytother Res 1991:5;245-249. 6. Szanto E, Gruber D, Sator M, et al. [Placebocontrolled study of melbrosia in treatment of climacteric symptoms.] Wien Med Wochenschr 1994;144:130-133. 7. Einer-Jensen N, Zhao J, Andersen KP, Kristoffersen K. Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats. Maturitas 1996;25:149-153. 8. Tosi B, Donini A, Romagnoli C, Bruni A. Antimicrobial activity of some commercial extracts of propolis prepared with different solvents. Phytother Res 1996;10335-336. Vohora SB, Sharma K, et al. Antibacterial, antifun9. Dobrowolski JW, gal, antiamebic, antiinflammatory and antipyretic studies on propolis bee products. J Ethnopharmacol19913577-82. 10. Tichy J, Novak J. Detection of antimicrobials in bee products with activity against viridans streptococci. J Altern Complement Med 2000;6:383-389. 11. Bratter C, Tregel M, Liebenthal C, Volk HD. [Prophylactic effectiveness of propolis for immunostimulation: a clinical pilot study.] Forsch Komplementarmed 1999;6256-260.

Propolis, and Royal Jelly

DRUG ~NTERAcT~oNs No drug interactions are known.

12. Crisan I, Zaharia CN, Popovici F, et al. Natural propolis extract NIVCRISOL in the treatment of acute and chronic rhinopharyngitis in children. Rom J Virol1995;46:115-133. 13.Pascual C, Gonzalez R, Torricella RG. Scavenging action of propolis extract against oxygen radicals. J Ethnopharmacol 1994; 41~9-13. 14. Lin SC,Lin YH, Chen CF, et al. The hepatoprotectiveand therapeutic effects of propolis ethanol extract on chronic alcohol-induced liver injuries. Am J Chin Med 1997;25:325-332. 15. Khayyal MT, El-Ghazaly MA, El-Khatib AS. Mechanisms involved in the antiinflammatory effect of propolis extract. Drugs Exp Clin Res 1993;19197-203. 16. Mirzoeva OK, Calder PC. The effect of propolis and its components on eicosanoid production during the inflammatory response. Prostaglandins Leukot Essent Fatty Acids 1996;55441-449. 17. Choi YH, Lee WY, Nam SY, et al. Apoptosis induced by propolis in human hepatocellular carcinoma cell line. Int J Mol Med 1999; 429-32. 18. Szmeja Z, Kulczynski B, Sosnowski Z, Konopacki K. [Therapeutic value of flavonoids in Rhinovirus infections.] Otolaryngol Pol 1989;43:180-184. 19. Golan R. Propolis. Townsend Letter for Doctors. June, 2001. 20. Miyares C, Hollands I, Castaneda C, et al. [Clinical trial with a preparation based on propolis "propolisina" in human giardiasis.] Acta Gastroenterol Latinoam 1988;18:195-201. 21. Vittek J. Effect of royal jelly on serum lipids in experimental animals and humans with atherosclerosis. Experientia 1995;51:927-935. 22. Greenberger PA, Flak MJ. Bee pollen-induced anaphylactic reaction in an unknowingly sensitized subject. Ann Allergy Asthma ImmUn012001;86239-242.

Beta-carotene and Other Carotenoids Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 771

Photoprotection 775 Commercial Forms 775

Dietary Sources 771 Metabolism 772 Absorption 772 Transformation in the Intestinal Mucosa 773 Transport, Storage, and Excretion 773

Clinical Applications 775 Prevention of Cancer 775 Prevention of Cardiovascular Disease 777 Immune Enhancement 778 Vaginal Candidiasis 778 Photosensitivity Disorders 778 Dosages 779

Physiologic Roles 774 Antioxidant Activity 774 Immune System 774 Reproduction 774

INTRODUCTION The carotenoids represent the most widespread group of naturally occurring pigments in nature. They are a highly colored (red and yellow) group of fat-solublecompounds, composed of hydrocarbons (carotenes) and their oxygenated derivatives (oxycarotenoids or xanthophylls). The basic carotenoid structure consists of eight isoprenoid units with a series of conjugated double bonds. All photosynthetic organisms, whether bacteria or plants, contain carotenoid pigments. These compounds not only function as auxiliary pigments in photosynthesis but also play a crucial role in protecting the organism or plant against photosensitization by its own chlorophyll. More than 600 carotenoids have been characterized, but only about 30 to 50 are believed to have vitamin A activity and some 20 are found in human plasma and tissues. Biologic activity of a carotenoid has historically been considered synonymous with its corresponding vitamin A activity. Beta-carotenehas been termed the most active of the carotenoids due to its higher provitamin A activity (Figure 71-1). However, recent research suggests that this function of carotenoids has been overemphasized, as they have been found to exhibit many other important physiologic activities. For a carotenoid to have

Toxicity 779 Drug Interactions 779

vitamin A activity, it must have an unaltered beta-ionone ring with an attached polyene side chain containing 11 carbon atoms. In contrast, apocarotenoids are compounds that have been shortened by the removal of at least one end of the molecule beyond a designated location (e.g.,beta-Apo-8’carotenal has been cleaved at the 8’ carbon). Apocarotenes and xanthophylls have reduced or no vitamin A activity, but many have been shown to have sigruficant antioxidant and physiologic benefits.’”

DIETARY SOURCES Among the richest sources of carotenes are green leafy vegetables. The carotenoids present in green plants are found in the chloroplastswith chlorophyll, usually in complexes with a protein or lipid. Beta-carotene is the predominant form in most green leaves. In general, the greater the intensity of the green color, the greater

Figure 71-1

Betacarotene.

771

the concentration of beta-carotene. Orange-colored fruits and vegetables (e.g., carrots, apricots, mangoes, yams, squash) typically have higher concentrations of provitamin A carotenoids, the provitamin A content again paralleling the intensity of the color. Yellow vegetables have higher concentrations of xanthophylls and hence a lowered provitamin A activity. In the orange and yellow fruits and vegetables, beta-carotene concentrations are high, but other provitamin A carotenoids typically predominate. Red and purple vegetables and fruits such as tomatoes, red cabbage, berries, and plums contain large portions of non-vitamin A-active pigments including flavonoids. Legumes, grains, and seeds are also significant sources of carotenoids. Carotenoids are also found in various animal foods such as salmon and other fish, egg yolks, shellfish, milk, and poultry. Carotenoids are also frequently added to foods as colorants. Table 71-1 lists carotenoids with provitamin A activity found in common food sources, while Table 71-2 lists some important carotenoids that have no vitamin A activity. The structures of two of these, lycopene and zeaxanthin, are illustrated in Figures 71-2 and 71-3.

According to a detailed analysis of the levels of carotenoids in 120 fruits and vegetables, lycopene is found in few." Table 71-3 lists the foods that contained lycopene. These values indicate that lycopene levels are retained in food processing.

METABOLISM Absorption Various factors are known to influence the absorption efficacy of vitamin A and carotenoids. Although retinol does not I.equirebile acids to assist absorption, carotenoids do. Other factors that affect vitamin A and carotenoid absorption include the following: The presence of fat, protein, and antioxidantsin the food The presence of bile and a normal complement of pancreatic enzymes in the intestinal lumen The integrity of the mucosal cells The absorption efficiency of dietary vitamin A is usually quite high (80% to 90%),with only a slight reduction in efficiency at high doses. In contrast, beta-carotene's

Provitamin A carotenoids and food sources Carotenoid

Vitamin A activitv (7')

Food sources Green plants, carrots, sweet potatoes, squash, spinach, apricots, green peppers

Beta-carotene

100

Alpha-carotene

50-54

Green plants, carrots, squash, corn, watermelons, green peppers, potatoes, apples, peaches

Gamma-carotene

42-50

Carrots, sweet potatoes, corn, tomatoes, watermelons, apricots

Beta-zeacarotene

20-40

Corn, tomatoes, yeast, cherries

Cryptoxanthin

50-60

Corn, green peppers, persimmons, papayas, lemons, oranges, prunes, apples, apricots, paprika, poultry

Beta-apo-W-carotenal

72

Citrus fruit, green plants

Beta-apo-l2'-carotenal

120

Alfalfa meal

.*Carotene

Vitamin A activity (%)

Food sources Green plants, carrots, sweet potatoes, squash, spinach, apricots, green peppers

Beta-carotene

100

Alpha-carotene

50-54

Green plants, carrots, squash, corn, watermelons, green peppers, potatoes, apples, peaches

Gamma-carotene

42-50

Carrots, sweet potatoes, corn, tomatoes, watermelons, apricots

Beta-zeacarotene

20-40

Corn, tomatoes, yeast, cherries

Cryptoxanthin

50-60

Lycopene

0

Corn, green peppers, persimmons, papayas, lemons, oranges, prunes, apples, apricots, paprika, poultry Tomatoes, carrots, green peppers, apricots, pink grapefruit

Zeaxanthin

0

Spinach, paprika, corn, fruits

Lutein

Green plants, corn, potatoes, spinach, carrots, tomatoes, fruits

Canthaxanthin

0 0

Crocetin

0

Saffron

Capsanthin

0

Red peppers, paprika

Mushrooms, trout, crustaceans

Beta-carotene and Other Carotenoids

Figure 71-2

Lycopene.

OH

HO Figure 71-3 Zeaxanthin.

Lycopene content of common foods Food

Lycopene (mg/lOO g)

Apricot, canned

0.06

Apricot, dried

0.8

Grapefruit (pink and raw)

3.4

Guava juice

3.3 3.1

Tomato, raw Tomato juice, canned

8.6

Tomato paste, canned

6.5

Tomato sauce, canned

6.3

Watermelon, raw

4.1

absorption efficiency is much lower (40% to 6O%), and it decreases rapidly with increasing Carotene supplementsare better absorbed than the carotenes from foods? Supplying only beta-carotene, whether natural or synthetic, may be exerting a detrimental effect to the absorption of other carotenes. For example,beta-carotene supplementation has been shown to inhibit the absorption of luteh6Studies in humans have shown that with beta-carotene supplementation, the absorption of lutein can drop by more than 50%? Interestingly the absorption of lutein from vegetables is five times greater than that of beta-carotene?

The conversion diminishes as carotene intake increases and when serum retinol levels are adequate.l0 Beta-carotene and other provitamin A carotenes were originally believed to be cleaved by carotene dioxygenase at the 15,15' double bond, which would yield two molecules of all-trans retinal. Current belief, however, is that the dioxygenase enzyme nonspecifically attacks any one of the double bonds of the beta-carotene,resulting in the formation of a corresponding apo-beta-carotenal or retinal." The apocarotenal formed can either be degraded to retinal or absorbed.The retinal formed is then converted to retinol by retinaldehyde reductase. Uncleaved provitamin A carotenoids, apocarotenoids, and non-provitamin A carotenoids like retinol are transported in the chylomicra.

Transport, Storage, and Excretion No specific carrier protein exists in the plasma for carotenoids. These compounds are typically transported in human plasma in association with the plasma lipoproteins, particularly by low-density lipoprotein (LDL). As a consequence, patients with high serum cholesterol or LDL levels tend to have high serum carotene levels. The concentrations found in the plasma usually reflect the dietary concentration, with beta-carotene typically comprising only 20% to 25% of the total serum carotene level.12 Lycopene is the most predominant carotenoid in human plasma, accounting for more than 50% of the carotenoids in human serum. Owing to its lipophilic nature, lycopene is found to concentrate in LDL and very-low-density lipoprotein (VLDL) fractions and not in high-density lipoprotein (HDL) fractions of the serum cholesterol. Interestingly, although trans-lycopene constitutes the predominant isomer in food sources, in human plasma 50%of the total lycopene has been found as cis isomers. Whether thisis due to in vivo isomerization or preferential absorption of cis-lycopene is still unclear. Little is known about in vivo metabolism of lycopene. Carotenes may be stored in adipose tissue, the liver, other organs (the adrenals, testes, and ovaries have the highest concentrations), and the skin (Table 71-4). Distribution of carotenoids in some human tissues ( W g )

Transformation in the Intestinal Mucosa As stated earlier, of the more than 600 carotenoids that have been reasonably well characterized, only about 30 to 50 are believed to have provitamin A activity. Yet carotenoids provide the majority of dietary vitamin A. Provitamin A carotene conversion to vitamin A depends on diverse factors9:

Tissue

Carotenoids

Beta-carotene

Adrenal

20.1 f 11.9 8.3 f 21.3

10.8f 5.5 4.7 f 2

Lung

5 f 7.7 3.9f 6 2.3 f 1.2 1.6 f 2.2 0.6 f 1 .O

Thyroid

0.6 f 0.4

-

Liver Testis Fat Pancreas

Protein status Thyroid hormones zinc Vitamin C

Spleen

1.3f1.1 1.1 fl 1.2f 0.5 -

Deposition in the skin results in carotenodermia. This is a benign (and probably beneficial) state. Carotenodermia not directly attributable to dietary intake or supplementation, however, may indicate a deficiency in a necessary conversion factor (e.g., zinc, thyroid hormone, vitamin C, or protein).

PHYSIOLOGIC ROLES Antioxidant Activity In general carotenes exert sigruficant antioxidant activity, while the antioxidant activity of vitamin A is relatively However, its antioxidant actions are specific in that they are involved primarily in scavenging singlet molecular oxygen and to a much lesser extent peroxyl radicals. The efficacy of the various carotenoids for physical quenching is related to the number of conjugated double bonds present in the molecule determining their lowest triplet energy level. The most efficient singlet oxygen quenching camtenoid is the open-ring camtenoid lycopene. The antioxidant activity of carotenes is thought to be responsible for their anticancer effects noted in population studies (discussed later). Because aging is associated with free radical damage, a hypothesis developed that carotenes may also protect against aging as well. Evidence seem to support this hypothesis. It appears that tissue carotenoid content is the most sigruficant factor in determining maximal life span potential (MLSP) of mammalian species (r = 0.835 for 12 mammalian species, and for primates alone, r = 0.939!).14For example, human MLSP of approximately 90 years correlates with a serum carotene level of 50 to 300 pg/dl, while other primates, such as the rhesus monkey, have an MLSP of approximately 34 years, correlating with a serum carotene level of 6 to 12 pg/dl. Although beta-carotene has received most of the attention, many carotenes that have either low or no vitamin A activity exert much greater protection compared with beta-carotene. For example, beta-carotene generates vitamin A much more efficiently than alpha-carotene, but alpha-carotene is approximately 38% stronger as an antioxidant and 10 times more effective in suppressing liver, skin, and lung cancer in animals compared with beta-~ar0tene.l~ Even more powerful are lycopene and lutein.’”20 Studies have shown lycopene to exhibit the highest overall singlet oxygen quenching of the carotenoids thus far studied.21 Its activity is roughly double that of beta-carotene. Furthermore, lycopene exerts even more impressive anticancer effects.”J8 To evaluate the role of lycopene as a protective factor in digestive tract cancers, a case-control study was conducted in northern Italy, where tomato intake is high but also heterogenous in that some people eat a lot of tomatoes while others eat few, if any. Tomatoes are a perfect

food to study as they are quite high in lycopene but low in carotene. The data were obtained from a series of hospital-based studies on various cancers of the digestive tract from 1985-1991.“ Frequency of consumption of raw tomatoes was divided into four levels: fewer than two; three to four; four; five to six; and more than seven servings per week. Results showed a consistent pattern of protection by high intake of raw tomatoes in all examined cancer sites of the digestive tract. The degree of protection was similar to, but somewhat more marked than, those afforded by green vegetables and fruit studies carried on in the same areas.The results support the findings of other researchers who found, for example, a 40% reduction in the risk of esophageal cancer by simply consuming one serving of raw tomatoes per week and a 50%reduced rate for cancers of all sites among elderly Americans reporting a high tomato intake. These results suggest that increasing dietary lycopene levels may be a sigruficant protector against cancer.17J8

Immune System Carotenes have demonstrated significant effects in enhancing immune function. Some of these effects are probably related to an ability to prevent stress-induced thymic involution, as well as promote thymus growth and function and increase interferon’s stimulatory action on the immune system.= Interferon is a powerful immuneenhancing compound that plays a central role in protection against viral infections.

Reproduction Beta-carotene reportedly has a specific effect in fertility distinct from its role as a precursor to vitamin In bovine nutritional studies cows fed beta-carotenedeficient diets exhibited delayed ovulation and an inmase in the number of follicular and luteal The corpus luteum has the highest concentration of beta-carotene of any organ The carotene cleavage activity changes with the ovulation cycle, with the highest activity occurring during the midovulation stage. It has been speculated that a proper ratio of carotene to retinol must be maintained to ensure proper corpus luteum function. As the corpus luteum produces progesterone, inadequate corpus luteum function could have significant deleterious effects. Inadequate corpus luteum secretory function is one of the characteristic features of infertile or irregular menstrual cycles, or both?’ Furthermore, an increased estrogen-to-progesterone ratio has been implicated in various clinical conditions including ovarian cysts, premenstrual tension syndrome, fibrocystic breast disease, and breast cancerF8Because supplemental betacarotene given to cows significantly reduced the incidence of ovarian cysts (42% in control group vs. 3% in the beta-carotene group), it may have a similar effect

Beta-carotene and Other Carotenoids

in humans.25,26 Another bovine condition that benefited from increased dietary betacarotene levels is cystic mastitis.27Apparently dairy farmers have a greater appreciation of beta-carotene than do many nutritionists. O f course, there are sigruficant financial reasons, as the annual monetary loss from bovine mastitis in the United Stateshas been estimated at 1.5 to 2 billion dollars, and ovarian cysts represent the major cause of infertility in cattle.

Photoprotection Photooxidative processes play a role in the pathology of light-exposed tissues including the eye and skin. Agerelated macular degeneration affects the macula lutea of the retina, the area of maximal visual acuity. It is a major cause of irreversible blindness among the elderly in the United States. Macular pigments protect against the photooxidative processes, which may be related to the antioxidant activities of the macular carotenoids or their light-filtering effects. Although lutein and zeaxanthin are responsible for coloration of the macula lutea, neither lycopene, alphacarotene or betacarotene are found in this tissue. Lutein supplementation has proven particularly beneficial in offeringprotection against macular degeneration, as well as improving visual acuity in the early stages of the disease.18J9In regard to protecting the skin against oxidative damage, though clinical applications have focused on beta-carotene, lycopene seems particularly well suited for this application.”

Commercial Forms Five primary sources of carotenes are on the market: Synthetic all-trans beta-carotene Beta- and alpha-carotene from the algae Dunaliella Mixed carotenes from palm oil Lutein Lycopene Of the three sources of beta-carotene, mixed carotenes from palm oil carotenes seem to be the best form (Table 71-5).

Palm oil carotenes appear to give much better antioxidant protection. The carotene complex of palm oil closely mirrors the pattern in high-carotene foods. In particular, unlike the synthetic version, which only provides the trans configuration of beta-carotene, natural carotene sources provide beta-carotene in both a trans and cis configuration:

60% beta-carotene (both trans and cis isomers) 34% alpha-carotene 3% gamma-carotene 3% lycopene Palm oil carotenes are absorbed about 4 to 10 times Carotenes better than synthetic all-trans beta-~arotenes.~-~~ from Dunaliella have also been shown to be well abs0rbed.3~The widespread health concerns over the use of “tropical oils” like palm and coconut do not apply to carotene products extracted from palm oil, as the fat content is minimal. In addition, the real problem with palm oil occurs when it is processed (i-e., partially hydrogenated). Lutein is used primarily for macular degenerati~n’~J~ (see Chapter 189, while lycopene is emerging as a valued carotene for protection against cancer and cardiovascular disease.

CLINICAL APPLICATIONS Prevention of Cancer Most epidemiologic studies have demonstrated a strong inverse correlation between dietary carotene intake and various cancers, especially those involving epithelial tissues (e.g., lung, skin, uterine cervix, gastrointestinal The epidemiologic association is much stronger for carotene than for vitamin A. This may reflect carotene’s superior antioxidant, immune-potentiating, and anticarcinogenic activity.37 Although there is no argument that a diet high in carotenesprotects against cancer, the big question is: “Can beta-carotene supplementationreduce the risk of cancer?” ne products (per 25,000 IU of vitamin A activity)

Source

Carotenoid

Palm oil

Alpha-carotene Beta-carotene Gamma-carotene Lycopene

Quenching rate

% in source

mg/25,000 IU

Antioxidant potential

1.9 1.4 2.5 3.1

33 63 2.5 0.1

7.36 14.04 0.56 0.02

2.6 3.66 0.26 0.01 ~~

6.53

TOTAL

Algal

Alpha-carotene Beta-carotene

1.9 1.4

4 96

0.61 14.69

1.4

100

14.97

4.05

TOTAL

Synthetic

Beta-carotene TOTAL

0.22 3.83 3.9 3.9

The answer appears to be that synthetic betatarotene supplementation does not. Three highly publicized reports on cancer prevention trials featuring synthetic alltrans beta-carotene in high-risk groups have produced negative results. Taking a close look at each of these studies is important to help put things into perspective.

The Alpha-toco herol, Beta-carotene Cancer Prevention S t u y Group

B

This study's population was 29,000 men in Finland who smoked and drank The men were given betacarotene (20 mg daily) or vitamin E, or both. The results of this study indicated an 18%increase in lung cancer in the beta-carotene group. This result was not totally unexpected, as studies in primates demonstrated that when animals were fed alcohol and beta-carotene, they experienced an increase in liver damage as a result of oxidative damage.39 Other researchers have pointed out that beta-carotene is susceptible to oxidative damage.40The protection against oxidative damage of beta-carotene is the presence of other antioxidant nutrientsjl Absence of these protective nutrients could result in formation of cancer-causing compounds, stressing the importance of relying on foods and broader-spectrum nutritional antioxidant support. Adding support to this statement is the fact that the group receiving both beta-carotene and vitamin E did not show an increase in cancer. In the group not receiving beta-carotene supplements, there was a strong protective effect of high dietary beta-carotene and blood carotenelevels against lung cancer. Altogether, these data strongly suggest that the protection offered by betacarotene is only apparent when other important antioxidant nutrients are provided and may not be provided by the synthetic forms.

Carotene and Retinol Efficacy Trial The second trial reporting on the role of beta-carotene in a high-risk group is the Carotene and Retinol Efficacy Trial (CARET)." This study comprised more than 18,000 U.S.men and women smokers and asbestos workers. It was halted 21 months prematurely in January 1996 after 4 years of intervention indicated that beta-carotene supplementation (30 mg daily) increased lung cancer by 28% and overall deaths by 17%. Although this appears dramatic, a closer look at the numbers and percentages puts them into proper perspective. Among active smokers, the risk of lung cancer during the CARET study was 5 per 1000. The 28% increase found with beta-carotene supplementation increased this number to roughly 6 per 1000.' Interestingly, once again in the group not taking betacarotene, the lowest rate of cancer was found among individuals with the highest blood beta-carotene levels; and in former smokers, beta-carotene supplementation actually reduced cancer risk by 20%.

The Physician's Health Study The Physician's Health Study was composed of 22,071 U.S.male physicians who took either 50 mg of betacarotene or a placebo every other day for 12 years. Results demonstrated no sigrufrcant effect-positive or negative-on cancer or cardiovascular disease, even in the group (11%0) that smoked."

General Comments on the "Negative" Studies Although scientific research is clear that diets high in antioxidants are protective against many cancers, the data are not as solid with antioxidant supplements. Three main points should be kept in mind when discussing research with antioxidants: The antioxidant system of the body relies on a complex interplay of many different dietary antioxidants. Taking any single antioxidant nutrient is not enough. Total protection requires a strategic, comprehensive dietary and supplement program. Although dietary supplements are important, they cannot replace the importance of consuming a diet rich in antioxidants. A shortcoming of many dietary studies is that researchers often focus on the effects of just one factor. In a way this is like judging an entire symphony by listening to a single trombone. Such research has its value, but it is not complete and often raises more questions than it answers. Another issue is that not all antioxidants are created equal.When it comes to quenching freeradicals, each may have a somewhat different (and usually narrow) range of activity. For example, beta-carotene is an effective quencher of a free radical known as singlet oxygen but is virtually powerless against the dozens of other types of free radicals. As a result, it has a narrow range of benefit and is susceptible to being damaged itself and forming a free radical without additional antioxidant support. Most antioxidants require some sort of "partner" antioxidant that allow them to work more efficiently. And research has shown that beta-carotene itself can become damaged if used alone (i.e., without its partner antioxidants vitamin C, vitamin E, and selenium).For example, while studies showed that synthetic beta-carotene supplements given alone actually increased the risk of cancer in smokers, when beta-carotene was given along with vitamin E and selenium, it reduced cancer deaths by a significant 13%.38Damaged beta-carotene is extremely toxic to the liver, the lining of the arteries, and the lungs. This fact alone may explain some of the disappointing results from recent beta-carotene studies. The results of these three studies indicate that synthetic beta-carotene supplementation may have adverse effects

Beta-carotene and Other Carotenoids

alone in the management of advanced prostate cancer.50 F&y-four patients with histologically confirmed metastatic prostatic cancer and a performance status of 0 to 2 (World Health Organization) were entered into the trial. At 6 months there was a significant reduction in PSA level in both treatments, but it was more marked in the lycopene group (mean 9.1 and 26.4 ng/ml). After 2 years these changes were more consistent in the lycopene group (mean 3.01 and 9.02 ng/ml). Eleven (40%)patients in the orchidectomy-alone group and 21 (78%) in the lycopene group had a complete PSA response, with a Other Prospective Studies partial response in 9 (33%)and 4 (15%) and progression in 7 (25%) and 2 (7%), respectively. Bone scans showed In addition to these three highly publicized studies, sevthat in the orchidectomy arm only 4 (15%)patients had a eral prospective and double-blind studies have shown complete response, versus 8 (30%)in the lycopene group, promising results. In particular, beta-carotene supplewith a partial response in 19 (70%) and 17 (63%)and promentation is especially effective in the treatment of early in 4 (15%) and 2 (7%), respectively. Of the cancerous lesions of the oral cavity and e s o p h a g u ~ . ~ t ~gression ~ 54 patients who entered the trial, 19 (35%)died, 12 (22%) Although beta-carotene has been shown to exert these in the orchidectomy group and 7 (13%) in the lycopene benefits on its own (in dosages ranging from 15to 180mg/ group. Researchers concluded that adding lycopene to day), one of the most positive studies showing a reducorchidectomy produced a more reliable and consistent tion in cancer risk with supplemental beta-carotene to date decrease in serum PSA level; it not only shrinks the priis one that featured a broader supplement program. The mary tumor but also diminishes the secondary tumors, Linxian Cancer Chemoprevention Study was a prospecproviding better relief from bone pain and lower urinary tive study of 30,000 rural Chinese adults. In one subtract symptoms and improving survival compared with study, subjects received one of four supplementprograms: orchidectomy alone. Retinol and zinc Riboflavin and niacin Prevention of Cardiovascular Disease Vitamin C and molybdenum Just as in the case of cancer prevention, while a high Beta-carotene, vitamin E, and selenium (dosages one to intake of carotene-rich foods appears to be protective, the three times greater than the U.S. recommended daily same may not be true for supplementation with synthetic allowance) beta-carotene. Double-blind trials wherein people are in high-risk groups for cancer and cardiovascular disease. These studies do not invalidate the hundreds of studies showing the preventive effect of a diet rich in carotenes and nutritional antioxidants against cancer and cardiovascular disease. These results seem to indicate the need for a diet high in carotenes and, if carotene supplementation is desired, people should not smoke, natural forms should be used, and the beta-carotene needs to be protected against the formation of toxic derivatives by taking extra vitamins C and E and selenium.

The latter group demonstrated 13% less cancer deaths These results and a reduction of 9% in overall again support the notion that a combination of antioxidants is superior to high levels of any single antioxidant.

Lycopene in the Treatment of Prostate Cancer In one of the more detailed studies of lycopene protection against cancer, Harvard researchers discovered that men who consumed the highest levels of lycopene (6.5mg per day) in their diet showed a 21% decreased risk of prostate cancer compared with those eating the lowest levels.48Men who ate two or more servings of tomato sauce each week were 23% less likely to develop prostate cancer during the 22 years of the study than men who ate less than one serving of tomato sauce each month. In addition to a protective effect, lycopene may exert a therapeutic effect as well. In a study of patients with existing prostate cancer, lycopene supplementation (15 mg daily) was shown to slow tumor growth, shrink the tumor, and lower the level of prostate specific antigen (PSA), a marker of cancer activity, by 18'70.~~ In another study, the efficacy of lycopene (4 mg daily) plus orchidectomy was compared with orchidectomy

supplemented with beta-carotene alone or placebo have not found benefit for synthetic beta-carotene supplement a t i ~ n .In ~ lfact, three of four have reported a higher risk of cardiovascular disease in the beta-carotene groups compared with those receiving placebo. The research implies that a full-spectrum of carotenes or more significant carotenes like lycopene or lutein would offer the greatest degree of pr~tection.l-~J~,~~,~~-~ Just as in cancer, a potential problem with much research on carotenes in cardiovascular disease protection has been the focus on beta-carotene. It may not be the most important marker of protection. A large clinical study evaluating the relationship between carotene status and heart attack (acute myocardial infarction) found that lycopene, but not beta-carotene, was p r ~ t e c t i v e . ~ ~ Lycopene exerts greater antioxidant activity compared with beta-carotene in general but specifically against LDL oxidation.52-M Betacarotene is likely of less importance compared with many other carotenes, especially lycopene and lutein, because it does not get incorporated into LDL effectively, though it may help protect the endothelium.&Lutein may turn out to be the most significant carotene in the battle

against atherosclerosis. On the basis of analysis of the different subtypes of LDL, it was found that lycopene, beta-carotene, and cryptoxanthin were mainly located in the larger, less-dense LDL particles, whereas lutein and zeaxanthin were found preferentially in the smaller, denser LDL parti~les.5~ Since the smaller, denser LDL subtype is most easily oxidized, lutein and zeaxanthin are particularly important in protecting against damage to LDL cholesterol. Despite the focus on protecting LDL cholesterol from damage, it appears that the protective effect of carotenes against the development of atherosclerosisdoes not occur early in the progression (i.e., they exert little effect on protecting against oxidative damage to LDL cholesterol), but rather later on by some undetermined mechanism. This conclusion is based on studies indicating that carotenoid-enriched diets are associated with less atherosclerotic plaque formation.

Immune Enhancement Carotenes have demonstrated a number of immmeenhancing effects in recent s t u d i e ~However, .~ these effects were demonstrated as far back as 1931, when it was found that a diet rich in carotenes, as determined by blood carotene levels, was inversely related to the number of school days missed by children.%Originally it was thought that the immune-enhancing properties of carotenes were due to their conversion to vitamin A. Now it is known that carotenes exert many immune system-enhancing effects independent of any vitamin A activity? In a recent study the relationship of plasma concentrations of six major carotenoids (beta-carotene, alphacarotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin) with the incidence and severity of acute respiratory infections was determined. The incidence rate ratio of acute respiratory infections at high beta-carotene status was 0.71 (95% confidence interval [CI] 0.54 to 0.92) as compared with the low beta-carotene concentration group. Interesting, alpha-carotene, beta-cryptoxanthin, lycopene, lutein, and zeaxanthin were not related to incidence or severity of infections, indicating that beta-carotene may exert the most significant immuneenhancing effe~ts.5~ One of the most impressive studies with supplemental beta-carotene was conducted on normal human volunteers.% Results demonstrated that oral beta-carotene (180 mg/day, approximately 300,000 international unit [ILJ]) sigruficantly increased the frequency of OKT4-t (helper/inducer T cells) by approximately 30% after 7 days, and of OKT3-t (all T cells) after 14 days.“ As T4-t lymphocytes play a critical role in determining host immune status, this study indicates that oral beta-carotene may be effective in increasing the immunologic competence of the host in conditions characterized by a selective diminution of the T4 subset of T cells,

such as the acquired immunodeficiencysyndrome (AIDS) and cancer. However, rather than supplementing the diet with synthetic beta-carotene, it may be more advantageous to use natural carotene sources or to increase the intake of carotene-rich foods. In another study, 126healthy college students were randomly assigned to one of the following groups: Group A, the control group Group B, a group that used a 15-mg (25,000 IU)betacarotene supplement daily Group C, a group that consumed approximately 15mg beta-carotene per day from carrots Better results (i.e., increase in white blood cell number and function) were achieved in the group eating the carrots.59 As the absorption studies have shown supplemental beta-carotene to be much better absorbed than the carotenes from carrots and other vegetables, the differences are likely the result of form (i.e., natural is better than synthetic)?

Vaginal Candidiasis It is a well-established fact that women are more susceptible to vaginal candidiasis when the immune system is depressed, which may be due to low carotene levels. Betacarotene levels were determined in exfoliated vaginal cells in 22 women with vaginal candidiasisand compared with vaginal cells from 20 controls. The beta-carotene level per 1million cells in the women with va@ candidiasis was 1.46 ng compared with 8.99 ng in the control group (i.e., one-sixth that of normal).60 These results, coupled with beta-carotene’s known effects on enhancing the immune system, suggest that a low tissue level of beta-carotene is associated with vaginal candidiasis, and a high dietary or supplemental intake of beta-carotene may be protective against vaginal candidiasis.

Photosensitivity Disorders kta-carotene has become the treatment of choice for photosensitivity disorders. It is most effective in the treatment of erythropoieticprotoporphyria (EPP).Its effectiveness in other photosensitivity disorders such as polymorphous light eruption, solar urticaria, and discoid lupus erythematosus is sigruficant but not as great?149 Beta-carotene also has a small but sigruficant effect in increasing the exposure at which manifestations of sunburn begin, thus allowing some subjects the opportunity to stay in the sun long enough to get a “tan” for the first Patients with EPP are characterized by elevated levels of porphyrins in blood, feces, and skin and by sensitivity to visible light. This sensitivity manifests after exposure to sunlight as a burning sensation followed by swelling

Beta-carotene and Other Carotenoids

and redness. Topical sunscreens are of no value. The photosensitivity is due to excitation of the porphyrin molecule by ultraviolet radiation, resulting in the production of free radicals that are deleterious to the skin. Direct cell damage results in the release of chemical mediators, which in turn damage other cells, resulting in the manifestations of itching, burning, redness, and swelling. In EPP it appears that carotene levels must be maintained in the blood at 600 to 800 Fg/d for optimum effects and that the protective effect is not usually observed until after 4 to 6 weeks of therapy. The actions of betacarotene and other carotenes in human tissue are similar to their action in plant cells (i.e., they function as a cellular screen against sunlight-induced free radical damage).

DOSAGES For carotenes, a daily dosage of 25,000 IU (15 mg of betacarotene) appears to be reasonable for general health. Mixed carotene preparations are preferred to isolated beta-carotene supplements to provide the full range of carotenes in a natural form. For the treatment of precancerous lesions and immune enhancement, the dosage range is 25,000 to 300,000 IU. In the treatment of EPP, the dosage is based on maintaining blood carotene levels between 600 and 800 yg/dl. Again, for the best clinical impact, it appears that natural mixed forms of carotene should be used in conjunction with a broad range of other natural antioxidants (see Chapter 109).

high doses in the treatment of numerous photosensitivity disorders (see earlier discussion). Occasionally patients complain of loose stools, which usually clears spontaneously and does not necessitate stopping treatment. Elevated carotene levels in the blood do not lead to vitamin A toxiaty, nor do they lead to any other sigruficant disturbance besides yellowing of the skin (carotenodermia). The ingestion of large amounts of carrots or carrot juice (0.45 to 1 kg/day of fresh carrots for several years) has, however, been shown to cause neutropenia, as well as menstrual disorder^.^^,^^ Although the blood carotene levels of these patients did reach levels (221 to 1007 pg/ dl) similar to those of patients taking high doses of betacarotene (typically 800 pg/dl), the disturbances are due to some other factor in carrots, as neither of these effects nor any others have been observed in subjects consuming high doses of pure beta-carotene (e.g., 300,000 to 600,000 IU/day [180 to 360 mg beta-carotene], which is equivalent to 4 to 8 lb of raw carrots) over long periods of time.n-76Doses up to 1000 mg/kg have been given to rats and rabbits for long periods of time with no signs of embryotoxicity, toxicity, tumorigenicity, or interference in reproductive functions."

DRUG INTERACTIONS

Supplementing the diet with beta-carotene has not been shown to possess any sigruficant toxiaty despite its use in

One study showed that beta-carotene in combination with selenium, vitamin C, and vitamin E appeared to decrease the effectiveness of the combination of simvastatin (Zocor) and niacin. The researchers proposed that this inhibition of HMG-CoA reductase inhibitors could reduce the effectivenessof similar drugs such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), and pravastatin ( P r a v a c h ~ l ) . ~ ~

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TOXICIN

15. Murakoshi M, Nishino H, Satomi Y, et al. Potent preventive action of alpha-carotene against carcinogenesis:spontaneousliver carcinogenesis and promoting stage of lung and skin carcinogenesis in mice are suppressed more effectively by alpha-carotene than by betacatonene. Cancer Res 1992326583-6587. 16.Hwang ES, Bowen PE. Can the consumption of tomatoes or lycopene reduce cancer risk? Integr Cancer Ther 2002;1:121-132. 17. Weisburger JH. Lycopene and tomato products in health promotion. Exp Biol Med 2002;227924927. 18. Alves-Rodrigues A, Shao A. The science behind lutein. Toxic01 Lett 2004;15057-83. 19. Granado F, Olmediia 8, Blanco I. Nutritional and clinical relevance of lutein in human health. Br J Nutr 2003;90:487-502. 20. Mares-Perlman JA, Millen AE, Ficek TL, et al. The body of evidence to support a protective role for lutein and zeaxanthin in delaying chronic disease.J Nutr 2002;1325185524S. 21. Di Mascio P, Kaiser S, Sies H. Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch Biochem Biophysics 1989;274532-538. 22. Franceschi S, Bidoli E, LaVecchia C, et al. Tomatoes and risk of digestive-tract cancers. Int J Cancer 1994;59:181-184. 23. Bendich A. Beta-carotene and the immune response. Proc Nutr Soc 1991;50:263-274. 24. Folman Y, Rosenberg M, Ascarelli I, et al. The effect of dietary and climatic factors on fertility, and on plasma progesterone and oestradiol-17 beta levels in dairy cows. J Steroid Biochem 1983;19 863-868. 25. [No authors listed]. Metabolism of beta-carotene by the bovine corpus luteum. Nutr Rev 1983;41:357-358. 26. Lotthammer KH. Importance of beta-carotene for the fertility of dairy cattle. Feedstuffs 1979;51:16-19. 27. O'Fallon JV, Chew BP. The subcellular distribution of betacarotene in bovine corpus luteum. Proc Soc Exp Biol Med 1984;1773 406-411. 28. Sherman BM, Korenman SG.Inadequate corpus luteum function: a pathophysiological interpretation of human breast cancer epidemiology. Cancer 1974333306-1312. 29. Ben-Amok A, Mokady S, Edelstein S, et al. Bioavailability of a natural isomer mixture as compared with synthetic all-trans-betacarotene in rats and chicks. J Nutr 1989;1191013-1019. 30. Mokady S, Avron M, Ben-Amok A. Accumulation in chick livers of 9 4 s versus all-trans beta-carotene. J Nutr 1990;120:889-892. 31. Carughi A, Hooper FG. Plasma carotenoid concentrations before and after supplementation with a carotenoid mixture. Am J Clin Nutr 1994;59:896-899. 32. Zhang J, Wang CR, Xue AN, et al. Effects of red palm oil on serum lipids and plasma carotenoidslevel in Chinese male adults. Biomed Environ Sci 2003;16:348-354. 33. Morinobu T, Tamai H, Murata T, et al. Changes in betacarotene levels by long-term administration of natural beta-carotene derived from Dunaliella bardawil in humans. J Nutr Sci Vitamin01 1994;40:421430. 34. Ziegler RG. A review of the epidemiologic evidence that carotenoids reduce the risk of cancer. J Nutr 1989;119:116-122. 35. National Research Council. Diet and health: implications for reducing chronic disease risk. Washington, DC:National Academy Press, 1989313-314. 36.Mannisto S, Smith-Warner SA, Spiegehnan D, et al. Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies. Cancer Epidemiol Biomarkers Prev 2004;13:40-48. 37. Gerster H. Anticarcinogenic effect of common carotenoids. Int J Vitam Nutr Res 1993;63:93-121. 38. [No authors listed]. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. N Engl J Med 1994;3301029-1035.

39. Leo MA, Kim C, Lowe N, et al. Interaction of ethanol with betacarotene: delayed blood clearance and enhanced hepatotoxicity. Hepatology 1992;15:883-891. 40.Krinsky NI. The biological properties of carotenoids. Pure Appl Chem 1994;66:1003-1010. 41. Krinsky NI. Antioxidant functions of carotenoids. Free Radic Biol Med 1989;7617-635. 42. Omenn GS, Goodman G, Thomquist M, et al. The beta-carotene and retinol efficacy trial (CARET) for chemoprevention of lung cancer in high risk populations: smokers and asbestos-exposed workers. Cancer Res 1994;54:2038~-2043s. 43. Rowe PM. Beta-carotene takes a collective beating. Lancet 1996; 347249. 44. Garewal H, Shamdas GJ. Intervention trials with beta-carotene in precancerous conditionsof the upper aerodigestivetract. In BendichA, Butterworth CE, eds. Micronutrients in health and in disease prevention. New York Marcel Dekker, 1991:127-140. 45. Toma S, Benso S, Albanese E, et al. Treatment of oral leukoplakia with beta-carotene.Oncology 1992;4977-81. 46.Blot WJ, Li JY, Taylor PR, et al. The Linxian trials: mortality rates by vitamin-mineral intervention group. Am J Clin Nutr 1995;62 142451426s. 47.Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;851483-1492. 48. Gann PH, Ma J, Giovannucci E, Wdett W, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 1999;59:1225-1230. 49. Kucuk 0,Sarkar FH, Sakr W, et al. Phase 11 randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev 2001;10861-868. 50. Awari MS, Gupta NP.A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int 200392375-378. 51. Street DA, Comstock GW, Salkeld RM, et al. Serum antioxidants and myocardial infarction. Are low levels of carotenoidsand alphatocopheral risk factors for myocardial infarction? Circulation 1994; 901154-1161. 52.Kohlmeier L, Kark JD,Gomez-Gracia E, et al. Lycopene and myocardial infarction risk in the EURAh4IC Study. Am J Epidemiol 1997;146:61&626. 53.Rao AV, Agarwal S. Role of antioxidant lycopene in cancer and heart disease. J Am Coll Nutr 2000;19563-569. 54. Agarwal S, Rao AV. Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids 199833: 981-984. 55. Lowe GM, Bilton RF,Davies IG, et al. Carotenoid composition and antioxidant potential in subfractions of human low-density lipoprotein. Ann Clin Biochem 1999;36323-332. 56. Clausen SW. Carotenemia and resistance to infection. Trans Am Pediatr Soc 1931;4327-30. 57. van der Horst-Graat JM, Kok FJ, Schouten EG. Plasma carotenoid concentrations in relation to acute respiratory infections in elderly people. Br J Nutr 2004;92113-118. 58.Alexander M, Newmark H, Miller RG. Oral beta-carotene can increase the number of OKTet cells in human blood. Immunol Lett 1985;9221-224. 59.Brevard PB. Beta-carotene affects white blood cells in human peripheral blood. Nutr Rep Int 1989;40:139-150. 60.Mikhail MS, Palan PR, Basu J, et al. Decreased beta-carotene levels in exfoliated vaginal epithelial cells in women with vaginal candidiasis. Am J Reprod Immunol1994;32221-225. 61. Mathews-Roth MM, Pathak UA, Fitzpatrick TB, et al. Beta-carotene as an oral photoprotective agent in erythropoietic protoporphyria. JAMA 1974;2281004-1008.

Beta-caroteneand Other Carotenoids 62. Mathews-Roth MM, Pathak UA, Fitzpatrick TB, et al. Beta carotene therapy for erythropoietic protoporphyria and other photosensitivity diseases. Arch Dermatol1977;1131229-1232. 63. Mathews-Roth MM. Photosensitization by porphyrins and prevention of photosensitization by carotenoids. J Natl Cancer Inst 1982;69:279-285. 64.Mathews-Roth MM. Treatment of erythropoietic protoporphyria with beta-carotene. Photodermatology 1984;1:318-321. 65. Wennersten G. Carotenoid treatment for light sensitivity: A reappraisal and six years’ experience. Acta Derm Vernereol 1980;60: 251-255. 66.Swanbeck G, Wennersten G. Treatment of polymorphous light eruptions with beta-carotene. Acta Derm Venereol1972;52462-466. 67. Newbold PC. Beta-carotene in the treatment of discoid lupus erythematosus. Br J Dermatol1976;95:100-101. 68. Fusaro RM, Johnson JA. Hereditary polymorphic light eruption in American Indians - photoprotection and prevention of streptococcal pyoderma and glomerulonephritis. JAMA 1980;244:1456-1459. 69. Mathews-Roth MM, Pathak MA, Parrish J ,et al. A clinical trial of the effects of oral beta-carotene on the responses of human skin to solar radiation. J Invest Dermatol1972;59349-353.

70. Shoenfeld Y,Shaklai M, Ben-Baruch N, et al. Neutropenia induced by hypercarotenemia. Lancet 1982;1:1245. 71. Kemmann E, Pasquale SA, Skaf R. Amenorrhea associated with carotenemia. JAMA 1983;249:926-929. 72. Mathews-Roth MM. Neutropenia and beta-carotene. Lancet 1982;2222. 73.Stampfer MJ, Willett W, Hennekens CH. Carotene, carrots, and white blood cells. Lancet 1982;2615. 74. Mathews-Roth MM, Abraham AA, Gabuzda TG. Beta-carotene content of certain organs from two patients receiving high doses of beta-carotene. Clin Chem 1976;22:922-924. 75. Mathews-Roth MM. Amenorrhea associated with carotenemia. JAMA 1983;250.731. 76. Poh-Fitzpatrick MB, Barbera LG. Absence of crystalline retinopathy after long-term therapy with beta-carotene. J Am Acad Dermatol 1984;11:111-113. 77. Heywood R, Palmer AK, Gregson RL, et al. The toxicity of betacarotene. Toxicology 19859691-100. 78. Brown BG, Zhao XQ, Chait A. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-1593.

Boron Peter B. Bongiorng, ND, Dip1 Ac Gregory S. Kelly, ND (:HAPTEK CONTENTS Introduction 783

Hormone Interactions 787

Sources 783

Clinical Applications 787 Osteoporosis 787 Osteoarthritis and Rheumatoid Arthritis Prostate Cancer 788

Metabolism 784 Chemical Properties 784 Biochemistry 784 Biologic Functions 785

Dosage 788

Deficiency Signs and Symptoms 785

Toxicology 788

Nutrient Interactions 786 Vitamin D 786 Calcium 786 Copper 786 Magnesium 786 Phosphorus 786 Methionine and Arginine 786

Drug Interactions 789

INTRODUCTION Boron is an ubiquitous constituent of man's external environment. It typically occurs in nature as borates hydrated with varying amounts of water. Boric acid and borax are important boron-containing compounds.' In trace amounts boron is essential for the growth of many plants, and it is found in animal and human tissues at low Concentrations.' In plasma boric acid is the predominate form, and its concentration reflects dietary intake and respiratory exposure? Although it has yet to be recognized as an essential nutrient for humans, recent data from animal and human studies suggest that boron is important for many life processes including embryogenesis; bone growth; immune function; psychomotor skill; cognitive function3; mineral metabolism; brain function and performance; and prevention of osteoporosis, osteoarthritis, and possibly prostate cancer.

SOURCES Because boron in plants depends on the availability of boron in the Samefood can greatly in boron content depending on where and how it is grown.

787

Summary 789

In general, soils exposed to high degrees of precipitation have decreased levels of boron? Food processing results in additional loss of boron? Foods of plant origin, such as leafy vegetables, noncitrus fruits, nuts, legumes, and sea vegetables are considered the best sources of boron.'J6 Wine has also been shown to contribute appreciable amounts of boron to the diet? A diet containing an abundance of these items would provide 2 to 6 mg/day of boron.6,8 Daily intake of boron depends on several variables. Concentration of boron in water varies considerably according to geographic source. In some areas boron in drinking water and water-based beverages may account for most of the total dietary boron intake. Individual food preference greatly influences daily intake of boron. Fruits, vegetables, tubers, and legumes have higher concentrations of boron than do cereal grains or animal tissues. For adults and seniors, though, the largest source of boron turns out to be instant regular coffee? Given the poor dietary intake of produce in the United States, the top two boron contributors to adult boron intake, coffee and The original version of this chapter was reprinted with permission from Alternative Medicine Review 1997;2:48-56.

783

Pharmacology of Natural Medicines milk, are actually deficient in this nutrient (Table 72-1)'O compared with other more nutritious foods. Nevertheless, these make up 12% of the total boron intake by virtue of the volume consumed.1°Boron has also been determined to be a notable contaminant or major ingredient of many personal care products, and it is occasionally used (boric acid) as a food preservative." In Sydney, Australia, 32 subjects age 20 to 53 years old were assessed over a 7-day period for their dietary intake of boron. The average boron intake in male and female subjects was found to be 2.28 k 1.3 and 2.16 f 1.1mg/day, respectively.' The boron content of selected Australian foods has been found to correlate with values in Finnish and U.S.Food and Drug Administration tables and is presented in Table 72-2.7

I

Concentration of boron in selected Australian foods

Food Almonds Apples (red) Apricots (dried) Avocados Bananas Beans (red kidney) Bran (wheat) Brazil nuts Broccoli Carrots Cashews (raw)

METABOLISM Chemical Properties

Celery Chick peas

Elemental boron was first isolated in 1808. It is the first member (atomic number 5) of the metalloid or semiconductor family of elements including silicon and germanium and is the only nonmetal of the group IIIA elements. Like carbon, boron has a tendency to form double bonds and macromolecules.'* Boron, as boric acid, acts as a Lewis acid, accepting hydroxyl (OH-) ions and leaving an excess of pr0t0ns.l~Because boron complexes with organic compounds containing hydroxyl groups, it interacts with sugars and polysaccharides, adenosine5-phosphate, pyridoxine, riboflavin, dehydroascorbic acid, and pyridine nu~leotides.'~ Borate cross-links with polysaccharides, most likely as borate di-esters, to form gels with unique properties. These gels are plastic in nature and quickly reassemble in response to externally applied stress.I3 Five naturally occurring boron ester compounds have been identified as antibiotic^.'^ ~

Coffee, from ground beans Milk, whole Apples, raw Beans, refried Potatoes, from French fries Orange juice Peanut butter Wine Apple juice Cola

Boron (mg/ml)

0.029 0.018 0.36 0.4 0.11 0.072 1.145 0.61 0.18 0.013

Modified from Rainey CJ, Nyquist LA. Christensen RE, et al. J Am Diet Assoc

1999;99:335-340.

Hazelnuts Honey Lentils Olives Onions Oranges Peaches Peanut butter Pears Potatoes Prunes Raisins Walnuts Wine (Shiraz Cabernet)

2.82 0.32 2.11 2.06 0.16 1.4 0.32 1.72 0.31 0.3 1.15 0.5 0.71 1.08 0.5 2.77 0.5 0.74 0.35 0.2 0.25 0.52 1.92 0.32 0.18 1.18 4.51 1.63 0.86

~~

Top contributors of dietary boron in the American diet Food

Dates Grapes (red)

Boron (rngll00g)

Biochemistry Boron in food, sodium borate, and boric acid are well absorbed from the digestive tract.I6 These compounds are also absorbed through damaged skin and mucous membranes; however, they do not readily penetrate intact skin.I7 No accumulation of boron has been observed in soft tissues of animals fed chronic low doses of boron; however, in acute poisoning incidents, the amount of boric acid in brain and liver tissue has been reported to be as high as 2000 ppm. Within a few days of consumption of large amounts of boron, levels in blood and most soft tissues quickly reach a plateau.18 Tissue homeostasis is maintained by the rapid elimination of excess boron, primarily in the urine, with bile, sweat, and breath also contributing as routes of e1iminati0n.I~In humans,

Boron urinary boron excretion increases over time in all boronsupplemented subjects who have been studied.I9 Evidence suggests that supplemental boron does accumulate in bone; however, cessation of exposure to dietary boron results in a rapid drop in bone boron levels. The half-life of boric acid in animals is estimated at about 1day.18

Biologic Functions Boron contributes to living systems by acting indirectly as a proton donor and exerting an influence on cell membrane structure and function.20 Although the absolute essentiality of boron for plants is well documented, studies to date have not shown it to be unequivocally essential for either animals or humans. However, boron supplementation has been shown to affect certain aspects of animal physiologic function. Experimental animals supplemented with boron demonstrate a high degree of variability in their response. In general, supplemental dietary boron has its most marked effects when the diet is deficient in known nutrients.2I Evidence suggests that boron might have a slight effect on decreasing fasting serum glucose concentrations in postmenopausal women.I5

Embryo Maturation Emerging research has shown that boron is an important player in the early stages of life? Boron defiaency negatively affects reproductive ability, as well as embryo development in both the African clawed frog (Xenopus laatis) and the zebrafish. Experimentation with Xenopus noted that dietary boron deprivation elicited necrotic egg increases combined with a high frequency of abnormal gastrulation. In the zebrafish model, 45% of borondeprived embryos died during the early postfertilization period. Conversely, only 2% of boron-supplemented embryos died. Other studies with rats and mice corroborate that low boron status may affect reproduction in mammals, although conclusions from these studies are not as clear.

Life Span Boron in an animal model has been shown to affect life span, although the process is undefined. Extremes in dietary boron, both a deficiency and an excess, decreased the median life span of Drosophila by 69%,while supplementing the diet with low levels of boron increased life span by 9.5%.=

Brain Function Brain electrophysiology and cognitive performance were assessed in response to dietary manipulation of boron (~0.25 vs. ~ 3 . 2 5mg boron/2000 kcal/day) in three studies with healthy older men and women. A low boron intake was shown to result in a decrease in the

proportion of power in the alpha band and an increase in the proportion of power in the delta band. Other changes in left-right symmetry and brain wave coherence were noted in various sites, indicating an influence on brain function. When contrasted with the high boron intake, low dietary boron resulted in significantly poorer performance (p < 0.05) on tasks emphasizing manual dexterity, eye-hand coordination, attention, perception, encoding, and short- and long-term memory. Collectively, the data from these studies indicate that boron may play a role in human brain function, alertness, and cognitive performance.23

Hematologic Boron supplementation to human subjects who had previously followed a dietary regimen deficient in boron increased blood hemoglobin concentrations, mean corpusd a r hemoglobin, and mean corpuscular hemoglobin concentration.It lowered hematocrit, red cell count, and platelet

Hepatoprotection Studies of fulminate hepatic failure in Wistar rat models have shown boron pretreatment to significantly reduce lipid peroxidation, as well as decrease serum liver enzymes in these animals. Boron pretreatment also increased the peroxide-metabolizing enzymes levels of glutathione peroxidase and catalase.%

Mineral Metabolism Boron also affects mineral metabolism and has been shown to affect levels of certain hormones in human subjects. In the first nutritional study with humans involving boron,” postmenopausal women first were fed a diet that provided 0.25 mg boron/2000 kcal for 119 days and then were fed the same diet with a boron supplement of 3 mg boron/day for 48 days. The boron supplementation reduced the total plasma concentration of calcium and the urinary excretions of calcium and magnesium and elevated the serum concentrations of 17 beta-estradiol and testosterone.6 In a study designed to determine the effects of boron supplementation on blood and urinary minerals in athletic subjects on Western diets, findings suggested that boron supplementation modestly affected mineral status.Ig

DEFICIENCY SIGNS AND SYMPTOMS Information on boron deficiency is limited, especially in humans. It is thought that insufficient intake of boron becomes obvious only when the body is stressed in a manner that enhances the need for it. When the diets of animals and humans are manipulated to cause functional deficiencies in nutrients such as calcium, magnesium,

vitamin D, and methionine, a large number of responses to dietary boron occur.26 Evidence suggests that more than 21 days on a boron-deficient diet are required to demonstrate detectable effects in humans.27The variables that are changed due to a boron-deficient diet abruptly improve about 8 days after boron supplementation is introduced.6 Evidence indicates that hemodialysis results in an excessive decrease in serum boron as compared with controls.28Although by no means is blood urea nitrogen pathognomonic for a boron deficiency, it has been found to be slightly elevated during boron depletion.B

NUTRIENT INTERACTIONS Vitamin D Considerable evidence indicates that dietary boron alleviates perturbations in mineral metabolism that are characteristic of vitamin D3 deficiency.30In one study chicks fed on a diet inadequate in vitamin D exhibited decreased food consumption and plasma calcium concentrations and increased plasma concentrations of glucose, beta-hydroxybutyrate, triglycerides, triiodothyronine, cholesterol, and alkaline phosphatase activity after 26 days. Supplementalboron returned plasma glucose and triglycerides to concentrations exhibited by chicks fed on a diet adequate in vitamin D.31 In rachitic chicks, boron elevated the numbers of osteoclasts and alleviated distortion of the marrow sprouts of the proximal tibia1 epiphysial plate, a distortion characteristic of vitamin D3 deficiency.3032Higher apparentbalance values of calcium, magnesium, and phosphorus have been observed for rats fed on a vitamin D-deprived diet if the diet is supplemented with boron.21 After supplementation with 3.25 mg boron daily, plasma levels of D2 increased in men older than age 45 and postmenopausal women on low magnesium and copper diets.33

Calcium Boron supplementation may have a favorable impact on calcium metabolism. A boron supplement of 3 mg/ day affected several indices of mineral metabolism of seven women consuming a low-magnesium diet and five women consuming a diet adequate in magnesium; the women had consumed a conventional diet supplying about 0.25 mg boron/day for 119 days. Boron supplementation modestly reduced the urinary excretion of calcium when dietary magnesium was low? In men older than age 45 and postmenopausal women, changes caused by boron supplementation include increased concentration of plasma ionized and total calcium, as well as reduced serum calcitonin concentration and urinary excretion of calcium.33 A 1993 study demonstrated that a low boron diet elevated

urinary calcium excretion. The high level of calcium excretion was maintained throughout the &week study; however, it remained elevated even after boron supplementa tion began.%

Copper Supplemental boron ads to increase serum levels of both copper and copper-dependent enzymes in humans. Boron supplementation (3 mg/day) to five men older than age 45, four postmenopausal women, and five postmenopausal women on estrogen therapy who had been fed a low boron diet (0.23 mg/2000 kcal) for 63 days resulted in higher erythrocyte superoxide dismutase, serum enzymatic ceruloplasmin, and plasma copper.33In a subsequent study, these same variables were again found to be higher during boron repletion than while subjects were fed on a diet low in boron.=

Magnesium When magnesium deprivation is severe enough to cause typical signs of deficiency, a significant interaction between boron and magnesium is found.12 A combined deficiency of boron and magnesium causes detrimental changes in the bones of animals.Supplemental boron elevates plasma Mg concentrations and enhances Boron supplementationhas resulted in inmased serum magnesium concentrations in human female subjects studied.ls Boron supplementation increases red blood cell magnesium concentrations.36It has been shown that serum magnesium concentrations are greater in sedentary females whose diets are supplemented with boron than in exercising female athletes who are supplemented with boron.37This finding, while unexplained to date, may indicate a n increased loss of boron through urine and perspiration during exercise.

Phosphorous Supplemental boron seems to lower serum phosphorus concentrations in female subjects 20 to 27 years old?’ However, exercise training diminishes these changes,’8 again possibly indicating increased losses or an increased need for boron as a result of exercise. A low magnesium status, along with supplementation of boron, may depress the urinary excretion of phosphorus. This does not occur in women with an adequate magnesium intake:

Methionine and Arginine In experimental animals, a beneficial impact is consistently observed after boron supplementation when the diet contains marginal methionine and excessive arginine. Among the signs exhibited by rats fed on a diet marginal in methionine and magnesium are depressed growth and bone magnesium concentration and elevated spleen weight/body weight and kidney weight/body weight ratios. Findings indicate that the

Boron

severity of these symptoms is alleviated with boron ~upplementation.~~

HORMONE INTERACTIONS

Boron's observed impact on

selected hormones Hormone Alkaline phosphatase

Increases

Decreases X

In rats, supplemental dietary boron substantially X Aspartate transaminase' depressed plasma insulin, plasma pyruvate concentraX Calcitonin tions, and creatine kinase activity and increased plasma X Cholecalciferol thyroxine (T4) concentrations. Boron supplementation X also decreased plasma aspartate transaminase a~tivity.3~ Creatine kinase* X 17 beta-estradiolt In animal experiments, boron supplementation offsets the elevation in plasma alkaline phosphatase caused by Insulin" vitamin D defi~iency.~~ Superoxide dismutase One researcher has hypothesized that boron might be Testosterone+ required for the synthesis of steroid hormones, as well as Thyroxine* vitamin D. Because the biosynthesis of steroids such as vitamin D, testosterone, and 17 beta-estradiol involves 'These interactions have only been demonstrated in animal models. These interactions have not been demonstrated unequivocally to date in all age one or more hydroxylation steps, and because of boron's and gender segment of a human population. ability as a Lewis acid to complex with hydroxyl groups, boron may assist the addition of hydroxyl groups to the steroid structures.6It has also been suggested that boron may act in an unspecified manner to protect hormones from rapid inactivation.6The current hypothesis suggests CLINICAL APPLICATIONS that boron can inhibit a range of microsomal enzymes Osteoporosis that insert hydroxyl groups near existing hydroxyls in steroids. These enzymes include those that catabolize A considerable body of evidence has shown that both compositional and functional properties of bone 25-hydroxyvitamin D.40Researchers supplemented boric are affected by boron statusa In experimental animals, acid to rat drinking water and observed significant histologic findings suggest that supplemental boron elevations in the plasma 1,25-dihydroxyvitamin D conenhances maturation of the growth ~ l a t e . 2Boron ~ is centration at week 2 and the plasma testosterone concenalso found at the highest concentrations in growing and tration at week 4 relative to the control gr0up.4~ calclfylng areas of long bones6 In two human studies, An increase in dietary intake of boron from 0.25 to boron deprivation caused changes in indices associated 3.25 mg/day has been reported to increaseplasma 17betawith calcium metabolism in a manner that could be estradiol by more than 50% and to more than double construed as being detrimental to bone formation and plasma testosterone levels in postmenopausalwomen. The maintenance; these changes were enhanced by a diet low elevation seemed more marked when dietary magnesium in m a g n e ~ i u m .The ~ , ~author ~ concluded that boron and was low! In a subsequent study of healthy men, boron magnesium are apparently necessary for optimal calsupplementation resulted in an increase in the concentracium metabolism and are thus necessary to prevent the tions of both plasma estrogen and testosterone; however, excessive bone loss that often occurs in postmenopausal not all published trials support these observations? women and older men.29 Ten male bodybuilders, 20 to 26 years old, were given a 2.5 mg boron supplement, while nine male bodyOsteoarthritis and Rheumatoid Arthritis builders, 21 to 27 years old, were given a placebo for A dietary boron deficiency may be a contributing factor in 7 weeks. Because both groups demonstrated sigruficant some cases of arthritis.44In areas of the world where boron increases in total testosterone (p < 0.01), lean body mass intake is routinely 1 mg/day or less, the estimated inci( p < O.Ol), one repetition maximum squat (p < 0.001), and dence of arthritis ranges from 20% to YO%, whereas in bench pressing (p < 0.01), the authors concluded that the areas where boron intake ranges from 3 to 10 mg/day, the gains were a result of 7 weeks of bodybuilding, not of estimated incidence of arthritis ranges from 0% to boron supplementation.42 Analytic evidence indicates that persons with arthritis Table 72-3 lists boron's impact on selected hormones in either animals or humans. Some of these interactions have lower boron concentrations in femur heads, bones, and synovial fluid when compared with persons withhave only been demonstrated in animal models, while out this disorder. In addition, bones of patients using others have not been demonstrated unequivocally boron supplements are more difficult to cut than those of to date in all age and gender segments of a human patients not taking boron supplements? population.

In 1961 the first anecdotal evidence suggesting that boron may be beneficial for osteoarthritis was presented when one patient had reduced swelling and stiffness and remained symptom free for 1year following supplementation with 3 mg of elemental boron twice daily for 3 weeks. A human study also offers evidence that boron supplementation may be beneficial in the treatment of this condition. In a double-blind, placebo-controlled trial of 20 subjects with osteoarthritis, 50% of subjects receiving a daily supplement containing 6 mg of boron noted a subjective improvement in their condition. Only 10% of those receiving the placebo improved during the same time interval. Greater improvement was noted in the condition of all joints (p < 0.01), as well as less pain on movement (p < 0.001) in subjects receiving the boron ~upplementation.4~ Clinical observations indicate that children with juvenile arthritis (Still disease) improve with boron supplementation (6 to 9 mg/day) in 2 to 3 weeks, while adults with osteoarthritis may require 2 to 4 months of supplementation before benefits are detected. Persons with rheumatoid arthritis may experience an aggravation of symptoms (Herxheimer response) for 1 to 3 weeks but generally notice improvement within 4 weeks of beginning boron ~upplementation.~

groups. Immunohistochemical studies demonstrated significantly less expression of IGF-1 levels, although circulating levels were unchanged among the groups.@ Although the exact mechanism to explain the antiproliferative effect is unclear, boric acid is known to bind to cis-diols on the ribose moiety of nucleotides, forming nucleotide-borate complexes including N A P and Saden~sylmethione.~’ Although not well understood, it is postulated that boric acid’s cellular effect rests in the ability of these complexes to induce changes in the function or utilization of the nucleotides.

Prostate Cancer

Although boron is potentially toxic to all organisms and, as boric acid and borax, has been used as a pesticide and food preservative, higher animals usually do not accumulate boron because of their ability to rapidly excrete it.13 Authenticated cases of poisoning in humans have been few and have primarily been the result of accidental ingestion of insecticides and household products containing borates or use of large amounts of boric acid in the treatment of b ~ r n s . 4 ~ Improper use of boric acid-containing antiseptics is still one of the most common causes of toxic accidents in newborns and infants. Sinceboric acid is readily absorbed through damaged skin, it should not be applied topically to extensive wounds.16 In animals, chronic low-level boron exposure has been shown to cause reduced growth, cutaneous disorders, and suppression of male reproductive system function?O Studies indicate that male rodents suffer testicular atrophy with dietary exposure to boric acid above 4500 ppm and have decreased sperm motility at all exposure levels above 1000 ppm-5I Goats orally dosed with toxic but sublethal amounts of boron show sigruficant increases in packed cell volume, hemoglobin, inorganic phosphate, creatine phosphokinase, conjugated bilirubin, sodium, glucose, cholesterol, and aspartate transaminase. Several serum components were significantly decreased after boron dosing including alkaline phosphatase, magnesium, glutamyltransferase, and potassium. There was also an elevation of

Given that boron may act as a possible modifier of the hormones testosterone and estrogen, some studies have looked into its possible role in prostate cancer. One controlled case study compared the boron intake of 95 prostate cancer cases with that of 8720 male controls. After controlling for age, race, education, smoking, body mass index, dietary caloric intake, and alcohol consumption, thisepidemiologic screening found the risk of prostate cancer to be inversely proportional to dietary intake of boron in a dose-responsive manner.& Other research purports that boron may act as an inhibitor of prostate specific antigen (PSA). It is thought that uninhibited PSA cleaves insulin-like growth factor binding protein-3, providing increased local levels of insulin-like growth factor 1(IGF-1),which then leads to tumor growth. Some in vitro research observes that boric acid indeed inhibits the proliferation of both the hormone-dependent and independent human prostate cancer cell lines in a dose-dependent ma1mer.4~A study of 3 groups of 10 mice were implanted subcutaneously with human prostate adenocarcinoma cells. Two of the murine groups were given boric acid solutions (at 1.7 or 9 mgB/kg/day) by gavage, whereas the control group received only water. After 8 weeks, tumor sues in the boric acid groups were decreased by 38% and 25%, respectively, and serum PSA levels decreased by 88.6% and 86.4%,respectively, as compared with the control group. Additionally, significantly less mitotic figures were seen in the boric acid

DOSAGE The optimal dose of boron for prevention of osteoporosis and proper physiologic function appears to be 3 to 6 mg/day. It is best to obtain boron by means of a diet abundant in fruits, vegetables, legumes, and nuts, but persons whose diets are limited may need a supplement containing 3 mg of elemental boron. In patients with either osteoarthritis or rheumatoid arthritis, a trial period of 2 to 4 months with a dose of 3 mg of boron three times daily seems to be indicated.

TOXICOLOGY

Boron

cerebrospinal fluid monoamine Rats given DRUG INTERACTIONS 2 mg of boron per day in their drinking water also Boron supplementation may increase serum magnesium showed decreases in HDL3 levels, which may confer and estrogen levels. However, no adverse clinical effects increased cardiovascular risk!* have been reported. Humans given 100 mg of boron intravenously or 270 mg of boric acid orally reported no discomfort and showed no obvious signs of t0xicity7~9Drinking water SUMMARY with high boron concentrations in Turkey have not been Although the skeletal response to boron is modified by shown to cause untoward effects in humans exposed other nutritional variables such as calcium, magnesium, over multiple generati0ns.5~ Airborne exposures to boron vitamin D, methionine, and arginine, considerable evioxide and its hydration product, boric acid, have been reported to cause respiratory and eye i r r i t a t i ~ n . ~ ~dence indicates that both compositional and functional properties of bone are affected by boron status. A fatal outcome has been reported following ingestion of Findings suggest that boron is an important nutrient 1g of boric acid by a child; however, adults have survived not only for mineral metabolism but also for varied acute intakes of nearly 300 g.57 aspects of optimal health in humans. Although all pubCommon signs and symptoms of acute boron toxicity lished trials are not in agreement on the impact of boron include nausea, as well as vomiting and diarrhea that supplementation on levels of 17 beta-estradiol and are blue-green in other symptoms seen with testosterone, evidence strongly suggests that boron defiacute exposure are abdominal pain, an erythematousrash ciency results in decreased levels in postmenopausal involving both the skin and mucous membranes, stimuwomen, while supplementation tends to normalize lation or depression of the central nervous system, convulsions, hyperpyrexia, renal tubular damage, abnormal levels in these same women. Boron's impact on sex liver function, and jaundice.16Increased urinary riboflavin hormones in other segments of the population is still equivocal. No evidence exists to suggest that boron supexcretion has also been reported subsequent to acute plementation acts pharmaceutically to increase levels of boric acid ingestion.58Symptoms of chronic intoxication either 17 beta-estradiol or testosterone above normal include anorexia, gastrointestinal disturbances, debility, physiologic levels. confusion, dermatitis, menstrual disorders, anemia, conOn the basis of available information, boron appears vulsions, and alopecia.I6In three cases of work-related to offer benefits in the prevention of osteoporosis and exposure, alopecia signs were reversed when boric acid arthritis. It is also a safe and potentially effective mineral exposure was reduced or elhh1ated.5~ to consider in any treatment regimen for rheumatoid, Because of its ability to increase the excretion of osteoarthritis, and prostate cancer. boron, in cases of toxicity, N-acetylcysteine is the preferred intervention.@'

of boron in nutrition and metabolism. Prog Food Nutr Sci 1993;17331-349. 2. Woods WG. An introduction to boron: history, sources, uses, and chemistry. Env Health Perspect 1994;102(suppl7):5-11. 3.Nielsen FH. The emergence of boron as nutritionally important throughout the life cycle. Nutrition 2OOO;16512-514. 4. Houng K-H. The physiology of boron and molybdenumin plants. In Okajima H, Uritani I, Houng H-K,eds. The siphcance of minor elements on plant physiology. Taipei: ASPAC, Food & Fertilizer Technology Center, 197561-66. 5. Newnham RE. The role of boron in human nutrition. J Appl Nutr 1994;46:81-85. 6. Nielsen FH, Hunt CD, Mullen LM,et al. Effect of dietary boron on mineral, estrogen, and testosterone metabolism in postmenopausal women. FASEB J 1987;1:394397. 7. Naghii MR, Wall PM, Samman S. The boron content of selected foods and the estimation of its daily intake among free-living subjects. J Am Col Nutr 1996;15:614-619. 8. McBride J. Banishingbrittle bones with boron? Agric Res 1987;Nov/ DeC12-13. 1.Naghii MR, Samman S. The role

9.Hunt CD, Meacham SL. Aluminum, boron, calcium, copper, iron, magnesium, manganese,molybdenum,phosphorus, potassium, sodium, and zinc: concentrations in common Western foods and estimated daily intakes by infants; toddlers; and male and female adolescents, adults, and seniors in the United States. J Am Diet AS= 2001;101:1058-1060. 10.Rainey CJ, Nyquist LA, Christensen RE, et al. Daily Boron Intake from the American Diet. J Am Diet Assoc 1999;99: 335-340. 11.Hunt CD, Shuler TR, Mullen LM.Concentration of boron and other elements in human foods and personal-care products. J Am Diet ASOC 1991;91:558-568. 12. Nielsen FH. Boron-an overlooked element of potential nutritional importance. Nutr Today 1988;234-77. 13. Loomis WD, Durst RW. Chemistry and biology of boron. Biofactors 19923:229-239. 14. Zittle CA. Reaction of borate with substances of biological interest. Adv Enzymol Relat Subj Biochem 1951;12:493-527. 15. Hunt CD. Biochemical effects of physiological amounts of dietary boron. J Trace Elem Exp Med 1996;9:185-213.

16. Nielsen FH. Ultratrace minerals: boron. In Shils ME, Young VR,eds. Modem nutrition in health and disease, ed 7. Philadelphia: Lea & Febiger, 198tk281-283. 17. Reynolds JE,ed. Martindale: the extra pharmacopoeia. London: Royal Pharmaceutical Society, 1996:1680. 18.Moseman RF. Chemical disposition of boron in animals and humans. Environ Health Perspect 1994;102:113-117. 19. Meacham SL, Taper LJ, Volpe SL. Effect of boron supplementation on blood and urinary calcium, magnesium, and phosphorus, and urinary boron in athletic and sedentary women. Am J Clin N u b 1995;61:341-345. 20. Barr RD, Barton SA, Schull WJ. Boron levels in man: preliminary evidence of genetic regulation and some implications for human biology. Med Hypotheses 1996;46:286-289. Keenan MJ, Hegsted M, et al. Effects of dietary boron in 21. Dupre JN, rats fed a vitamin Ddeficient diet. Environ Health Perspect 1994;102:5558. 22. Massie HR, Whitney SJ, Aiello VR,et al. Changes in boron concentration during development and ageing of Drosophila and effect of dietary boron on life span. Mech Ageing Dev 1990;53:1-7. 23. Penland JG. Dietary boron, brain function, and cognitive performance. Environ Health Perspect 1994;102(suppl7):65-72. 24. Nielsen FH, Mullen LM, Nielsen EJ. Dietary boron affects blood cell counts and hemoglobin concentrations in humans. J Trace Elem Exp Med 1991;4211-223. 25. Ali S, Pawa S, Abdulla M. Fulminant hepatic failure and its protection by boron. J Hepatol2003~8(suppl2):190. 26. Nielsen FH. New essential trace elements for the life sciences. Biol Trace Elem Res 1990;26-27599-611. 27. Nielsen FH. Facts and fallacies about boron. Nutr Today 1992;27 6-12. 28. Usuda K, Kono K, @chi K, et al. Hernodialysis effect on serum boron level in the patients with long term hemodialysis. Sci Total Environ 1996;191:283-290. 29. Nielsen FH. Studies on the relationship between boron and magnesium which possibly affects the formation and maintenance of bones. Magnes Trace Elem 1990;9:61-69. 3O.Hunt CD. The biochemical effects of physiologic amounts of dietary boron in animal nutrition models. Environ Health Perspect 1994;102(suppl7):3543. 31. Hunt CD,Herbel JL, Idso Jl?Dietary boron modifies the effects of vitamin D3 nutrition on indices of energy substrate utilization and mineral metabolism in the chick. J Bone Miner Res 1994;9:171-182. 32. Hunt CD. Dietary boron modified the effects of magnesium and molybdenum on mineral metabolism in the cholecalciferoldeficient chick. Biol Trace Elem Res 1989;22:201-220. 33. Nielsen FH, Shuler TR, Gallagher SK. Effects of boron depletion and repletion on blood indicators of calcium status in humans fed a magnesium-low diet. J Trace Elem Exp Med 19903:45-54. 34.Beattie JH,Peace HS. The influence of a low-boron diet and boron supplementation on bone, major mineral and sex steroid metabolism in postmenopausal women. Br J Nutr 1993;69871-884. 35. Nielsen FH. Biochemical and physiologic consequences of boron deprivation in humans. Environ Health Perspect 1994;102(suppl7): 59-63. %.Hunt CD, Herbel JL, Nielsen FH.Metabolic responses of postmenopausal women to supplemental dietary boron and aluminum during usual and low magnesium intake: boron, calcium, and magnesium absorption and retention and blood mineral concentrations. Am J Clin Nutr 1997;65:803-813. 37. Meacham SL, Taper LJ, Volpe SL. Effects of boron supplementation on bone mineral density and dietary, blood, and urinary calcium, phosphorus, magnesium, and boron in female athletes. Environ Health Perspect 1994;10279-82.

38.Nielsen FH, Shuler TR, Zimmerman TJ,et al. Magnesium and methionine deprivation affect the response of rats to boron deprivation. Biol Trace Elem Res 1988;1791-107. 39. Hunt CD, Herbel JL. Boron affects energy metabolism in the streptozotocin-injected, vitamin D3deprived rat. Magnes Trace Elem 1991-92;10374386. 40.h4iljkovic D, Miljkovic N, McCarty ME Up-regulatory impact of boron on vitamin D function-does it reflect inhibition of 24-hydroxylase? Med Hypotheses 2004;631054-1056. 41. Naghh MR, Samman S. The effect of boron on plasma testosterone and plasma lipids in rats. Nutr Res 1997;17523-531. 42. Ferrando AA, Green NR. The effect of boron supplementation on lean body mass, plasma testosterone levels, and strength in male bodybuilders. Int J Sport Nutr 1993;3140-149. 43. McCoy H, Kenney MA, Montgomery C, et al. Relation of boron to the composition and mechanical properties of bone. Environ Health Perspect 1994;102:49-53. 44.Newnham RE. Agricultural practices affect arthritis. Nutr Health 1991;789-100. 45.Travers RL, Rennie GC, Newnham RE. Boron and arthritis: the result of a double-blind pilot study. J Nutr Med 1990;1:127-132. 46.Cui Y, Wmton MI, Zhang ZF, et al. Dietary boron intake and prostate cancer risk. Oncol Rep 2004;11:887-892. 47.Barranco WT, Eckhert CD. Boric acid inhibits human prostate cancer cell proliferation. Cancer Lett 2004;21621-29. 48. Gallardc-Williams MT, Chapin RE, King PE, et al. Boron supplementation inhibits the growth and local expression of IGF-1 in human prostate adenocarcinoma (LNCaP) tumors in nude mice. Toxicol Pathol2004;32:73-78. 49. Locatelli C, Minoia C, Tonini M, et al. Human toxicology of boron with special reference to boric acid poisoning. G Ital Med Lav 1987;9:141-146. 50. Minoia C, Gregotti C, Di Nucci A, et al. Toxicology and health impact of environmental exposure to boron. A review. G Ital Med L ~ 1987;9:119-124. v 51.Chapin RE, Ku WW. The reproductive toxicity of boric acid. Environ Health Perspect 1994;102(suppl7):87-91. 52. Sisk DB, Colvin BM, Merrill A, et al. Experimental acute inorganic boron toxicosis in the goat: effects on serum chemistry and CSF biogenic amines. Vet Hum Toxicol 1990;32:205-211. 53. Jansen JA, Anderson J, Schou JS. Boric acid single dose pharmacokinetics after intravenous administration to man. Arch Toxicol 1984;55:64-67. 54. Jansen JA, Schou JS, Aggerbeck B. Gastro-intestinal absorption and in vitro release of boric acid from water-emulsdying ointments. Food Chem Toxicol 1984;22:49-53. 55.Sayli BS, Tuccar E, Elhan AH. An assessment of fertility in boron-exposed Turkish subpopulations. Reprod Toxicol 1998;12 297-304. 56. Garabrant DH, Bernstein L, Peters JM, et al. Respiratory and eye irritation from boron oxide and boric acid dusts. J Occup Med 1984;26584-586. 57. Von Burg R. Boron, boric acid, and boron oxide. J Appl Toxicol 1992;12:149-152. 58. Pinto J, Huang YP, McConnell RJ, et al. Increased urinary riboflavin excretion resulting from boric acid ingestion. J Lab Clin Med 1978;92126-134. 59. Beckett WS, Oskvig R, Gaynor ME, et al. Association of reversible alopecia with occupational topical exposure to common boraxcontaining solutions. J Am Acad Dermatol2001;42:599-602. 60.Banner W Jr, Koch M, Capin DM, et al. Experimental chelation therapy in chromium, lead, and boron intoxication with Nacetylcysteine and other compounds. Toxicol Appl Pharmacol 1986;83:142-147.

Bromelain Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 791

Antibiotic, Mucolytic, and Permeability-Modifying Activities 792

Chemical Composition 791 History 791 Pharmacology 791 Activating and Deactivating Factors 792 Activity 792 Absorption 792 Digestive Activity 792 Antiinflammatory Activity 792 Inhibition of Platelet Aggregation 792

Clinical Applications 793 Respiratory Tract Diseases 793 Thrombophlebitis 794 Surgical Procedures and Athletic injuries 794 Dysmenorrhea 794 Adjunct in Cancer Treatment 794 Dosage

794

Toxicity

795

Proteolybc enzyme of Ananas comosus (family:Bromeliaceae) Synonyms: bromelin, plant protease concentrate

and its molecular weight has been reported as 18,000 by one group of investigators and 31,000 by another.'

GENERAL DESCRIPTION

HISTORY

Bromelains are sulfhydryl proteolytic enzymes obtained from the pineapple plant. Commercial bromelain is usually derived from the stem, which differs from the bromelain derived from the fruit. Commercialbromelain is a mixture of several proteases (including carboxypeptidase) and small amounts of several nonproteolytic enzymes (acid phosphatase, peroxidase, and cellulase), polypeptide protease inhibitors, and organically bound calcium. Japan, Taiwan, and Hawaii are the major suppliers of commercial bromelain.'

Bromelain was introduced as a therapeutic agent in 1957. Since then more than 200 scientific papers on its therapeutic applications have appeared in the medical literature.*J Many early studies were with Ananase (Rorer), an enteric-coated bromelain tablet. Later studies implied that the failure of bromelain in some of these early studies was due to the enteric coating and inadequate dosages.

CHEMICAL COMPOSITION Stem bromelain (in its purified form) is a basic glycoprotein with one oligosaccharide moiety and one reactive sulfhydryl group per molecule. It has a molecular weight of 28,000, and its isoelectric point is pH 9.55. It exhibits activity over the pH range of 3 to 10, with optimal activity between 5 and 8, depending on the substrate. Fruit bromelain is an acidic protease (isoelectric point pH 4.6). Its status as a glycoprotein is still in dispute,

PHARMACOLOGY Commercial bromelain has been reported to exert a wide variety of pharmacologic Digestion assistance Antiinflammatory activity B u m dkbridement Prevention of induced pulmonary edema Smooth muscle relaxation Inhibition of blood platelet aggregation Enhancement of antibiotic absorption Cancer prevention and remission Ulcer prevention 791

Sinusitis relief Appetite inhibition Shortening of labor Enhanced wound healing

Inhibition of biosynthesis of proinflammatory prostaglandins and induction of prostaglandin El accumulation (which tends to inhibit the release of neutrophil lysosomal enzyme^)^,^,^

Bromelain is absorbed via a number of routes. It has been effectively administered orally and parenterally and through intravenous infusion.'*& Experiments with dogs have shown oral administration to result in peak levels at 10 hours, while detectable levels are still apparent at 48 hours. Intravenous infusion peaks in 50 minutes and Evidence indicates that, remains detectable for 5 in both animals and humans, up to 40% of the absorbed orally administered bromelain can be absorbed intact.&

The first hypothesis has not been substantiated, while the latter three may be part of the same mechanism of action. After tissue injury the kinin, complement, fibrinolytic, and clotting systems are activated. These systems are closely interrelated via activation of the Hageman factor (Xn) and feedback mechanisms. Fibrin's role in promotion of the inflammatory response is to form a matrix that walls off the area of inflammation, resulting in blockage of blood vessels and inadequate tissue drainage and edema. The kinin system cascade produces kinins (e.g., bradykinin, kallidin), which increase vascular permeability and cause edema, as well as evoke pain. Bromelain activates fibrinolysis by stimulating plasmin production (Figure 73-l), resulting in depolymerization of fibrin and thereby preventing fibrin-clogged venous stasis and localized edema.811 Plasmin has been shown to block the mobilization of endogenous arachidonic acid by phospholipases, thereby reducing platelet aggregation and possibly other prostaglandin-mediated phenomena.12 Bromelain has also been shown to reduce plasma kininogen, resulting in inhibition in the production of kinins.13 The depletion of kininogen has been demonstrated to significantly reduce edema. These actions, the activation of plasmin and the reduction of kinin levels, are probably the main pharmacologic effects of bromelain. Its ability to reduce inflammation has been documented in various experimental models and clinical studies.

Digestive Activity

Inhibition of Platelet Aggregation

Bromelain is effective as a substitute for trypsin or pepsin in cases of pancreatic insufficiency and postpancreatectomy.2Because of bromelain's wide pH activity, it can act on substrates in the low pH of the stomach, as well as in the high pH of the small intestine. The combination of bromelain with pancreatin and ox bile has been demonstrated via double-blind studies to be highly effective in the treatment of patients with pancreatic in~ufficiency.~

Bromelain has been demonstrated to be a potent inhibitor of platelet aggregation, both in vitro and in v~vo.'~ Again, this is probably due to its plasmin-increasing effects. Plasmin is known to inhibit platelet aggregation by blocking the mobilization of arachidonic acid from membranebound phospholipid pools.12 Platelet aggregation is a major factor in atherogenesis (seeChapter 150).Bromelain supplementation (in conjunction with potassium and magnesium) has been reported to be quite effective in treating angina (Box 73-1).15

Most of these effects are discussed later.

Activating and Deactivating Factors Being sulfhydryl proteases, like papain and ficin, both stem and fruit bromelains are inhibited by oxidizing agents such as hydrogen peroxide, methyl bromide, and iodoacetate and by metallic ions such as lead, mercury, cadmium, copper, and iron. Bromelain is also inhibited by human serum both in vivo and in vitro. Magnesium and cysteine are activators of commercial bromelain.'

Activity The activity of bromelain is expressed in various enzyme units. The use of milk-clotting units (MCUs) is the officially recognized method in the Food Chemistry Codex (FCC). Different grades of bromelain are available on the basis of MCUs.

Absorption

Antiinflammatory Activity Several mechanisms may account for bromelain's antiinflammatory effects: Activation of proteolytic activity at sites of inflammation (although bromelain's proteolytic actions are inhibited by serum factors) Fibrinolysis activity via the plasminogen-plasmin system Depletion of kininogen

Antibiotic, Mucolytic, and Permeability-ModifyingActivities Bromelain has been shown in clinical studies to increase serum levels of various antibiotics (e.g., amoxicillin, tetracycline, penicillin) in many different tissues and body fluids (e.g., cerebral spinal fluid, sputum, mucus, blood, urine, uterus, salpinx, ovary, gallbladder, appendix, and In these studies the researchers conepithelial tissue).1G18 cluded that bromelain itself possesses significant effects.

Bromelain

+ Factor Xlla

Factor XI1 (Hageman Factor)

I ' Prekallikrein activators

XI

++ Xla

(Clotting system)

II Plasminogen

++

Fibrinogen

Plasmin

\1

++

Prekallikrein

Fibrin

++ Kallikrien

Kininogen

\1

++++Kinin

+(Fibrinolysis)

T

\1

Fibrinopeptides

++ = Enhancedactivates ++ = Inhibitshlocks Figure 73-1 Bmmelain's effects on the fibrin and kinin pathways.

Angina Maldigestion Arthritis Pancreatic insufficiency Athletic injury Phytobezoar Bronchitis Pneumonia Burn debridement Scleroderma Cellulitis Sinusitis Dysmenorrhea Staphylococcal infection Ecchymosis Surgical trauma Edema Thrombophlebitis Data from references 1-36.

Bromelain was as effectiveas antibioticsin treatingvarious infectious processes (i.e., pneumonia, perirectal abscess, cutaneous staphylococcus infection, pyelonephritis, bronchitis)

Immune Modulation and Antitumor Effects Recent results from preclinical and pharmacologicstudies indicate that bromelain acts as an immunomodulator by raising the impaired immunocytotoxicity of monocytes against tumor cells from patients and by inducing the production of distinct cytokines such as tumor necrosis factor-alpha (TNF-a), interleukin-1 beta (IL-lp), IL-6,

and IL-8. In a recent clinical study with mammary tumor patients, these findings could be partially ~onfirmed.'~ Especially promising are reports on animal experiments claiming an antimetastatic efficacy and inhibition of metastasis-associated platelet aggregation, as well as inhibition of growth and invasiveness of tumor cells. Apparently, the antiinvasive activity does not depend on the proteolytic activity.lJ9

CLINICAL APPLICATIONS As is evident, bromelain has wide-ranging clinical utility. It is particularly effective in virtually all inflammatory conditions, regardless of etiology, including those resulting from physical trauma, infectious agents, surgical procedures, immunologic reactions, and prostaglandin metabolism.

RespiratoryTract Diseases Apparently bromelain's mucolytic activity is responsible for its particular effectiveness in respiratory tract diseases.20In the treatment of chronic bronchitis, bromelain was shown to have an antitussive effect and to reduce the viscosity of sputum. Spimmetricexaminationof patients before and after treatment indicated increased vital capacity and FEV1, while the residual volume was reduced. These favorable effects were believed to be the results of enhanced resolution of respiratory congestion, due to bromelain's ability to act as a mucolytic and decrease bronchial secretions. Acute sinusitis has also responded to bromelain therapy. Good to excellent results were obtained in 87'70 of bromelain-treated patients, compared with 68% of the placebo gr0up.2~

Thrombophlebitis Numerous investigators have demonstrated that orally administered bromelain has a potent favorable effect on acute thrombophlebitis, deep vein thrombosis, cellulitis, ecchymosis, and edema.15p-24 In a double-blind study involving 73 patients with acute thrombophlebitis,bromelain, as a n adjunct to analgesics, was shown to reduce all the symptoms of inflammation: pain, edema, redness, tenderness, elevated skin temperature, and disability? In thisstudy and others, the common daily dose of brome lain was 60 to 160 mg of 1200 MCU bromelain. According to some researchers, doses of 400 to 800 mg are necessary to achieve consistent results in patients with thrombophlebitis; this probably holds true for most other conditi~ns.'~

Surgical Procedures and Athletic Injuries The effect of orally administered bromelain on the reduction of edema, bruising, healing time, and pain following various surgical procedures has been demonstrated in several clinical studies.',2528Tassman's studies of patients undergoing oral surgery concluded that, although postsurgical medication alone is effective, a regimen of presurgical and postsurgical medication is recommended.25*26 In a double-blind study of patients undergoing oral surgery, bromelain was found to be sigruficantly superior to placebo: Swelling decreased in 3.8 days with bromelain, compared with 7 days for the placebo, and the duration of pain was reduced to 5.1 days in the bromelain group, compared with 8.1 in the placebo?6 Similar observations were made in studies of episiotomy cases. Bromelain reduced edema, inflammation, and pain, and preoperative administration potentiated the effects.27 Bromelain has been used in various sports-related injuries. A 1960 study involving boxers highlights its effects.28Among the 74 boxers receiving bromelain, in 58 all signs of bruising cleared completely within 4 days. In the remainder, complete clearance took 8 to 10 days. Among the 72 controls, at the end of 4 days only 10 showed bruises completely cleared, the remainder taking 7 to 14 days. Importantly, although bromelain has been shown to effectively reduce pain, this probably is the result of a reduction in tissue inflammation and edema rather than a direct analgesic effect. In an open clinical trial, 59 patients with blunt injuries to the musculoskeletal system (e.g., contusions, muscle strains, ligament tears) were given 500 mg of bromelain three times daily, 30 minutes before meals. Swelling, pain at rest and during motion, signs of inflammation, and tenderness to palpation all rapidly impr0ved.2~ Another open study investigated the effects of bromelain on mild acute knee pain of less than 3 months' duration in otherwise healthy adults.30 Two validated questionnaires (western Ontario and McMaster

Universities [WOMAC] Knee Health Index and the Psychological Well-Being Index) were completed at baseline, and after 1 month's intervention with bromelain, randomly allocated to volunteers as either 200 mg or 400 mg per day. Seventy-seven subjects completed the study. In both treatment groups all WOMAC symptom dimension scores were significantly reduced compared with baseline, with reductions in the final battery (total symptom score) of 41% and 59% in the low- and high-dose groups, respectively. In addition, improvements in total symptom score and the stiffness and physical function dimensions were sigruficantlygreater in the high-dose group (400 mg per day) compared with the low-dose group. Compared with the baseline, overall psychologic well-being was sigruficantlyimproved in both groups after treatment with a sigruficantdose-response relationship was observed.

Dysmenorrhea Bromelain and papain have been used successfully in the treatment of dy~menorrhea.~' Bromelain is believed to be a smooth muscle relaxant, since it decreases the spasms of the contracted cervix in these patients. Failure of the bromelain protease, when used alone (purified by adsorption), to produce this effect was the first indication that the pharmacologically important factor is not the main protease. The muscle-relaxing effects of bromelain on the uterus are believed to be a result of decreasing prostaglandins of the 2-series (e.g., PGF2, and PGE2), while increasing levels of PGEl-like compound^.^

Adjunct in Cancer Treatment Like other proteolytic enzymes, bromelain appears useful as an adjunct in cancer treatment. Many mechanisms appear to be responsible for the clinical benefit. In a clinical study in 16 women with breast cancer, bromelain had a sigruficant impact on monocytes, natural killer cells, and lymphocyte^.'^ When the patients were classified on the basis of bromelain effects on the monocytic cytotoxicity into bromelain responders and nonresponders, about 40% of the patients responded to bromelain with an increase of cytotoxicity from 7.8%to 54% (bh4AK-cell activity).These data suggest that bromelain stimulates the deficient monocytic cytotoxicity of cancer patients, which may partially explain its antitumor activity, though bromelain has also been shown to induce the production of distinct cytokines such as TNF-a,IL-lp, IL-6, and L-8.'

DOSAGE Unless bromelain is being used as a digestive aid, administration should be on an empty stomach (between meals). The dosage depends largely on the potency of the bromelain preparation. Most currently available bromelain is in the 1200 to 2000 MCU range, with the typical dosage being 125 to 500 mg three times a day between meals.

Bromelain

TOXICITY Large doses of bromelain (nearly 2 g) have been given with no side It is virtually nontoxic, as no LDso exists up to 10 g/kg. Chronic use appears to be well tolerated. Although no significant side effects have been noted, as with most therapeutic agents, allergic reactions may occur in sensitive individuals or with prolonged occupational exp~sure.~~Jp

1. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci 2001;58:1234-1245. 2. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas cornosus) and its clinical application. An update. J

Ethnopharmacol1988;22.191-203. 3. Felton GE. Does kinin released by pineapple stem bromelain stimulate production of prostaglandin El-like compounds? Hawaii Med J 1977;36:39-47. 4. Miller JM, %her AW. The increased proteolyhc activity of human blood serum after oral administration of bromelain. Exp Med Surg 1964;22:277-280. 5. Izaka KI, Yamada M, Kawano T, Suyama T. Gastrointestinal absorption and antiinflammatory effect of bromelain. Jpn J Pharmacol 1972;22:519-534. 6. Seifert J, Ganser R, Brendel W. [Absorption of a proteolytic enzyme originating from plants out of the gastro-intestinal tract into blood and lymph of rats.] Z Gastroenterol1979;171-8. 7. Balakrishnan V, Hareendran A, Nair CS. Double-blind cross-over trial of an enzyme preparation in pancreatic steatorrhoea. J Assoc Physicians India 1981;29:207-209. 8. Lotz-Winter H. On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects. Plant Med 1990;56249-253. 9. Taussig SJ. The mechanism of the physiological action of bromelain. Med Hypotheses 1980;699-104. 10. Pirotta F, de Giuli-Morghen C. Bromelain-a deeper pharmacological study. Note I-antiinflammatory and serum fibrinolyhc activity after oral administration in the rat. Drugs Exp Clin Res 1978;41-20. 11. de Giuli-Morghen C, Pirotta F. Bromelain-a deeper pharmacological study. Note U-interaction with some protease inhibitors and rabbit specific antiserum. Drugs Exp Clin Res 1978;421-37. 12. Schafer AI, Adelman B. Plasmin inhibition of platelet function and of arachidonic acid metabolism. J Clin Invest 1985;75456-461. 13. Katori M, Ikeda K, Harada Y, et al. A possible role of prostaglandins and bradykinin as a trigger of exudation in carrageenin-induced rat pleurisy. Agents Actions 1978;8108-112. 14. Heinicke RM, van der Wal L, Yokoyama M. Effect of bromelain (Ananase) on human platelet aggregation. Experentia 1972;28: 844-845. 15. Taussig S, Nieper H. Bromelain: its use in prevention and treatment of cardiovascular disease present status. J Int Assoc Prev Med 1979;6 139-151. 16. Neubauer RA. Aplant protease for the potentiation of and possible replacement of antibiotics. Exp Med Surg 1961;19143-160. 17.Luerti M, Vignali M. Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. Drugs Exp Clin Res 1978; 4:45-48.

Bromelain can induce IgE-mediated respiratory and gastrointestinal allergic reactions, as well as cross-react with papain, wheat flour,rye flow, grass pollen, and birch pollen.33” Although side effects are seldom observed, sensitivity manifested by urticaria or skin rash has occurred. No anaphylactic reactions have been reported. Other possible, but unconfirmed, reactions include nausea, vomiting, diarrhea, metrorrhagia, and men~rrhagia.~~

18. Tiiozzi S, Venegoni A. Effect of bromelain on serum and tissue levels of amoxicillin. Drugs Exp Clin Res 1978;439-44. 19. Eckert K, Grabowska E, Stange R, et al. Effects of oral bromelain administration on the impaired immunocytotoxicityof mononuclear cells from mammary tumor patients. Oncol Rep 1999;6:1191-1199. 20. Rimoldi R, Ginesu F, Giura R. The use of bromelain in pneumological therapy. Drugs Exp Clin Res 1978;455-66. 21. Ryan RE. A double-blind clinical evaluation of bromelains in the treatment of acute sinusitis. Headache 1967;713-17. 22. Seligman 8. Oral bromelains as adjuncts in the treatment of acute thrombophlebitis. Angiology 1969;20:22-26. 23.Seligman B. Bromelain: an anti-inflammatory agent. Angiology 1962;1350&510. 24. Felton GE. Fibrinolyticand antithrombotic action of bromelain may eliminate thrombosis in heart patients. Med Hypotheses 1980;61123-1133. 25. Tassman GC, Zafran JN, Zayon GM. Evaluation of a plant proteolytic enzyme for the control of inflammation and pain. J Dent Med 1964;19:73-77. 26.Tassman GC, Zafran JN, Zayon GM. A double-blind crossover study of a plant proteolytic enzyme in oral surgery. J Dent Med 1965;2051-54. 27.Howat RC, Lewis GD. The effect of bromelain therapy on episiotomy wounddouble blind controlled clinical trial. J Obstet Gynaecol Br Commonw 1972;79951-953. 28. Blonstein JL. Control of swelling in boxing injuries. Practitioner 1969;203206. 29. Masson M. [Bromelain in blunt injuries of the locomotor system. A study of observed applications in general practice.] Fortschr Med 1995;113303-306. 30.Walker AF, Bundy R, Hicks SM, Middleton RW. Bromelain reduces mild acute knee pain and improves well-being in a dose-dependent fashion in an open study of otherwise healthy adults. Phytomedicine 2002;9681-686. 31. Hunter RG, Henry GW, et al. The action of papain and bromelain on the uterus. Am J Obstet Gynecol1957;73:867-880. 32. Gutfreund AE, Taussig SJ, Morris AK. Effect of oral bromelain on blood pressure and heart rate of hypertensive patients. Hawaii Med J 197837143-146. 33. Baur X. Studies on the specificity of human IgE-antibodies to the plant proteases papain and bromelain. Clin Allergy 1979;9:451-457. 34.Baur X, Fruhmann G. Allergic reactions, including asthma, to the pineapple protease bromelain following occupational exposure. Clin Allergy 1979;9443-450. 35. Physicians Desk Reference. Ananase (Rorer). Boston: Medical Economics Company, 19821645. 36. Ballard T. Bromelain.J John Bastyr Col Nat Med 1979;1:37-41

Camellia sinensis (Green Tea) Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac C H A P T E R (1 0 N T E N T S General Description 797 Green Tea versus Black Tea

Photoprotective Effects 800 797

Oral Cavity Diseases 800 Chemical Composition 797 Dosage 800 Pharmacology 798 Toxicity Clinical Application 798 Cancer 798 Cardiovascular and Liver Disease 799

800

Drug Interactions 800

Camellia sinensis (family: Theaceae) Common name: green tea

countries in North Africa and the Middle East (Table 741). Consumption is increasing in the United States.

GENERAL DESCRIPTION

CHEMICAL COMPOSITION

Both green tea and black tea are derived from the same plant, the tea plant (Camellia sinensis). The tea plant originated in China but is now grown and consumed worldwide. The tea plant, an evergreen shrub or tree that can grow up to a height of 30 feet, is usually maintained at a height of 2 to 3 feet by regular pruning. The shrub is heavily branched with young hairy leaves. Parts used are the leaf bud and the two adjacent young leaves together with the stem, broken between the second and third leaves. Older leaves are considered of inferior quality.

The chemical composition of green tea varies with climate, season, horticultural practices, and age of the leaf (position of the leaf on the harvested shoot). The major components of interest are the polyphenols.'r2 The major polyphenols in green tea are the following flavonoids:

Green Tea versus Black Tea Green tea is produced by lightly steaming the freshly cut leaf, while black tea is produced by allowing the leaves to oxidize. During oxidation, enzymes present in the tea convert many polyphenolic therapeutic substances to compounds with much less activity. With green tea, oxidation is not allowed to take place because the steaming process inactivates these enzymes. Green tea is high in polyphenols with potent antioxidant and anticancer properties. Oolong tea is a partially oxidized tea. Of the nearly 2.5 million tons of dried tea produced each year, only 20%is green tea. India and Sri Lanka are the major producers of black tea. Green tea is produced and consumed primarily in China, Japan, and a few

Catechin Epicatechin Epicatechin gallate Epigallocatechin gallate Proanthocyanidins Epigallocatechin gallate is viewed as the most significant active component. The leaf bud and the first leaves are richest in epigallocatechingallate. The usual concentration of total polyphenols in dried green tea leaf is around 0% to 12%. Other compounds of interest in dried green tea leaf include the following: Caffeine (3.5%) An unusual amino acid known as theunine (one half of

the total amino acid content, which is usually 4%) Lignin (6.5%) Organic acids (1.5%) 797

World tea production by type Type

Dry weight (xlOO0tons)

Black

1940

Green

515

Oolong

60 -

TOTAL

2515

Protein (15%) Chlorophyll (0.5%) One cup of green tea usually contains about 300 to 400 mg of polyphenols and between 50 and 100 mg of caffeine. Commercial preparations that have been decaffeinated and concentrated for polyphenols to between 60%and 80% total polyphenols are available.

PHARMACOLOGY Most epidemiologicand experimental studies on tea have focused on cancer-protective aspects. Tea polyphenols are potent antioxidant compounds that have demonstrated greater antioxidant protection than vitamin C and E in experimental studies? Although the antioxidant capacity of tea is well established, some clinical trials have not found a demonstrated oxidative protection in humans? Since reliable antioxidantbiomarkers have not been established: it is questionable whether the protective benefits of green tea will be fully elucidated in the near future. In addition to exerting antioxidant activity on its own, green tea may increase the activity of antioxidant enzymes. In mice, oral feeding of a polyphenolic fraction isolated from green tea in drinking water for 30 days resulted in SigTUficantly increased activities of antioxidant and detoxifying enzymes (glutathione peroxidase, glutathione reductase, glutathione-S-transferase,catalase, and quinone reductase) in the small intestine, liver, lungs, and small bowel? With regard to cancer, a number of in vitro and experimental models of cancer have shown that green tea polyphenols may offer significant protection.'-1° Specifically, green tea polyphenols inhibit cancer by blocking the formation of cancer-causing compounds like nitrosamines, suppressing the activation of carcinogens and increasing detoxification or trapping of cancercausing agents. Numerous studies have shown that green tea (including green tea polyphenols and extracts) exerts sigruhcant inhibitory effects on the formation of nitrosamines in various animal and human models. For example, when human volunteers ingested green tea along with 300 mg sodium nitrate and 300 mg proline, nitrosoproline formation was strongly inhibited."

CLINICAL APPLICATION The primary clinical application for green tea is in the prevention of cancer. Epidemiologic studies have demonstrated that green tea consumptionmay be a major reason why the cancer rate is so low in Japan. In contrast, however, black tea consumption appears associated with a substantial increase in the risk of several forms of cancer (discussed later in the section on black tea). Green tea also appears to be of value in several chronic diseases, especially those of the heart and liver.

Cancer Green Tea Epidemiologic correlations regarding the relationship between tea consumptionand human cancer are confounded by numerous variables.12 The forms of cancer that appear to be best prevented by green tea are those of the gastrointestinal tract including cancers of the stomach, small intestine, pancreas, and colon; the lung; and estrogen-related cancers, including most breast cancers,13 skin cancer,14J5and prostate cancer. A study in Shanghai, China, found a strong inverse association between green tea consumption and various cancers.IbFor men, compared with nonregular green tea drinkers, the group with the highest green tea consumption had an 18% reduced risk for colon cancer; 28% for rectal cancer; and 37% for pancreatic cancer. In women, the highest group of green tea consumers had a reduced risk of 33% for colon, 43%for rectal, and 47% for pancreatic cancer. A second Shanghai cohort study of 18,244 men demonstrated that the presence of urinary epigallocatechins correlated with a statistically significant inverse association with gastric cancer. This conclusion came after adjustment for the presence of Helicobuctor pylori, smoking, alcohol drinking, and level of serum carotenes. Interestingly, the protective effect was primarily seen among subjects with low levels of serum carotenes." It is possible that raising carotene intake may then preclude the benefits of tea intake. A population-based study of women in Shanghai found that among nonsmokers, the consumption of green tea was associated with a clearly reduced risk of lung cancer, in a dose-dependent manner.'R One corollary to this exists with regard to smoking. Studies have shown that little benefit in antioxidant levels are found in smokers who drink green tea.19*20 In preventing breast cancer, in vitro studies have shown that green tea extracts have inhibitory effects on the growth of mammary cancer cell lines.'O The main anticancer action is inhibiting the interaction of estrogen with its receptors. Polyphenol compounds in green tea extracts block the interaction of tumor promoters, hormones, and growth factors with their receptors-a kind of sealing-off effect. This effect would account for the reversible growth arrest noted in the in vitro studies.

Camellia sinensis (Green Tea) Green tea may soon be considered as a standard treatment for early-stage breast cancer. An observational study of 1160 surgical cases of invasive breast cancers were followed for 9 years. During a review of 5264 personyears follow-up, 133 subjects (12%) were documented to suffer recurrence of breast cancer. A decreased hazard ratio for recurrence adjusted for stage was observed with consumption of three or more daily cups of green tea. Particularly in stage I, the hazard ratio was decreased quite significantly. A similar tendency was observed for stage I1 subjects but was not present among more advanced stages.20 In animal studies green tea has been shown to effectively inhibit the lung carcinogenesisinduced by injections of asbestos and benzoalphapyrene. Rats consuming water with 2% green tea experienced a cancer rate of only 16% compared with 46% for those consuming water without green tea extract.21 Green tea components such as epigallocatechin-3gallate have been shown to have antiproliferative properties through the induction of apoptosis and cell cycle arrest in cervical cancer cell lines.z Topical and oral treatments of green tea flavonoid components have also been explored to treat human papillomavirus (HPV)-related cervical cancer. A randomized controlled clinical trial of 51 patients with cervical lesions including chronic cervicitis, mild dysplasia, moderate dysplasia, and severe dysplasia were divided into four treatment groups, while 39 untreated patients served as a control. A second trial used a polyphenol ointment made with epigallocatechin-3-gallateapplied locally to 27 patients twice a week for 12 weeks. For oral delivery, 200 mg of the ointment or an epigallocatechin-3-gallate capsule was taken orally every day for 8 to 12 weeks. Overall, a 69%response rate (35/51) was noted for treatment with green tea extracts, with each treatment showing a similar response, as compared with a 10% response rate (4/39) in untreated controls. A response was considered positive when pretreatment and posttreatment biopsies and Pap smears detected an elimination of abnormal cells, a decrease in or complete elimination of HPV, or a decrease in the size of the cervical lesion. The authors of this study concluded that green tea extracts may be a potential therapy regimen for patients with HPV-infected cervical lesions.= Male reproductive tract cancer may similarly benefit from green tea. In animal studies green tea components were found to inhibit the growth of prostate cancer cells and diminish the size of existing tumors.” Green tea’s pigallocatechin gallate has shown marked inhibition of hormone-insensitive prostate cancer cells. One murine study used green tea in oral liquid extract, which was the equivalent of 6 cups of green tea daily in humans. The mice taking green tea exhibited complete inhibition of metastasis of their prostate cancer, and there was

significant apoptosis in the prostate cancer cells compared with mice given only plain water.

Black Tea In contrast to green tea, population studies analyzing black tea consumption are not as clear regarding cancer protection. Some early studies even indicated that black tea consumption may increase the risk for certain cancers (e.g., rectum, gallbladder, endometrium).25*26 For example, in one study, the relationship between black tea consumption and cancer risk was analyzed using data from an integrated series of case-control studies conducted in Northern Italy between 1983 and 1990.25 The data set included 119 biopsy-confirmed cancers of the oral cavity and throat, 294 of the esophagus, 564 of the stomach, 673 of the colon, 406 of the rectum, 258 of the liver, 41 of the gallbladder, 303 of the pancreas, 149 of the larynx, 2860 of the breast, 567 of the endometrium, 742 of the ovary, 107 of the prostate, 365 of the bladder, 147 of the kidney, 120 of the thyroid, and a total of 6147 controls admitted to the hospital for acute noncancerous conditions. The risk of developing cancer due to tea consumption was derived after allowance for age, sex, area of residence, education, smoking, and coffee consumption. Results indicated an increased risk with tea consumption for cancers of the rectum, gallbladder, and endometrium. There was no association with cancers of the oral cavity, esophagus, stomach, bladder, kidney, prostate, or any other site considered. In another study, men of Japanese ancestry were clinically examined, during the period 1965-1968.26For 7833 of these men, data on black tea consumption habits were recorded. Since 1965, newly diagnosed cancer incidence cases have been identified: 152 colon, 151 lung, 149 prostate, 136 stomach, 76 rectum, 57 bladder, 30 pancreas, 25 liver, 12 kidney, and 163 at other (miscellaneous) sites. Compared with ”almost-never” drinkers, men who habitually drink black tea more than once a day had a four times greater chance of developing rectal cancer.26

Cardiovascular and Liver Disease A prospective epidemiologic study begun in 1986 by researchers in Japan evaluated the relationship between diet and chronic disease in Japanese men aged 40 and olderF7 As daily green tea intake increased from less than three, to four to nine, to more than 10 cups, significant increases in serum high-density lipoprotein and decreases in low-density lipoproteins (LDLs) were found. In addition, green tea consumption was found to significantly improve liver profiles, with aspartate aminotransferase and alanine aminotransferase levels decreasing significantly with increasing green tea consumption.

However, one study from the Netherlands evaluating ORAL CAVITY DISEASES inflammatory markers such as interleukin (IL)-6, IL-1 Inflammatory gingival reactions, tooth decay, and oral beta, tumor necrosis factor-alpha, C-reactive protein cancer may also benefit by the use of green tea. By study(CRP), and fibrinogen found no benefit for 59 healthy ing the amount of dental plaque present, as well as a smoking volunteers who drank tea with regard to bleeding index, green tea chews and rinses have been inflammation, hemostasis, and the endothelial cardioshown to positively affect the level of gum inflammavascular risk factors measured.28Given other studies of One trial evaluated volunteers who held 2 g of green tea that show little protection for s r n o k e r ~(dis~ ~ * ~ tion.32*33 ~ brewed black tea or unbrewed green tea leaves in the cussed in the section on cancer earlier), and the strong mouth for 2 to 5 minutes. Results showed that this body of literature regarding its efficacy in nonsmoking simple use of tea leaves acted upon by salivary esterases populations, it is possible that the level of oxidative can release high levels of catechins and theaflavin galdamage sustained by regular smoking may be too great lates into the oral cavity? Routine prophylaxis, as well for tea’s demonstrated antioxidant capacities. as treatment of gum disease, may be well served by the Although not shown to have any effect on antioxidant addition of green tea support to standard brushing, status, one small study has shown black tea to exhibit flossing, and dental care regimens. benefits in reducing LDL cholesterol by 7.5% over n0nusers.2~A double-blind crossover study of 10 healthy male volunteers studied the effects of both black tea and DOSAGE separate caffeine on the flow velocity reserve of coronary The normal amount of green tea consumed by Japanese vessels before and after consumption. Two-way analysis and other green tea drinking cultures is about 3 cups of variance showed a sigruficant improvement in corodaily or about 3 g of soluble components providing nary flow before after tea consumption and was greater roughly 240 to 320 mg of polyphenols. For a green tea than caffeine by almost a factor of 4.30 extract standardized for 80% total polyphenol and 55% epigallocatechin gallate content, this would mean a daily PHOTOPROTECTIVE EFFECTS dose of 300 to 400 mg. When selecting commercial green tea extracts, it is Research has shown that topical treatment or oral important to look for the level of epigallocatechin consumption of green tea polyphenols inhibits chemical gallate, as well as total polyphenol content. carcinogen- or ultraviolet (W) radiation-induced skin tumorigenesis in different animal In one study, volunteers were treated with an extract of green tea TOXICITY or one of its constituents and subsequently exposed to Green tea is not associated with any significant side graded doses of ultraviolet radiation 30 minutes later. Weffectsor toxicity. As with any caffeine-containingbevertreated skin was examined clinically for UV-induced eryage, overconsumption may produce a stimulant effect thema, looking histologically for the presence of sunburn (e.g., nervousness, anxiety, insomnia, irritability). cells or Langerhans cell distributions for UV-induced DNA damage. On histologic examination, skin treated with green tea extracts reduced the number of sunburn DRUG INTERACTIONS cells and protected epidermal Langerhans cells from UV damage. In a dose-dependent manner, epigallocatechin- Populations with marginal or deficient iron status have been shown to have lower serum ferritin or hemoglobin 3-gallate and epicatechin-3-gallate polyphenols proved to levels, or both, presumably due to iron bindi11g.3~ be the most efficient at inhibiting erythema. It was noted Theoretic concerns have been raised for interactions that the epigallocatechin and epicatechin fractions with anticoagulants due to caffeine’s antiplatelet activity, showed almost no effect. Green tea extracts also reduced but no interactions have been reported in humans. the DNA damage that formed after UV radiation.3l

1. Graham HN. Green tea composition, consumption, and polyphenol chemistry. Prev Med 1992;21:334-350. 2. Min Z , Peigen X. Quantitative analysis of the active constituents in green tea. Phytother Res 1991;5:239-240. 3. Ho CT,Chen Q, Shi H, et al. Antioxidative effect of polyphenol extract prepared from various Chinese teas. Prev Med 1992;21:520-525.

4. HodgsonJM, Croft KD, Mori TA, et al.Regular ingestion of tea does not inhibit in vivo lipid peroxidation in humans. J Nutr 2002;13255-58. 5. Reweld A, Wiseman S. Antioxidant effects of tea: evidence from human clinical trials. J Nutr 2003;133:328553292S. 6. Khan SG,Katiyar SK, Aganval R, et al. Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in

Camellia sinensis (Green Tea) drinking water to SKH-1 hairless mice. Possible role in cancer chemoprevention. Cancer Res 1992;524050-4052. 7. Katiyar SK, Agarwal R, Mukhtar H. Green tea in chemoprevention of cancer. Compr Ther 1992;183-8. 8. Mukhtar H, Wang ZY, Katiyar SK, et al. Tea components: antimutagenic and anticarcinogenic effects. Prev Med 1992;21:351-360. 9. Wang ZY, Khan WA, Bickers DR, et al. Protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice by green tea polyphenols. Carcinogenesis 1989;10411-415. 10. Komori A, Yatsumi J, Okabe S, et al. Anticarcinogenic activity of green tea polyphenols. Jpn J Clin Oncol1993;23:186-190. 11. Stich HE Teas and tea components as inhibitors of carcinogen formation in model systems and man. Pmv Med 1992;21:377-384. 12. Blot WJ, Chow WH, McLaughl~nJK. Tea and cancer-a review of the epidemiological evidence. Eur J Cancer Prev 1996;5:425-428. 13.Yang CS, Wang ZY. Tea and cancer. J NatI Cancer Inst 1993;85 1038-1049. 14. Katiyar SK, Elmets CA. Green tea polyphenolic antioxidants and skin photoprotection (Review). Int J Oncol2001;181307-1313. 15. Agarwal R, Katiyar SK, Khan SG,et al. Protection against ultraviolet B radiation-inducedeffects in the skin of SKH-1 hairless mice by a polyphenolic fraction isolated from green tea. Photochem Photobiol 1993;58:695-700. 16.Ji HT, Chow WH, Hsing A, et al. Green tea consumption and the risk of pancreatic and colorectal cancer. Int J Cancer 1997;7 255-258. 17. Sun CL, Yuan JM, Lee MJ, et al. Urinary tea polyphenols in relation to gastric and esophageal cancers: a prospective study of men in Shanghai, China. Carcinogenesis 2002;231497-1503. 18. Bong L, Goldberg MS, Gao YT, et al. A population-based casecontrol study of lung cancer and green tea consumption among women living in Shanghai, China. Epidemiology 2001;12:695-700. 19. Princen HM, van DuyvenvoordeW, Buytenhek R, et al. No effect of consumption of green and black tea on plasma lipid and antioxidant levels and on LDL oxidation in smokers. Arterioscler Thromb Vasc Biol1998;18:833-841. 20.Inoue M, Tajima K, Mizutani M, et al. Regular consumption of green tea and the risk of breast cancer recurrence: follow-up study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. Cancer Lett 2001 26;167 175-182.

21. Luo SQ, Liu XZ,Wang CJ.Inhibitory effect of green tea extract on the carcinogenesis induced by asbestos plus benzo(a)pyrenein rat. Biomed Environ Sci 1995;85458. 22. Ahn WS, Huh SW, Bae SM, et al. A major constituent of green tea, EGCG, inhibits the growth of a human cervical cancer cell line, CaSki cells, through apoptosis, G(1) arrest, and regulation of gene expression. DNA Cell Biol2003;22.217-224. 23. Ahn WS, Yoo J, Huh SW, et al. Protective effects of green tea extracts (polyphenonE and EGCG) on human cervical lesions. Eur J Cancer Prev 2003;12:383-390. 24. Rake1 D. Prostate health. Clin Fam Pract 2002;4;967. 25. La Vecchia C, Negri E, Franceschi S, et al. Tea consumption and cancer risk.Nutr Cancer 1992;1727-31. 26. Heilbrun LK, Nomura A, S t e m e r m m GN. Black tea consumption and cancer risk a prospective study. Br J Cancer 1986;54:677-683. 27. ImaiK, Nakachi K. Cross secfional study of effects of drinking green tea on cardiovascular and liver disease. BMJ 1995;310693-696. 28.de Maat MP, Pijl H, Kluft C, et al. Consumption of black and green tea had no effect on inflammation, haemostasis and endothelial markers in smoking healthy individuals. Eur J Clin Nutr 2ooO; 54:757-763. 29. Davies MJ, Judd JT, Baer DJ, et al. Black tea consumption reduces total and LDL cholesterol in mildly hypercholesterolemic adults. J Nutr 2003;133:3298S3302S. 30. Hirata K, Shimada K, Watanabe H, et al. Black tea increases coronary flow velocity reserve in healthy male subjects. Am J Cardiol 2004;931384-1388, A6. 31. Elmets CA, Singh D, Tubesing K, et al. Cutaneous photoprotection from ultraviolet injury by green tea polyphenols. J Am Acad Dermatol2001;44:425-432. 32.Wdershausen B, Gruber I, Hamm G. The influence of herbal ingredients on the plaque index and bleediig tendency of the gingiva. J C l i Dent 1991;275-78. 33. Krahwinkel T, Willershausen 8. The effect of sugar-free green tea chew candies on the degree of inflammation of the gingiva. Eur J Med Res 2000;5:463-467. 34. Lee MJ, Lambert JD, Prabhu S, et al. Delivery of tea polyphenols to the oral cavity by green tea leaves and black tea extract. Cancer Epidemiol Biomarkers Prev 2004;13132-137. 35. Temme EH, Van Hoydonck PG. Tea consumption and iron status. Em J Clin Nutr 200256379-386.

Capsicum fi-utescens (Cayenne Pepper) Michael T. Murray, ND Joseph E. Pizzorno Jr, N D CHAPTER C O N T E N T S General Description 803 Chemical Composition 803 History and Folk Use

803

Diabetic Neuropathy 805 Cluster Headaches 805 Arthritis 805 Psoriasis 805 Pruritus Ani 806

Pharmacology 803

Dosage 806

Clinical Applications 804 Postherpetic Neuralgia 804 Trigeminal Neuralgia 804 Postmastectomy Pain 804 Mouth Pain Due to Chemotherapy or Radiation 805

Toxicity 806

Capsicumfru tescens (family: Solanacea) Common names: cayenne pepper, capsicum, chili pepper, red pepper, American pepper

GENERAL DESCRIPTION Cayenne pepper (also known as chili or red hot pepper) is the fruit of Capsicum annuum, a shrubby, tropical plant that can grow up to 3 feet high. The fruit is technically a berry. Paprika is a milder and sweeter-tasting fruit produced from a different variety of Capsicum. Although cayenne pepper is native to tropical America, it is now cultivated in tropical locations throughout the world and has found its way into the cuisine of many parts of the world, particularly Southeast Asia, China, Southern Italy, and Mexico.

CHEMICAL COMPOSITION The most important constituents of cayenne pepper are the pungent compounds, with capsaicin being the most prominent (Figure 75-1). Typically, cayenne pepper contains about 1.5% capsaicin and related principles. Other active constituents present include carotenoids, vitamins A and C, and volatile oils.

Drug Interactions 806

HISTORY AND FOLK USE The folk use of cayenne pepper is quite extensive. It has been used for the following: Asthma Fever Sore throats and other respiratory tract infections Digestive disturbances Poultices Cancer It has also been used as a counterirritant in the topical treatment of arthritis and neuralgia.

PHARMACOLOGY The pharmacology of cayenne pepper centers around its capsaicin content. When topically applied to the skin or mucous membranes, capsaicin is known to stimulate and then block small-diameter pain fibers by depleting them of the neurotransmitter substance P.' Substance P is thought to be the principal chemomediator of pain impulses from the periphery. In addition, substance P has been shown to activate inflammatory mediators into joint tissues in osteoarthritis and rheumatoid arthritis.2 803

HO

-

0

Figure75-1 Capsaicin.

may offer significant benefits in a number of conditions including the pain associated with pain disorders, diabetic neuropathy, cluster headache, osteoarthritis, and rheumatoid arthritis. In addition, topically applied capsaicin may be useful in psoriasis.

Postherpetic Neuralgia

The first studies and approved use for topically applied capsaicin were in relieving postherpetic neuralgia. Numerous studies now document this Food and Drug Administration-approved application. For example, in one study 39 patients with chronic postherpetic neuralgia (average duration 24 months) were treated with 0.025%capsaicin cream for 8 weeks. During therapy the patients rated their pain. Nineteen patients (48.7”/0)substantially improved after the 8-week trial; five (12.8%) discontinued therapy due to side effects such as intolerable capsaicin-induced buming sensations (four)or mastitis (one);and 15 (38.5%)reported no benefit. The decrease in pain ratings was sigruficant after 2 weeks of continuCLINICAL APPLICATIONS ous application. Of the responders, 72.2% still reported improved 10 to 12 months after the study; with most Cayenne pepper should be recommended as a food for its beneficial antioxidant and cardiovascular effects. continuing to apply the cream regularly. In general the results of this study are consistent Although people with active peptic ulcer may be bothwith other studies (i.e., about 50% of people with posered by “spicy” foods containing cayenne pepper, spicy therpetic neuralgia respond to topically applied capsaicin foods in normal individuals do not cause ulcers. In fact, (0.025%).1419 Although this may not be a great response, cayenne pepper exerts several beneficial effects on gasit is better than the 10% response noted in the placebo trointestinal function, including acting as a digestant group. Higher concentration(0.075%vs. 0.025%)may proand carminative? Double-blind studies have shown that duce better results (as high as 75% response).20Another red pepper consumption protects against aspirin-induced study showed that capsaicin responders have been charstomach damage and improves epigastric pain, fullness, and nausea scores in people with nonulcer dy~pepsia.73,~ acterized by higher average daily pain, higher allodynia ratings, and relatively preserved sensory function at baseCapsicum does, however, lower the threshold for heartbum, presumably by direct effects on sensory neurons.1o line compared with the nonresponders. In three of the ”capsaicin responders” the area of allodynia expanded Interestingly, capsaicin, although hot to the taste, has actually been shown to lower body temperature by stim- into previously nonallodynicand nonpainful skin that had normal sensory function and cutaneous innervation?’ ulating the cooling center of the hypothalamus.” The ingestion of cayenne peppers by cultures native to the Trigeminal Neuralgia tropics appears to offer a way for these people to deal Topically applied capsaicin may be effective in reducwith high temperatures. ing the pain of trigeminal neuralgia.z In one study Capsicum ingestion may also prove to be helpful in 12 patients were followed up for 1 year after the topical promoting weight loss in obese individuals, as clinical application over the painful area of capsaicin three times studies have shown capsicum increases the basal metabolic rate while reducing appetite and caloric intake.12J3 a day for several days. Six patients had complete and four patients had partial relief of pain; the remaining two In one study, after ingesting a standardized dinner on patients had no relief of pain. Of the 10 patients who the previous evening, the subjects ate one of the followwere responsive to therapy, 4 had relapses of pain within ing for breakfast: a high-fat meal, a high-fat meal with 95 to 149 days. No relapses followed the second therapy red pepper (10 g), a high-carbohydrate meal, or a highfor the remainder of the year. These results are promiscarbohydrate meal with red pepper (10 g). Diet-induced thermogenesis was sigruficantly enhanced by the addition ing for a condition that usually does not respond to any therapy short of surgery. of red pepper to either meal, but especially the highfat meal.I4 Postmastectomy Pain Modem clinical use of cayenne pepper has focused Topically applied capsaicin may help in the relief of pain on the use of topical capsaicin-containing preparations. after breast reconstruction or mastectomy. In one Commercialointments containing 0.025% or 0.075%capdouble-blind study 23 patients with postmastectomy saicin are available over the counter. These preparations

When taken internally, cayenne pepper exerts a number of benefiaal effects on the cardiovascular system. In addition to possessing several antioxidant compounds, studies have shown that cayenne pepper reduces the likelihood of developingatherosclerosisby reducingblood cholesterol and triglyceride levels and platelet aggregation, as well as increasing fibrinolytic a~tivity.”~ (For the signhcance of these effects, see Chapter 150.) Cultures consuming large amounts of cayenne pepper have a much lower rate of cardiovascular disease.

Capsicum frutescens (Cayenne Pepper) pain syndrome (PMPS)applied either capsaicin (0.075%) days 8 to 15 of the study were significantly less severe in the capsaicin group versus the placebo group. There was or vehicle (placebo)-onlycream four times daily for 4 to also a sigruficant decrease in headache severity in the 6 weeksz3There was a significant difference in jabbing capsaicin group on days 8 to 15 compared with days 1 pain, in category pain severity scales, and in overall pain to 7, but not in the placebo group. Episodic patients relief scales in favor of capsaicin. Five of 13 patients on appeared to benefit more than chronic patients. capsaicin were categorized as good-to-excellent responses, with eight (62%) having 50% or greater improvement. Arthritis Only 1 of 10 cases had a good response to vehicle, with Topically applied capsaicin may be effective in relieving three rated as 50% or better. the pain of osteoarthritis and rheumatoid arthritis. In another study 14 patients with postmastectomy pain had sigrufcant pain relief following application of Although one study showed it to be more effective in 0.025%capsaicin cream four times daily for 4 to 6 ~ e e k s . 2 ~ osteoarthritis, another study showed just the opposite. In the double-blind study showing more effect in Unpleasant or painful sensations to light touch or pressure osteoarthritis, seven patients with rheumatoid arthritis in the painful area (hyperesthesia, allodynia) were also and 14 patients with osteoarthritis who had painful improved. involvement of the hands applied either capsaicin Mouth Pain Due to Chemotherapy 0.075% or vehicle-only cream to the hands four times or Radiation daily. Capsaicin reduced tenderness and pain associated with osteoarthritis, but not rheumatoid arthritis.% In a study conducted at the Yale Pain’ Management In the study showing greater benefit for rheumatoid Center, capsaicin was shown to dramatically reduce the arthritis, 70 patients with osteoarthritis and 31 with pain from mouth sores as a result of chemotherapy or rheumatoid arthritis received capsaicin or placebo for radiation treatment.25The interesting feature in thisstudy 4 weeks.35The patients were instructed to apply 0.025% was the vehicle used to deliver the capsaicin-taffy. The capsaicin cream or its vehicle (placebo) to painful knees researchers chose taffy because it could be held in the four times daily. Significantly more relief of pain was mouth long enough to desensitize the neurons, its sugar reported by the capsaicin-treatedpatients than the placebo decreased the initial burning sensation, and its soft edges would not aggravate sore mouths like a hard candy. All patients throughout the study; after 4 weeks of capsaicin treatment, rheumatoid and osteoarthritis patients demon11 patients in the Yale study said their pain decreasedin two cases stopping entirely-after eating the capsaicin- strated mean reductions in pain of 57%and 33%, respectively. These reductions in pain were statisticallysigrufcant laced candy. compared with those reported with placebo. According Diabetic Neuropathy to overall evaluations, 80°/0 of the capsaicin-treated patients experienced a reduction in pain after 2 weeks of Topically applied capsaicin has been shown to be of considerable benefit in relieving the pain of diabetic treatment. neuropathy in numerous double-blind In Psoriasis one large double-blind, 8-week study, investigators at 12 sites enrolled 277 men and women with painful diabetic Excessive substance P levels in the skin have been linked neuropathy of the hands and feet; 69.5% of the group to psoriasis. This finding prompted researchers to study applying the capsaicin cream (0.075%)showed improvethe effects of topically applied capsaicin. In one doublement compared with 53.4% in those applying only the blind study 44 patients with symmetrically distributed vehicle cream. psoriasis lesions applied topical capsaicin to one side of In another study 40 patients applied either 0.075% their body and a placebo to the other side.%After 3 to capsaicin cream or placebo to their affected extremities 6 weeks, sigruficantly greater reductions in scaling and daily. After 4 weeks, 76% of treated patients had some redness were observed on the capsaicin side. Burning, pain relief compared with 50% of placebo patients. In stinging, itching, and skin redness were noted by nearly addition, those responding to capsaicin said their pain half of the patients initially, but these diminished or was cut in half, while those on placebo averaged vanished upon continued application. In a later study 197 patients applied capsaicin 0.025% between 15%and 20% relief. cream or placebo cream four times a day for 6 weeks.37 Cluster Headaches Efficacy was based on a physician’s evaluation and a combined psoriasis severity score including scaling, Several studies have found that intranasal application of thickness, erythema, and pruritus. Capsaicin-treated capsaicin ointment by a physician may relieve cluster patients demonstrated sigruficantly greater improveheadaches. In one double-blind study, patients in acute ment in physician’s evaluation and in pruritus relief, as cluster were randomized to receive either capsaicin or well as a significantly greater reduction in combined placebo in the nostril for 7 days.%Patients recorded the psoriasis severity. severity of each headache for 15 days. Headaches on

Pruritus Ani Pruritus ani is a common condition that can be difficult to treat. Results from a double-blind study indicate that capsaicin is a safe and highly effective treatment for severe intractable idiopathic pruritus ani3 This study involved two 4-week treatment phases separated by a l-week washout phase. Forty-four patients were randomized to receive locally either active capsaicin (0.006%) or placebo (menthol 1%)ointment over a 4-week period. After 4 weeks of treatment and a 1-week washout period, the placebo group began to receive capsaicin while the treated group received placebo (menthol 1%)for another 4 weeks. At the end of the controlled study, responders from both groups continued with capsaicin treatment in an open-labeled manner. Results indicated that 31 of 44 patients experienced relief during capsaicin treatment periods and did not respond to menthol; all patients not responding to capsaicin also failed on menthol. In 13 patients, treatment with capsaicin was unsuccessful: 8 patients did not respond to capsaicin treatment, 1 responded equally to capsaicin

1.Szallasi A. Vanilloid (capsaicin) receptors in health and disease. Am J Clin Pathol2002;118:110-121. 2. Cordell GA, Araujo OE. Capsaicin: identification, nomenclature, and pharmacotherapy. Ann Pharmacother 1993;27330-336. 3. Kawada T, Haghara K, Iwai K. Effects of capsaicin on lipid metabolism fed a high fat diet. J Nutr 1986;116:1272-1278. 4. Wang JP, Hsu MF, Teng CM. Antiplatelet effect of capsaicin. Thromb Res 1984;36:497-507. 5. Visudhiphan S, Poohuppasit s, Piboonnukarintr, Tumliang S. The relationship between high fibrinolytic activity and daily capsicum ingestion in Thais. Am J C h Nutr 1982;35:1452-1458. 6. Horowitz M, Wishart J, Maddox A, Russo A. The effect of chilli on gastrointestinal transit. J Gastroenterol Hepatol1992;752-56. 7. Yeoh KG, Kang JY, Yap I, et al. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig Dis Sci 1995;40: 5m-583.

8. Bortolotti M, Coccia G, Grossi G, Miglioli M. The treatment of functional dyspepsia with red pepper. Aliment Pharmacol Ther 2002;161075-1082. 9. Drewes AM, Schipper Is,Dimcevski G, et al. Gut pain and hyperalgesia induced by capsaicin: a human experimental model. Pain 2003;104:333-341. 10. Rodriguez-Stanley S, Collings KL, Robinson M, et al. The effects of capsaicin on reflux, gastric emptying and dyspepsia. Aliment Pharmacol Ther 2ooO;14:129-134. 11. Dib B. Effects of intrathecal capsaicin on autonomic and behavioral heat loss responses in the rat. Pharmacol Biochem Behavior 1987;28: 65-70. 12. Yoshioka M, St-Pierre S, Drapeau V, et al. Effects of red pepper on appetite and energy intake. Br J Nutr 1999;82115-123. 13.Yoshioka M, St-Pierre S, Suzuki M, Tremblay A. Effects of red pepper added to high-fat and high-carbohydrate meals on energy metabolism and substrate utilization in Japanese women. Br J Nutr 1998;80503-510.

and placebo, and 4 others dropped out because of side effects.

DOSAGE Cayenne pepper can be used liberally in the diet. Creams containing 0.025%or 0.075% capsaicin or poultices can be applied to affected areas up to four times daily.

TOXICITY Cayenne pepper is generally recognized as safe in the United States. Topically applied capsaicin may produce a local burning sensation; however, this effect goes away with time and rarely is severe enough to warrant discontinuation of use of the cream. This was the only adverse effect noted.

DRUG INTERACTIONS Although several theoretic interactions have been postulated, no clinical cases have been documented.

14. Lysy J, Sistiery-Ittah M, Israelit Y, et al. Topical capsaicin-a novel and effective treatment for idiopathic intractable pruritus ank a randomised, placebo controlled, crossover study. Gut 2003;52: 1323-1326. 15. Peikert A, Hentrich M, Ochs G. Topical 0.025% capsaicin in chronic post-herpetic neuralga: efficacy, predictors of response and long-term course. J Neurol1991;238:452-456. 16. Bjerring P, Arendt-Nielsen L, Soderberg U. Argon laser induced cutaneous sensory and pain thresholds in post-herpetic neuralgia. Quantitative modulation by topical capsaicin. Acta Derm Venereol 1990;70121-125. 17. Bemstein JE, Korman NJ, Bickers DR, et al. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989; 21:265-270. 18. Watson CP, Evans RJ, Watt VR.Post-herpetic neuralgia and topical capsaicin. Pain 1988;33333-340. 19. Watson CP, Evans RJ, Watt VR, Brkett N. Post-herpetic neuralgia: 208 cases. Pain 1988;35:289-297. 20. Bemstein JE, Bickers DR, Dahl MV, et al. Treatment of chronic postherpetic neuralgia with topical capsaicin. A preliminary study. J Am Acad Dermatol1987;1793-96. 21. Petersen KL, Fields HL, Brennum J, et al. Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain 2000;88:125-133. 22. Fusco BM, Alessandri M. Analgesic effect of capsaicin in idiopathic trigeminal neuralgia. Anesth Analg 1992;74:375-377. 23. Watson CP, Evans RJ. The postmastectomy pain syndrome and topical capsaicin: a randomized trial. Pain 1992;51:375-379. 24. Watson CP, Evans RJ, Watt VR. The post-mastectomy pain syndrome and the effect of topical capsaicin. Pain 1989;38:177-186. 25. Nelson C. Heal the burn. Pepper and lasers in cancer pain therapy. J Natl Cancer Inst 1994;86:1381-1382. 26. The Capsaicin Study Group. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. Diabetes Care 1992;15:159-165.

Capsicum frufescens (Cayenne Pepper) 27. Biesbroeck R, Bril V, Hollander P, et al. A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy. Adv Ther 1995;12:111-120. 28.Tandan R, Lewis GA, Krusinski PB, et al. Topical capsaicin in painful diabetic neuropathy. Controlled study with long-term follow-up. Diabetes Care 1992;15:8-14. 29. Tandan R, Lewis GA, Badger GB, et al. Topical capsaicin in painful diabetic neuropathy. Effect on sensory function. Diabetes Care 1992;15:15-18. 30. Basha KM, Whitehouse FW.Capsaicin: a therapeutic option for painful diabetic neuropathy. Henry Ford Hosp Med J 1991;39: 138-140. 31. Pfeifer MA, Ross DR, Schrage JP,et al. A highly successful and novel model for treatment of chronic p a a diabetic peripheral neuropathy. Diabetes Care 1993;16:1103-1115. 32. Forst T, PohImann T, Kunt T, et al. The influence of local capsaicin treatment on small nerve fibre function and neurovascular control in symptomatic diabetic neuropathy. Ada Diabetol2002;39:1-6.

33. Marks DR, Rapoport A, Padla D, et al. A double-blind placebocontrolled trial of intranasal capsaicin for cluster headache. Cephalalgia 1993;13:114-116. 34.McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol1992;19: 604-607. 35. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical capsaicin: a doubleblind trial. Clin Ther 1991;13:383-395. 36.Bemstein JE,Parish LC, Rapaport M, et al. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986;15:504-507. 37. Ellis CN, Berberian 8, Sulica VI, et al. A double-blind evaluation of topical capsaicin in pruritic psoriasis. J Am Acad Dermatol1993;29 438-442. 38. Lysy J, Sistiery-Ittah M, Israelit Y, et al. Topical capsaicin-a novel and effective treatment for idiopathic intractable pruritus ani: a randomised, placebo controlled, crossover study. Gut 2003;52 1323-1326.

Carnitine Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 809 Biosynthesis 810 Metabolism 810 Transportation into Tissues 810 Excretion and Degradation 810 Physiologic Functions 810 Deficiency

811

Carnitine as a Nutrient 811 Carnitine in the Infant Diet 811 Dietary Carnitine Content 812 Clinical Applications 812 Cardiovascular Disease 812 Angina 813 Recovery from Myocardial Infarction 813 Arrhythmias 813 Congestive Heart Failure 813

INTRODUCTION Camitine is an essential nutrient for the transport of long-chain fatty acids into the mitochondria1 matrix. Carnitine (beta-hydroxy/gamma-butyrobetaine) was originally isolated from meat extracts in 1905, and its exact chemical structure was determined in 1932 (Figure 76-1). However, despite extensive physiologic and pharmacologic studies in the 1930s, no physiologic role for carnitine could be Its role in human physiology remained a mystery until nearly 50 years after its discovery. The compound was virtually forgotten until Carter and colleagues4created new interest in carnitine in 1952, when they established it as a growth factor for the meal worm Tenebrio molitor (hence camitine’s other name, “vitamin BY-B for the family of vitamins and T for Tenebrio molitor). When other species of organisms were

Peripheral Vascular Disease 814 Enhancing Physical Performance 814 Alzheimer’s Disease, Senile Depression, and Age-Related Memory Defect 815 Down Syndrome 815 Kidney Disease and Hemodialysis 816 Diabetes 816 Liver Disease 816 Muscular Dystrophies 817 Low Sperm Counts and Decreased Sperm Motility 817 Chronic Obstructive Pulmonary Disease 817 Acquired ImmunodeficiencySyndrome 817 Inborn Errors of Amino Acid Metabolism 817 Protection Against Drug Toxicity 818 Attention Deficit Hyperactivity Disorder 818 Dosage 818 Toxicology 818 Drug Interactions 818

also shown to be dependent on camitine, researchers began to reexamine its role in humans. Researchers soon found that carnitine was essential in the oxidation of When the first camitinedeficient human subjects were described in 1973, it stimulated greater investigation? It had always been assumed that an individual could synthesize adequate amounts of carnitine, ingest adequate amounts of dietary camitine, or meet needs by a combination of both. The discovery that some individuals required supplemental camitine to maintain normal energy metabolism resulted in the need to consider carnitine as a vitamin or essential.6 Since camitine can be synthesized (as described later) from the essential amino acid lysine, many nutritionists and researchers have argued that it should not be considered a vitamin. Others argue that if niacin, which can be synthesized from the essential amino acid tryptophan, can be labeled a vitamin, then so should carnitine. 809

Pharmacology of Natural Medicines 0

CH3

I

II

H3C-"+-CH,-CH

I

-CH,-C-O-

I

OH

CH3 Figure 76-1

Protein bound

I I I I 1

Lysine S-adenosylmethionine SAH Trimethyllysine

L-carnitine.

Ascorbate, Fez+

BlOSYNTHESIS Carnitine is synthesized in humans from lysine with the aid of another essential amino acid, methionine. In nonmammalians, carnitine synthesis begins with stepwise methylation of free lysine by S-adenosylmethionine to produce trimethyllysine. In mammals, however, protein-bound trimethyllysine, rather than free lysine, appears to be the major precursor for carnitine ~ynthesis.*-~ Trimethyllysine is then converted through a series of enzymatic reactions to butyrobetaine. This can occur in the liver, kidney, brain, heart, and skeletal muscle. However, the conversion of butyrobetaine to camitine can only occur in the liver, kidney, and brain, as the enzyme required, butyrobetaine hydroxylase, is only present in these tissues.'" The synthesis of carnitine is largely controlled by the activity of butyrobetaine hydroxylase. This enzyme appears to be age dependent. In infancy, the activity of butyrobetaine hydroxylase has been shown to be only 12% of the normal adult mean. By 2.5 years, the activity is 30% of the adult mean, and by 15 years the level is within the standard deviation of the adult mean.1-3These data would seem to indicate the importance of preformed carnitine in breast milk. As apparent from Figure 76-2, two essential amino acids (lysine and methionine), three vitamins (ascorbate, niacin, and vitamin B6), and a metal ion (reduced iron) are required for the synthesis of carnitine. Obviously, a deficiency of any one of these nutrients would result in sigruficantly impaired carnitine ~ynthesis.'-~

METABOLISM Transportation into Tissues The heart and skeletal muscles, as well as many other tissues, depend primarily on fatty acid oxidation as a source of energy. Because they cannot synthesize carnitine, its transport into these tissues is of critical importance. Specific carnitine-binding transport proteins have been identified for several tissues (e.g., cardiac muscle, skeletal muscle, epididymis, liver, kidney).'" The transport proteins assist the transfer of carnitine from the serum into the cells via carrier-mediated transport mechanism. This active transport mechanism allows the tissues

k

Alpha-ketoglutarate + 0, Succinate + CO,

Hydroxy-trimethyllysine

Pyridoxine

Glycine

Gamma-butyrobetaine aldehyde

Gamma-butyrobetaine Ascorbate, Fez+

k

Alpha-ketoglutarate + 0, Succinate + CO,

L-carnitine 'In humans, the enzyme catalyzing this reaction occurs only in the liver, kidney, and brain Figure 76-2 Biosynthesis of carnitine.

to concentrate carnitine at levels 10 times greater than those found in the plasma.

Excretion and Degradation Urinary excretion of unchanged carnitine is the major route of elimination of carnitine. As the tubular reabsorption of camitine by the kidneys is extremely efficient, the daily turnover of carnitine is estimated to be only 4% to 6% of the total body pool of the healthy indi~ i d u a l . ' -Factors ~ that increase carnitine excretion and degradation are discussed later under causes of carnitine deficiency.

PHYSIOLOGIC FUNCTIONS Carnitine's basic function is in the transport of longchain fatty acids into the mitochondrial matrix and the facilitation of beta-~xidation.'-~ As acyl coenzyme A formed in the endoplasmic reticulum or outer mitochondrial membrane cannot penetrate the inner mitochondrial membrane to the site of fatty acid beta-oxidation, the acyl group must be transferred from CoA to carnitine. The acyl-carnitine molecule then transports the fatty acid molecule to the mitochondrial surface of the inner mitochondrial membrane and releases the fatty acid into the matrix, where beta-oxidation occurs. Figure 76-3 summarizes this process.

Carnitine CoASH

Fatty acyl-CoA

Outside mitochondrion

Mitochondria1 membrane

-

-

-

’

’

--- - - Carnitine-

Acyl-carnitine -

A---A-

- - _ _ - -

-----Inside mitochondrion

CoASH

Dietary deficiency of the precursor amino acids lysine and methionine Deficiency of any cofactor (e.g., iron, ascorbic acid, pyridoxine, niacin) required by the enzymes of the lysine to carnitine pathway Genetic defect of carnitine biosynthesis Defective intestinal absorption of carnitine Liver or kidney dysfunction that impairs carnitine synthesis Increased metabolic losses of carnitine due to catabolism, impaired tubular resorption, or genetic defect Defective transport of carnitine from tissues of synthesis to tissues where it is maximally used Increased carnitine requirement due to a high-fat diet, drugs (e.g., valproic acid), metabolic stress, or disease

Fatty acyl-CoA

Beta-oxidation of fatty acid Figure 76-3 Role of carnitine in the transport of longchain fatly acids through the inner mitochondria1membrane.

Camitinehas several other physiologicfunctionsincluding oxidation of the ketoacid analogs of the branchedchain amino acids valine, leucine, and is~leucine.~‘~ This function is extremely important during fasting, starvation, and exercise. Camitine concentrations are extremely high in the epididymis and spermatozoa, suggesting a role for carThe epididymis nitine in male reproductive functi~n.l-~ derives the majority of its energy requirements from lipids, as do the spermatozoa, during transport through the epididymis. After ejaculation, spermatocytesdepend on glycolysis of glucose and fructose and on oxidation of lactate and pyruvate. Carnitine (in the form of acetylcarnitine, which is derived from pyruvate) serves as a readily available substrate. The motility of ejaculated sperm correlates positively with acetylcarnitine ~0ntent.l.~

DEFICIENCY Carnitine deficiency may arise from several causes, as listed in Box 76-1. Carnitine deficiency states have been classified into two major groups: Systemic carnitine deficiency Myopathic deficiency Diagnosis of systemic camitine deficiency can be made using serum or 24-hour urine samples. Total, free, and esterified camitine levels should be determined. In myopathic carnithe defiaency, diagnosis quires skeletal muscle b i ~ p s y . ~ To date, no patients with primary systemic camitine deficiency have been identified. The systemic deficiency has always been secondary to some other factor rather than a defect in carnitine ~ynthesis.l-~,~fi

The consequences of systemic carnitine deficiency are impaired lipid metabolism and lipid accumulation in the skeletal muscles, myocardium, and liver. Progressive muscle weakness with lipid storage myopathy is found in all patients.’”r7 In adults, auxiliary nonmitochondrial oxidation mechanisms are apparently stimulated, resulting in some degree of adaptation. This adaptation occurs in starvation, diabetes, high-fat diets, and other causes of secondary carnitine deficiency. Systemic camitine deficiencies usually respond dramatically to orally administered supplemental ~-carnitine.’,~ Children are apparently unable to adapt to low carnitine levels as well as adults? Several cases of carnitine deficiency in children, presenting a clinical picture resembling Reye syndrome (acute encephalopathy associated with altered liver function due to lipid accumulation), have been reported.810 The clinical presentation of secondary carnitine deficiency in children includes hypotonia, failure to thrive, recurrent infections, encephalopathy, nonketotic hypoglycemia, and cardiomyopathy.7 Several fatal cases of systemic camitine deficiency have been In primary myopathic carnitine deficiency, there is an inborn error of carnitine metabolism that is limited to skeletal muscle.7,8The defect appears to be in the transport of camitine into the skeletal muscle as serum carnitine, and the camitine levels in other tissues are normal. Severe lipid-storage myopathy is the result. Supplemental camitine is generally of no value in myopathic carnitine deficiency. Rather, improvements have been noted using diets high in medium-chain triglycerides and low in long-chain triglycerides.7

CARNlTlNE AS A NUTRIENT Carnitine in the Infant Diet Oxidation of long-chain fatty acids, which requires carnitine, is well known to be critical to the survival and normal development of the newborn? Carnitine concentrations in fetal and umbilical cord blood are higher than in maternal blood, suggesting the placenta may actively

transport carnitine to the fetus, since camitine synthesis is not fully d e ~ e l o p e d .The ~ initial camitine concentration in the newborn depends on maternal camitine concentration. Supplementation of carnitine during pregnancy may be necessary to ensure adequate tissue concentrations in the fetus, as well as the mother. Serum camitine levels are typically lower in pregnant women than nonpregnant women, presumably due to increased excretion.'*J3 The newborn infant is almost entirely dependent on external sources of ~ a m i t i n eBreastfed .~ infants have the best chance of achieving optimal camitine concentrations. The bioavailability of camitine from breast milk is significantly greater than that in cow's milk-based formulas,t4 and soy-based infant formulas contain no detectable carnitine.3 Formula feeding may necessitate supplemental camitine to achieve normal carnitine concentrations in these infants. Camitine administration to preterm infants has potentiated weight gain and growth.I5 In preterm infants, serum values of carnitine decrease dramatically due to limited storage capacity coupled with a decreased ability to synthesize carnitine. Administration of L-camitine (LC) to preterm infants is considered important.

Dietary Carnitine Content Analysis of several hundred foods for carnitine content indicates that meat and dairy products are the major dietary sources of camitine.3 In general, the redder the meat, the higher the carnitine content. Cereals, fruits,and vegetables contain little or no camitine. Preliminary studies indicate that the daily diet contains 5 to 100 mg of ~arnitine.~

CLINICAL APPLICATIONS Many disease states, in addition to classical as well as secondary camitine deficiency, may benefit from camitine administration. Evidence supports the assertion that supplemental carnitine may benefit the conditions listed in Box 76-2 and discussed later. Carnitine is available in several different forms. The form being used must be LC alone or bound to either acetic or propionic acid. The D form of camitine (discussed later in the section on safety issues) should never be used. As to which form is best, it depends on the objective. For Alzheimer's disease and brain effects, it appears that L-acetylcarnitine (LAC) may provide the greatest benefit. For angina, L-propionylcamitine (LPC) may be the best choice because the myocardium appears to prefer it to L-acetylcamitine, followed by LC.16,17LC is, however, the most widely available, least expensive, and best studied form of camitine.

Cardiovascular diseases Angina pectoris Acute myocardial infarction Myocardial necrosis Arrhythmias and cardiotoxicity induced by drugs Familial endocardial fibroelastosis Cardiac myopathy Idiopathic mitral valve prolapse Elevated cholesterol levels Elevated triglyceride levels Enhancing physical performance Alzheimer's disease, senile depression, and age-related memory defects Kidney disease and hemodialysis Diabetes Liver diseases Alcohol-induced fatty liver disease Liver cirrhosis Muscular dystrophies Low sperm counts and decreased sperm motility Chronic obstructive pulmonary disease Acquired immunodeficiency syndrome Inborn errors of amino acid metabolism Organic aciduria Glutaric aciduria lsovaleric acidemia Propionicacidemia Methylmalonic aciduria Toxicity from various drugs

Cardiovascular Disease Normal heart function is critically dependent on adequate concentrations of carnitine. A deficiency of camitine in the heart would be similar to trying to run an automobile without a fuel pump. Despite plenty of fuel, there is no way to get it to the engine. Although the normal heart stores more camitine than it needs, if the heart does not have a good supply of oxygen, carnitine levels quickly decrease. This lack of oxygen leads to decreased energy production in the heart and increased risk for angina and heart disease. Camitine is useful in angina due to its ability to improve oxygen usage and energy metabolism by the myocardium. As a result of improving fatty acid usage and energy production, camitine also prevents the production of toxic fatty acid metabolites.18 These compounds are extremely damaging as they disrupt cellular membranes. Changes in the properties of cell membranes throughout the heart are thought to contribute to impaired contraction of the heart muscle and increased susceptibility to irregular beats, and eventual death of heart tissue. Supplementing the diet with carnitine increases heart camitine levels and has been shown to prevent the production of fatty acid metabolites, which

Carnitine can damage the heart, as well as boost antioxidant enzyme levels. In addition to angina, all of these effects make carnitine beneficial in recovery from a heart attack, cardiomyopathies, arrhythmias, and congestive heart failure.19,20 Carnitine also exerts a beneficial effect on blood lipids by lowering triglycerides and total cholesterol levels while raising high-density lipoprotein (HDL) cholesterol. After 4 months of therapy with LC in patients with elevated blood lipids, typical changes observed are a 20% reduction for total cholesterol, a 28% decrease in triglycerides, and a 12% increase in HDL levels.21PDue to the higher cost of carnitine compared with other natural agents (e.g., inositol hexaniacinate, garlic, and guguhpid), its use should be reserved for those cases unresponsive to these more cost-effective measures. Carnitine has also been shown beneficial in the treatment of intermittent claudication, which is a condition like angina, but, instead of the pain occurring in the heart, it occurs usually in the calf muscle. Like angina, the pain is described as a cramp or tightness. The cause of the pain is reduced oxygen delivery, along with an increase in the production of toxic metabolites and cellular free radicals. Its benefits in peripheral vascular disease are the result of improved energy production during ischemia rather than any effect on blood flow. Nonetheless, good results have been obtained in intermittent claudication and other peripheral vascular diseases (discussed later).

Angina Numerous clinical trials have demonstrated that camitine improves angina and heart disease (note that all three commercial forms have been used).19,23-29 Supplementation with carnitine normalizes heart carnitine levels and allows the heart muscle to use its limited oxygen supply more efficiently. This translates to an improvement in cases of angina. Improvements have been noted in exercise tolerance and heart function. The results indicate that carnitine is an effective alternative to drugs in cases of angina. LPC may offer the greatest benefit in angina, as well as in other cardiovascular conditions. LPC is taken up by myocardial cells much more rapidly than other forms of carnitine.16In one study LPC (15 mg/kg intravenously) significantly diminished myocardial ischemia as demonstrated by a sigruficant 12% and 50% reduction in STsegment depression and left ventricular end-diastolic pressure, respectively, during the atrial pacing test?O Left ventricular ejection fraction increased by 18%. Recovery of heart function after exercise occurred much quicker in the LPC group compared with the placebo group. LC and LAC have also shown good results. In one of the larger studies, 200 patients with exercise-induced stable angina received either standard therapy alone (e.g., nitroglycerine, calcium channel blockers, beta-blockers,

antihypertensives, diuretics, digitalis, antiarrhythmics, anticoagulants, hypolipidemics) or in combination with 2000 mg/day of LC over a 6-month period.31Compared with the control group, the patients on LC exhibited a significant reduction in premature ventricular contractions at rest, as well as an increased tolerance to exercise as demonstrated by an increased maximal cardiac frequency, increased maximal systolic blood pressure, cardiac output, and reduced ST-segment depression (70% reduction in the LC group vs. no change in the control group). Reductions in low-density lipoprotein (LDL) cholesterol (So/)and triglycerides (12%)were also noted. These results are highly significant and provide a strong rationale for the inclusion of carnitine in patients using standard medical therapy.

Recovery from Myocardial Infarction In addition to benefiting angina patients, carnitine has also been shown to be useful in helping individuals recover more quickly from a heart attack.19 In one double-blind study of 160 patients who had been released from a hospital after a heart attack, the group receiving 4 g of LC daily showed significant improvements in heart rate, blood pressure, angina attacks, rhythm disturbances, and clinical signs of impaired heart function compared with the control In Italy a larger study involving 472 patients showed additional benefits3 The study was performed to evaluate the effects of LC administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction. Placebo or LC was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital, and at 3,6, and 12 months after acute myocardial infarction. A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with LC compared with those receiving placebo. The percent increase in both end-diastolic and end-systolic volumes from admission to 3-, 6-, and 12-month evaluation was significantly reduced in the LC group.

Arrhythmias In double-blind trials, reductions in the use of conventional antiarrhythmic drugs have occurred in patients with angina who have received carnitine.19

Congestive Heart Failure Several double-blind clinical studies have shown that carnitine (again, LPC appears to be more effective than LC or LAC) improves cardiac function in patients with In one double-blind study of congestive heart fai1~re.l~ LPC versus placebo in a group of 60 patients with mild

Pharmacology of Natural Medicines

to moderate (New York Heart Association [NYHA] classes I1 and 111)congestive heart failure, LPC produced demonstrable benefit.MThe group was made up of men and women between 48 and 73 years old in chronic treatment with digitalis and diuretics for at least 3 months and who still displayed symptoms. Thirty of these patients were chosen randomly and for 180 days received 500 mg of LPC three times a day in addition to their usual treatment. At basal conditions and after 30, 90, and 180 days, the maximum exercise time was evaluated using an exercise tolerance test performed on an ergometer bicycle, and the left ventricular ejection fraction was tested by means of echocardiography. After 1 month of treatment, the patients treated with LPC, compared with the control group, showed signhcant increases in the values of both tests, increases that became even more evident after 90 and 180 days. At the stated times, the increases in the maximum exercise time were 16.4%,22.9%, and 25.9%, respectively. The ventricular ejection fraction increased by 8.4%, ll.6%, and 13.6%, respectively. In another double-blind study with similar patients, at the end of 6 months of treatment, maximum exercise time on the treadmill increased 16.4% and the ejection fraction increased by 12.1% after 180 days in the group treated with PLC at a dosage of 1 g twice Even more obvious benefits were seen in a 3-year study of 80 patients with moderate to severe heart failure (NYHA class 111 to IV)caused by dilated cardiomyopathy. After a period of stable cardiac function up to 3 months, patients were randomly assigned to receive either carnitine (2 g/day orally) or placebo. After a mean of 33.7 months of follow-up (range 10 to 54 months), 70 patients were in the study: 33 in the placebo group and 37 in the camitine group. At the time of analysis, 63 patients were alive. Six deaths occurred in the placebo group, and one death in the camitine group. Survival analysis showed that patients’ survival was statistically sigruficant in favor of the camitine group.%

Peripheral Vascular Disease All three forms of carnitine (2 to 4 g daily) have been shown to improve the walking distance without pain in patients with intermittent claudication. Presumably this improvement is the result of improved energy metabolism within the muscle, as carnitine was not shown to improve blood flow to the calf. LPC appears to offer better effects than either LC or However, in one double-blind study, LC at a dosage of 2 g twice daily demonstrated a 75% increase in walking distance after only 3 weeks of therapy.39 In the largest study with LPC, 485 patients with intermittent claudication were randomized to placebo or LPC (2 g/day) for 12 months. Maximal walking distance increased by 62% on LPC and by 46% on placebo in all

patients. However, when only those patients with more severe disease status were analyzed, the maximal walking distance increased by 98% in the LPC group compared with only 54% in the placebo g r o u ~ . ~

Enhancing Physical Performance The ability to enhance exercise tolerance and physical performance with camitine may not be limited to patients with cardiovascular disease, as carnitine supplementation has also been shown to be of benefit in healthy subjects and athletes. Efficient use of fatty acids by skeletal muscle, like the myocardium, also depends on an adequate supply of carnitine. Carnitine supplementation (usually 2 g two to three times daily) has resulted in sigruficant improvements in cardiovascular function in response to exercise in several double-blind studies in both athletes and normal subj e c t ~ ! Compared ~~~ with control groups, the subjects on carnitine have shown not only improvements in exercise intensity over time, but also evidence of improved energy metabolism within the muscle (lowered blood lactic acid and free fatty acid levels). Obviously, the improved production of energy by the exercising muscle, as well as improved heart function, could be responsible for carnitine’s ability to enhance physical performance. Although at least three studies have shown the benefits of carnitine on exercise performance to be of no more value than a placebo, carnitine supplementation should still be viewed as beneficial, especially in endurance-related events.M The reason behind this statement is the fact that studies have demonstrated carnitine improves energy-producing enzyme levels in longdistance runners.47 These athletes received either a placebo or 2 g of LC twice daily for 4 weeks. Runners receiving LC showed a significant increase in enzymes involved in energy production (cytochrome c reductase and cytochrome oxidase). In contrast, there were no changes in the placebo group. One study examined the influence of L-carnitine L-tartrate (LCLT) at a dosage of 2 g per day for 3 weeks on markers of purine catabolism, free radical formation, and muscle tissue disruption after squat exercise. Exercise-induced increases in plasma markers of purine catabolism (hypoxanthine, xanthine oxidase, and serum uric acid) and circulating cytosolic proteins (myoglobin, fatty acid-binding protein, and creatine kinase) were significantly reduced by LCLT supplementation. Exerciseinduced increases in plasma malondialdehyde returned to resting values sooner during LCLT compared with placebo. The amount of muscle disruption from MRI scans during LCLT was 41% to 45% of the placebo area. These data indicate that LCLT supplementation is effective in assisting recovery from Interestingly, normal subjects taking carnitine have improved cardiovascular function and a more rapid

Carnitine

return of heart rate to the resting rate after e~ercise.4~ The significance of these improvements is that camitine apparently mimics the benefits in heart and vascular function produced by regular exercise training without working up a sweat. Carnitine supplementation appears to be beneficial in elderly subjects complaining of muscle fatigue. In one double-blind study, 84 elderly subjects with onset of fatigue following even the slightest physical activity were randomized to receive carnitine 2 g twice daily or a placebo for 30 days. At the end of the study, compared with placebo, the carnitine-treated patients showed significant improvements in the followingparameters: total fat mass (-3.1 vs. -0.5 kg), total muscle mass (+2.1 vs. +0.2 kg), total cholesterol (-1.2 vs. +0.1 mmol/L), LDL-C (-1.1 VS.-0.2 m o l / L ) , HDL-C (+0.2 VS. +0.01 m o l / L ) , triglycerides (-0.3 vs. 0 mmol/L), apoAl(4.2 vs. 0 g/L), and apoB (-0.3 vs. -0.1 g/L). Fatigue scores decreased significantly by 40% (physical) and 45% (mental) in subjects taking carnitine, compared with 11% and 8%, respectively, in the placebo group.5o

Alzheimer’s Disease, Senile Depression, and Age-Related Memory Defect Much research has been conducted over the past 20 years with LAC in the treatment of Alzheimer’s disease, senile depression, and age-related memory defects. As described earlier, LAC is a molecule composed of acetic acid and LC bound together. This reaction occurs naturally in the human brain; therefore it is not exactly known how much greater an effect is noted with LAC versus LC or PAC. However, LAC is thought to be substantially more active than these other forms of camitine in conditions involving the brain.5152 LAC is structurally related to acetylcholine, a major neurotransmitter responsible for memory and proper brain function. In Alzheimer’s disease, and to a lesser extent the normal aging human brain, there is a defect in the utilization of acetylcholine. The close structural similarity between LAC and acetylcholine led researchers to begin testing LAC in Alzheimer’s disease. The results have been encouraging. Researchers have now shown that LAC does indeed mimic acetylcholine and is of benefit not only in patients with early-stage Alzheimer’s disease but also in elderly patients who are depressed or who have impaired memory.52It has also been shown to act as a powerful antioxidant within the brain cell, stabilize cell membranes, improve energy production within the brain cell, and enhance or mimic the function of a~etylcholine.5~ The results in delaying the progression of Alzheimer’s disease have been promising. The studies have been well controlled and extremely t h o r o ~ g h .For ~ ~example, ,~~ in one study LAC (2 g twice daily) or placebo was given to 130 patients with Alzheimer’s disease over the course

of 1 year.56The patients were evaluated by 14 different outcome measures such as assessment scales, cognitive function tests, memory tests, and physician evaluations. The group receiving the LAC had better outcome scores in all cases. Positive studies, however, have been somewhat offset by studies showing little benefit. For example, in a 1-year, multicenter, double-blind study in 229 patients with mild Alzheimer’s disease, LAC alone failed to slow decline, though it did reduce the decline in attenti0n.5~ Memory impairment need not be as severe as in Alzheimer’s disease in order for LAC to demonstrate benefit.= In one double-blind study of 236 elderly subjects with mild mental deterioration, as evident by detailed clinical assessment, the group receiving 1500 mg of LAC daily demonstrated sigruficant improvement in mental function, particularly in memory and constructional thinking.@-’ Many of the elderly suffer from depression not only as a result of experiencing a great deal of loss in their lives but also because of the biochemical changes in the brain associated with aging. LAC has been shown to improve depression in elderly subjects in double-blind studies using assessment scales standard to scientific research of antidepressant drugs (e.g., Hamilton Depression Scale, Clinical Global Impression, Sandoz Clinical Assessment). The usual dosage has been 500 mg three times daily. Elderly subjects with the highest depression scores are usually the ones who benefit the most from LAC.61*62 LAC also appears helpful in enhancing the effects of acetylcholinesterase inhibitors. In one open study, LAC (2 g/day orally for 3 months) was given to 23 patients with mild Alzheimer’s disease who had not responded to treatment in association with donepezil or rivastigmine. Clinical effects were evaluated by assessing cognitive functions, functional status, and behavioral symptoms. The response rate, which was 38% after the drug treatment alone, increased to 50% after the addition of LAC.63 This additive effect may be useful whenever a patient does not respond to either treatment alone.

Down Syndrome Given that both Down syndrome and Alzheimer’s disease are characterized by a deficit in cholinergic transmission, a study was conducted to assess the effect of a 90-day treatment with LAC in individuals with Down syndrome.” Findings were evaluated statistically and compared with three further groups of subjects: untreated Down syndrome, mental deficiency due to other cases treated, and not treated with LAC. Treated Down syndrome patients showed statistically significant improvements of visual memory and attention both in absolute terms and in comparison with the other groups. No improvement was found in mentally deficient non-Down syndrome subjects, so the favorable effect of LAC appears to be

Pharmacology of Natural Medicines specific for Down patients. An effective dosage is 20 mg of LAC per 2 lb of body weight. The action of LAC in these pathologies may be related to its direct and indirect cholinomimetic effect.

Kidney Disease and Hemodialysis Carnitine supplementation is much indicated in kidney diseases because the kidney is a major site of camitine synthesis.Damage to the kidney or reduced kidney function has a profound effect on camitine metabolism. It is well established that patients undergoing hemodialysis suffer from carnitine deficiency due to the loss of considerable quantities of camitine during dialysis, as well as decreased synthesis. Serum camitine levels drop nearly 80% during hemodialysis.’” Supplementation with LC (15 mg/kg of intravenous LC at the end of each hemodialysis) helps maintain carnitine status6 Carnitine supplementation has been extensively studied in patients undergoing hemodialysis due to chronic renal failure. These studies indicated that LC supplementation is effective in reducing triglyceride levels while raising HDL-cholesterol levels and thus helps to decrease the risk of heart disease in dialysis Carnitine-treated dialyzed patients have also shown additional benefits, including the f~llowing~O-~~: Disappearance of angina pectoris and arrhythmias occurring during dialysis Reduction of muscle symptoms including muscle cramps Increased muscle mass Sigruficant improvement of the chronic anemia seen in these patients as demonstrated by an increased hematocrit, hemoglobin, and red blood cell count Improved insulin sensitivity and reduced stress on pancreatic beta cells Since the early 199Os, a major advancement in the treatment of anemia associated with hemodialysis is recombinant human erythropoietin (EPO) therapy. However, this therapy is expensive and has side effects. In one study LC (1 g intravenously after every dialysis session) administered for 6 months led to a significantreduction in dosage, as well as improvements in membrane fragility and endogenous EPO secretion.74Given the high cost of EPO, if doctors are unwilling to follow this procedure, insurance companies should get involved and force dialysis units to employ LC.

Diabetes Patients with diabetes typically have deficient carnitine status. Studies reveal relationships between low camitine status and increased plasma fatty acids, which negatively affect insulinaction, so it has been recommended that free camitine determinations should be made even if the patient has good metabolic ~0ntr0l.7~ Given the risk of atherosclerotic cardiovascular disease and reduced

kidney and liver function found in diabetic patients, it may simply be more rational to supplement all diabetic patients with LC. Carnitine supplementation has been shown to greatly improve peripheral vascular function, as well as nerve function, in patients with In one doubleblind study, 333 patients with diabetic neuropathy were given LAC or placebo intramuscularly at a dosage of 1000 mg/day for 10 days and continued orally at a dosage of 2000 mg/day for the remainder of the 12-month study. Among the 294 patients with impaired electrophysiologic parameters at baseline, those treated with LAC showed a statistically sigruficant improvement in mean nerve conduction velocity and amplitude compared with placebo. After 12 months of treatment, mean VAS scores for pain were sigruficantly reduced from baseline by 39% in LAC-treated patients compared with 8% in placebo recipients?* Camitine supplementation may also affect blood lipids in patients with type 2 diabetes, particularly lipoprotein(a). In a study in type 2 diabetes, 2000 mg of carnitine daily lowered lipoprotein(a) levels by roughly 20% after 6 months, while in another study of patients with markedly elevated lipoprotein(a) levels, even greater reductions were n ~ t e d . ~ ~ , ~

Liver Disease Carnitine plays an extremely important role in the usage and metabolization of fatty acids in the liver. Some evidence indicates that carnitine deficiency within the liver promotes fatty infiltration (also known as steatosis or liver Alcohol ingestion is a common cause of fatty infiltration of the liver. It has been suggested that chronic alcohol consumption results in a functional deficiency of carnitine. A functional deficiency means that there is plenty of carnitine around, but its function is inhibited just as if there was a deficiency. Many commonly used agents for fatty infiltration such as choline, niacin, and cysteine appear to have little value in relieving alcohol-induced fatty liver. However, camitine sigruficantly inhibits, and reverses, alcohol-induced fatty liver disease!* Since carnitine normally assists fatty acid transport and oxidation in the mitochondria, a high liver carnitine level may be necessary to handle the increased fatty acid load produced by alcohol consumption or other liver injury.“ Supplementalcarnitine has been shown to reduce free fatty acid levels in patients with liver cirrhosis and to reduce serum triglycerides and liver enzyme levels while elevating HDL-cholesterol in alcohol-induced fatty liver di~ease.*l-~~ Camitine’s use in liver disorders associated with fatty infiltration appears warranted, especially when these changes are due to the ingestion of alcohol or exposure to xenobiotics (manmade chemicals toxic to biologic processes such as pesticides and herbicides).

Carnitine Carnitine has also proven helpful in relieving the tremendous fatigue associated with interferon-alpha (IFN-a)treatment for hepatitis C. In one study 50 patients with chronic hepatitis treated with IFN-a at a dosage of 3 million IUthree times weekly were given either carnitine (2 g daily) or placebo for 6 months. While IFN-a alone induces fatigue in the majority of cases, in contrast patients treated with IFN plus carnitine show a marked and early sigruficantreduction of both mental and physical fatigue levels.@

Muscular Dystrophies Patients with various muscular dystrophies have reduced levels of carnitine in their skeletal muscles.s87 Although levels are not as low as those observed in patients with classical myopathic carnitine deficiency, the low carnitine levels are thought to contribute to the muscular weakness experienced by these patients. Unfortunately, it is undetermined if supplemental carnitine would be of any value in patients with muscular dystrophy.

In another double-blind study, 86 men with infertility received carnitine therapy (2 g/day) or placebo for 2 months followed by a 2-month washout period, crossover, and another 2-month study. A statistically significant improvement in semen quality was seen after the LC therapy for sperm concentration and total and forward sperm motility. The increase in forward sperm motility was more significant in patients with lower initial values (i.e., 42 mmHg), detailed evaluations using laser Doppler flowmetry, transcutaneous oxygen and carbon dioxide tension measurements, as well as determination of capillary filtration rate, ankle circumference, and ankle edema along with detailed symptom evaluation clearly demonstrated that centella extracts are clinically effective in dealing with this The standardized extract of C. asiutica has also shown an ability to improve diabetic microangiopathy; prevent the edema and microcirculation alterations seen during medium- to long-distance flights; and normalize the echographic character of carotid arteries with significant plaq~e.8~~

Wound Healing Standardized extracts of C. asiuticu have been shown in many clinical studies to greatly aid wound repair.'3J0*42ia7-60 The types of wounds healed include the following: Surgical wounds such as episiotomies and ear, nose, and throat surgeries Skin ulcers due to arterial or venous insufficiency Traumatic injuries to the skin Gangrene Skin grafts Schistosomiasis lesions Perineal lesions produced during childbirth

Centella asiatica (Gotu Kola)

DOSAGE The majority of clinical studies on C. usiuticu used proprietary formulas available in Europe (e.g., Madecassol, TECA, Centelase). These standardized extracts contain asiaticoside (40%), asiatic acid (29% to 30%), madecassic acid (29% to 30%), and madecassoside (1%to 2%). Because the concentration of triterpenes in centella varies between 1.1%and 8%, it is difficult to calculate an appropriate dosage when simply using the crude plant material. However, because most samples yield a concentration between 2.2% and 3.4%, approximately 2 to 4 &day of crude plant material would contain an appropriate quantity of triterpenes, although it is unknown if this correlates with the clinical efficacy of the standardized extracts. Daily dosages of the various forms of centella are as follows: Standardized extract (40% asiaticoside, 29% to 30% asiatic acid, 29% to 30% madecassic acid, and 1%to 2% madecassoside): 60 to 180 mg/day

1.Kartnig T. Clinical applications of Centella asiatica (L) Urb. In Craker LE, Simon JE, eds. Herbs, spices, and medicinal plants: recent advances in botany, horticulture, and pharmacology, vol3. Phoenix: O r y Press, ~ 1986145-173. 2. Brinkhaus 8, Lindner M, Schuppan D, Hahn EG. Chemical, pharmacological and clinical profile of the East Asian medical plant Centella asiatica. Phytomedicine 2000;7427-448. 3. Battacharya SC.Constituents of Centella asiutica. I. Examination of the Ceylonese variety. J Ind Chem Soc 1956;33579-586. 4. Battacharya SC. Constituents of Centella asiafica. I. Examination of the Indian variety. J Ind Chem Soc 195633B93-898. 5.Rao PS, Seshadri TR. Variation in the chemical composition of Indian samples of Centella asiutica. Curr Sci 1969;38:77-79. 6. Duke JA. Handbook of medicinal herbs. Boca Raton, n:CRC Press, 1985. 7. Tyler V, Brady L, Robbers J. Pharmacognosy,ed 8. Philadelphia: Lea & Febiger, 1981. 8. Boiteau,'F Ratsimamanga AR. Asiaticoside extracted from Centella asiatica, its therapeutic uses in the healing of experimental or refractory wounds, leprosy, skin tuberculosis, and lupus. Therapie 1956; 11325-149. 9. Boiteau P, Nigeon-Dureuil M, Ratsimamanga AR. Action of asiaticoside on reticuloendothelial tissue. Acad Sci Compt Rend 1951;232 760-762. 10. Monograph. Centella asiatica. Milan: Indena S.p.A. 1987. 11.Abou-Chaar CI. New drugs from higher plants recently introduced into therapeutics. Leban Pharm J 1963;8:15-37. 12. Lawrence JC. The morphological and pharmacological effects of asiaticoside upon skin in vitro and in vim. Eur J Pharmacol 1967;1:414-424. 13.Bonte F, Dumas M, Chaudagne C, Meybeck A. Influence of asiatic acid, madecassic acid, and asiaticoside on human collagen I synthesis. Planta Med 1994;60:133-135. 14. May A. The effect of asiaticoside on pig skin in organ culture. Eur J Pharmacol1968;4:331-339.

Crude dried plant leaves: 2 to 4 g/day Tincture (1:5):10 to 20 ml/day Fluid extract (1:l):2 to 4 &/day

TOXICOLOGY C. asiuticu and its extracts are well tolerated, especially orally.',2 However, the topical application of a salve containing centella has been reported to cause contact dermatitis, although quite infrequently.' Although the oral administration of asiaticoside at a dose of 1 g/kg body weight has not proved toxic in toxicology studies, the toxic dose of asiaticoside by intramuscular application to mice and rabbits is reported as 40 to 50 mg/kg body weight.' Asiaticoside has been implicated as a possible skin carcinogen where repeated applications are used in an experimental animal Teratologic studies using the extract in rabbits have proved negative.31

15. Bensaude A. [The treatment of anal fissure.] Phleobologie 1980;33683-688. 16. Fam A. Use of titrated extract of Centella asiutica (TECA) in bilharzial bladder lesions. Int Surg 1973;58:451-452. 17. Etrebi A, Ibrahim A, Zaki K. Treatment of bladder ulcer with asiaticoside. J Egypt Med Assoc 1975;58:324-327. 18. Gravel JA. [Oxygen dressings and asiaticoside in the treatment of bums.] Laval Med 1965;36:413-415. 19. Boiteau P, Ratsimamanga AR. Important cicatrizants of vegetable origin and the biostimulins of Filatov. Bull Soc Sci Bretagne 1959; 34~307-315. 20. Bourguignon D. Study of the action of titrated extract of Centella asiatica. Gaz Med Fr 1975fl24579-4583. 21.Bonnett GF. Treatment of localized cellulitis with asiaticoside Madecassol. Progr Med 1974;102109-110. 22. Grosshans E, Keller F. Cellulite: reality or imposter? J Med Strasb 1983;14563-567. 23. Keller F, Grosshans E.Cellulitis: reality or fraud? Med Hyg 1983;l: 1513-1518. 24. Tenailleau A. On 80 cases of cellulitis treated with the standard extract of Centella asiatica. Quest Med 1978;31:919-924. 25. Carraro Pereira I. Treatment of cellulitis with Centella asiatica. Folha Med 1979;79401414. 26. D a d s F, Orcel L, de Saint-Maur PP, Mamou P. [Use of a titrated extract of Centelk asiutica in chronic hepatic disorders.] Sem Hop 1979;55:1749-1750. 27. El Zawahry MTI, KhaIil AM, El Banna h4H. Madecassol, a new therapy for hepatic fibrosis. Bull !%c Int Chir (Belgium) 1975;W 573-577. 28. Fmcato M. On the treatment of cutaneous lesions with extract of Centella asiutica. Minerva Chir 1960;15:1235-1238. 29. Sterkers Desagnat M, Philbert M, Moreau L. Medical treatments for benign disease of the breast. Therapeutique 1975;51:121-124. 30.Guarnerio F, Sansonetti G, Donzelli R, Marelli C. Treatment of hemorrhoids with Centella asiatica. G Ital Angiol 1986;6:46-52.

Pharmacology of Natural Medicines 31.Bosse JP, Papillon J, Frenette G, et al. Clinical study of a new antikeloid agent. Ann Plast Surg 1979;3:13-21. 32. Basset A, Ullmo A, Maleville J, Alt J. [Treatment of keloids with Madecassol per os.]Bull Soc Fr Dermatol Syphiligr 1970;77:826-827. 33. Ippolito F. Medical treatment of keloids. G Ital Dermatol 1977;112377-381. 34. Chakrabarty T, Deshmukh S. Centella asiatica in the treatment of leprosy. Sci Cult 1976;42573. 35. Chaudhuri S, Ghosh S, Chakraborty T, et al. Use of a common Indian herb "Mandukapami" in the treatment of leprosy. J Indian Med As= 1978;70177-180. 36. Wolfram VS. Erfahrungem mit Maddecassol bei der behandlung ulzereroserser hautveranderungen. Wien Med Wochenschr 1%5;115 439-442. 37.Appa Rao MVR, Srinivasan K, Koteswara RTL. The effect of Centella asiatica on the general mental ability of mentally retarded children. Indian J Psychiatry 1977;1954-59. 38. Kyoo WC. Medical treatment of peptic ulcer. J Korean Med Assoc 1980;23:31-35. 39. Pergola F. Treatment of peptic ulcer with a titrated extract of Centella asiatica. Med Chir Dig 1974;36:445-448. 40.Baudon-Glanddier B. Perineal lesions and asiaticoside. Gaz Med Fr 1963;70:2463-2464. 41. BenedicentiA, Galli D, Merlini A. [The clinical therapy of periodontal disease. The use of potassium hydroxide and the water-alcohol extract of Centella asiatica in combination with laser therapy in the treatment of severe periodontal disease.] Parodontol Stomatol 1985;24:11-26. 42. Abou-Shousha ES, Khalil HA. Effect of asiaticoside (Madecassol) on the healing process in cataract surgical wounds and retinal detachment operations (clinical and experimental study). Bull Ophthalmol Soc Egypt 1%7;60:451-470. 43. Bletry 0. Comment on the treatment of scleroderma. Gaz Med Fr 1980;871989-1990. 44.Fontan I, Rommel A, Geniaux M, Maleville J. Localized sderoderma. Concours Med 1987;109:49&504. 45. Sasaki S, Shinkai H,Akashi Y, Kishihara Y.Experimental and clinical effects of asiaticoside (Madecassol) on fibroblasts, granulomas, and sderoderma. Jap J Clin Dermatol1971;25:58!5-593. 46. Sasaki S, Shinkai H, Akashi Y, Kishihara Y. Studies on the mechanism of action of asiaticoside (Madecassol) on experimental granulation tissue and cultured fibroblasts and its clinical application in systemic s d e r o d e m . Acta Derm Venereol 1972;52141-150. 47.Balina LM, Cardama JE,Gatti JC, et al. Clinical results of an asiaticoside in cutaneous ulcerous lesions. Dia Med 1961;33: 1693-1696. 48.Bazex J, N o p e J, Peyrot J. Periulcerous eczema type cutaneous reaction during and after ulcers of the leg. Rev Med Toulouse 1982; 18171-174. 49. Dulauney MM. Postphlebitic leg ulcers and indications for therapy. Bord Med 1979;121807-1810. 50. Hanna LK, Amin L, El Serafy I. Trophic ulcers and their treatment with Madecassol. Afr Med 1969;8:315-318. 51. Huriez C. [Action of the titrated extract of Centella asiatica on cicatrization of leg ulcers (10 mg tablets). Apropos of 50 cases.] Lille Med 1971;17574579. 52.Sarteel AM, Merlen JF. [Treatment of leg ulcers. Martorell ulcer, superficial gangrene, so-called capillaritic ulcers.] Phlebologie 1983;36.375-379. 53. Thiers H, Fayolle J, Boiteau P, Ratsimamanga AR. Asiaticoside, the active principle of Centella asiatica, in the treatment of cutaneous ulcers. Lyon Med 1957;197389-395. 54. Vittori F. The treatment of ulcus cruris. J Med Lyon 1982;63:429432. 55.Castellani C, Gillet JY, Lavemhe G, Dellenbach P. [Asiaticoside and cicatrization of episiotomies.] Bull Fed Soc Gynecol Obstet 1966;18184-186.

56. Colonna d'Istria J. [Research on the healing action of Madecassol in cervical and laryngeal surgery after ionizing radiations.] J Fr Otorhinolaryngol Audiophonol Chir Maxillofac 1970;19:507-510. 57. OKeeffe P. A trial of asiaticoside on skin graft donor areas. Br J Plast Surg 1974;27194-195. 58. Pignataro 0, Teatini GP. [Clinical research on the cicatrizing action of Madecassol in comparisons of oropharyngeal mucosa.] Minerva Med 1965;56:2683-2686. 59.Riu R, Alavoine J, Auriault A, Le Moue1 C. [Clinical study of Madecassol in otorhinolaryngology.] J Med Lyon 1966;47 693-706. 60.Sevin P. Some observations on the use of asiaticoside (Madecassol) in general surgery. Progr Med (France) 1962;90:23-24. 61. King DS.Tuberculosis. N Engl J Med 1950;243:530-536,565571. 62.Allegra C. [Comparative capillaroscopic study of certain bioflavonoids and total triterpenic fractions of Centella asiatica in venous insufficiency.] Clin Ter 1984;110555-559. 63. Allegra C, Pollari G, Criscuolo A, et al. [Centella asiatica extract in venous disorders of the lower limbs. Comparative clinicoinstrumental studies with a placebo.] Clin Ter 1981;99:507-513. 64.Barletta S, Borgioli A, Corsi C. Results with Centella asiatica in chronic venous insufficiency. Gazz Med Ital1981;14033-35. 65. Basellini A, Agus GB, Antonucci E, Papacharalambus D. [Varicesin pregnancy (an update).] Ann Ostet Ginecol Med Perinat 1985; 106~337-341. 66. Boely C. Indications of titrated extract of Centella usiatica in phlebology. Gaz Med Fr 1975;82741-744. 67. Bolgert M, Gautron G. An extract from Centella asiatica in phlebology. Progr Med (France) 1972;10031-32. 68. Cappelli R. Clinical and pharmacological study on the effect of an extract of Centella asiatica in chronic venous insufficiency of lower limbs. G Ital Angiol19833:44-48. 69. Cospite M, Ferrara F, h4ilio G, Meli F. Study about pharmacologic and clinical activity of Centella asiatica titrated extract in the chronic venous deficiency of the lower limbs. Valuation with strain gauge plethysmography. G Ital Angiol1984;4200-205. 70. Frausini G, Rotatori T, Oliva S. Controlled trial on clinical-dynamic effects of three treatments in chronic venous insufficiency. G Ital Angi011985;5147-151. 71. Marastoni F, Baldo A, Redaelli G, Ghiringhelli L. [Centella asiatica extract in venous pathology of the lower limbs and its evaluation as compared with tribenoside.] Minerva-Cardioangiol 1982;30: 201-207. 72.Mariani G, Patuzzo E. Treatment of venous insufficiency with extract of Centella asiatica. Clin Eur (Italy) 1983;22:154-158. 73. Mazzola C, Gini h4M. Centella asiatica extract in treatment of chronic venous insufficiency. Clin Eur (Italy) 1982;21:160-166. 74. Pointel JP,Boccalon H, Cloarec M, et al. litrated extract of Centella asiatica (TECA) in the treatment of venous insufficiency of the lower limbs. Angiology 1987;38:46-50. 75. Ramaswamy AS, Periyasamy SM, Basu N. Pharmacological studies on Centella asiatica L. (Brahma manduki) (N.O. Umbelliferae). J Res Indian Med 1970;4:160-175. 76. Laerum OD, Iversen OH. Reticuloses and epidermal tumors in hairless mice after topical skin applications of cantharidin and asiaticoside. Cancer Res 1972321463-1469. 77. Veerendra Kumar MH, Gupta YK. Effect of different extracts of Centella asiatica on cognition and markers of oxidative stress in rats. J Ethnopharmacol2002;79253-260. 78. Lee MK, Kim SR, Sung SH, et al. Asiatic acid derivatives protect cultured cortical neurons from glutamate-induced excitotoxicity. Res Commun Mol Pathol Pharmacol2O00;108:75-86. 79. Veerendra Kumar MH, Gupta YK. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer's disease in rats. Clin Exp Pharmacol Physiol2003;30:336-342.

Centella asiatica (Gotu Kola) 80. Bradwejn J, Zhou Y, Koszycki D, Shlik J. A double-blind, placebocontrolled study on the effects of Gotu Kola (Centella asiatica) on acoustic startle response in healthy subjects. J Clin Psychopharmacol

2000;20:680-684. 81. Incandela L, Belcaro G, De Sanctis MT, et al. Total triterpenic fraction of Centella asiatica in the treatment of venous hypertension: a clinical, prospective, randomized trial using a combined microcirculatory model. Angiology 2001;52(suppl2):S61-S67. 82. De Sanctis MT, Belcaro G, Incandela L, et al. Treatment of edema and increased capillary filtration in venous hypertension with total triterpenic fraction of Centella asikticu: a clinical, prospective, placebo-controlled, randomized, dose-rangingtrial. Angiology 2001; 52(s~pp12):555-S59. 83.Cesarone MR, Belcaro G, Rulo A, et al. Microcirculatory effects of total triterpenic fraction of Centella asiatica in chronic venous hypertension: measurement by laser Doppler, TcPO2-CO2, and leg volumetry. Angiology 2001;52(suppl2):S45-S48.

84. Cesarone MR, Belcaro G, De Sanctis h4T, et al. Effects of the total triterpenic fraction of Centella usiatica in venous hypertensive

microangiopathy: a prospective, placebo-controlled, randomized trial. Angiology 2001;52(suppl2):S15-S18. 85. Cesarone MR, Incandela L, De SanctisMT, et al. Evaluation of treatment of diabetic microangiopathy with total triterpenic fraction of Centella asiatica: a clinical prospective randomized trial with a microcirculatorymodel. Angiology 2001;52(suppl2):S49-S54. 86. Cesarone MR, Incandela L, De Sanctis MT, et al. Flight microangiopathy in medium- to long-distance flights: prevention of edema and microcirculation alterations with total triterpenic fraction of Centella asiatica. Angiology 2001;52(suppl2):S33-S37. 87.Cesarone MR, Belcaro G, Nicolaides AN, et al. Increase in echogenicity of echolucent carotid plaques after treatment with total triterpenic fraction of Centella asiatica: a prospective, placebo-controlled, randomized trial. Angiology 2001;52(suppl 2): S19-S25.

Chinese Prepared Medicines Mark Harrison Nolting, ND, LAC Qiang Cao, LAC,OMD, ND CHAPTER CONTENTS Introduction 837

Adulterants, Endangered Species, and Standards 839

Global Market 838 Dispensary Guide 840 Formulationsand Preparations 838

INTRODUCTION Chinese prepared medicine (CPM) is the "over-thecounter [OK]" medicine of the traditional Chinese pharmacy, thousands of various preparations of classical and conventional Chinese herbal formulas. Much of this medicine has been in constant use for hundreds, even thousands, of years, often maintaining original formulations. One example is a frequently sold CPM called Jie Geng Wan (Platycodon Root Pills).* The source of this respiratory system medicine is the ling Kui Yao Lue Fang Lun ("synopsis of the Golden Chamber"), written by Zhang Zhong Jing in 219 AD.* Zhu? writing in his highly useful and informative Clinical Handbook of Chinese Prepared Medicines, explained the following: The overtaxed Sung-dynasty merchant, as well as the frazzled h4ing mother, appreciated the simple convenience and economy of a well-prepared herbal pill, powder, or syrup as much as does his or her modem counterpart. Yan Bian Lian, the phrase commonly used when referring to these Zhong Cheng Yuo ("Chinese Ready-to-be-Taken Medicines"), may best express fundamental reason-for-being of ready-to-take medicaments in any tradition: "Effectiveness, Convenience, Economy."

Secret family (or company) recipes called patent medicines were first produced in the Song Dynasty (960-1234 AD) and were dispensed by government agencies such as the Imperial Benevolent Prescriptions of the Taiping Period? Few true patent medicines exist anymore in the Chinese pharmacy. Many of these medicines have become part of the public domain, making it more appropriate to refer to them collectively as CPMs. Unfortunately, there are too many dubious CPMs in the worldwide market that have been adulterated in various ways, some

containing Western prescriptive medicines, toxic elements, and endangered species often hidden from the unsuspecting consumer? Consumers may find in their quest for safe, natural, and effective medicine serious medical consequences they had not expected. This is an issue that deserves scrutiny by consumers, practitioners, and regulators alike. Typical images of the U.S."Wild West" include cowboys, American Indians, farms, and the frontier life. But there was another, lesser known presence in the West, the lives of Chinese immigrants. Many had come to America seeking life on the "Gold Mountain," the view of America that had been created in China during the 1800s. According to Paul Buell? writing in his Chinese Medicine on the Golden Mountain book When in the mid-nineteenth century Chinese immigrants began to arrive in America, all kinds of traditional medical practitioners came with them . . . well-practiced Chinese medicine was often superior to contemporary western practice.

The immigrants, mostly men, left their families to mine for gold. Many ended up working as miners or other laborers. They brought their traditional form of Chinese medicine and their traditional herbal medicine, which included various forms of CPM. Chinese herbal medicine is a highly evolved system of traditional medicine that draws from a Materia Medica composed of thousands of individual herbs (herbs in traditional Chinese medicine [TCM] include plant, mineral, and animal).7 CPMs would generally be considered an adjunct to Chinese herbal medicine in most practices because they are convenient and good alternatives to the strong, bitter-tasting decoctions often used in practice. 837

Pharmacology of Natural Medicines

Many practitioners, particularly in the West, prefer to use granulated Chinese herbs or powered herbs.

GLOBAL MARKET The market for CPMs is huge. China will become the largest pharmaceutic market in the world within a few years. Chinese sales of herbal medicine alone were 2.3 billion dollars in 1995.More than 5OOO “licensed patent medicines” are estimated to exist in China.EAccording to China Today, exports of Chinese herbal medicines worldwide reached 20 billion dollars in 2002. About 5% of this amount was China’s share, and prepared medicines comprised less than one third of this.In China the famous Tong Ren Tang factory, which exports the most CPMs in China, earned 14.5 million dollars? Outside of the enormous “inside China market,” the growing interest and use of natural medicine worldwide are driving the consumption of prepared medicines rapidly upward. As mentioned already, this growth has sparked abuse and problems with product labeling and safety that the entire profession is working to counteract. Although Chinese medicine and pharmacy began to spread outside of China’s borders nearly 2000 years ago, it is only in the past 20 years that interest has grown in North America. Much of this is due to former President Richard Nixon’s trip to the People’s Republic of China in the early 1970s and subsequent reporters’ visits and articles, especially those of James Reston of the N a u York Times.The growth of acupuncture and oriental medical practices such as herbal medicine in the United States has been steady since that time. The traditional loose herb recipes used in Chinese herbal medicine are cooked and made into medicinal soups, which are often bitter and difficult for the American palate. The Chinese solution to this dilemma is to increase the use of raw licorice in the formula and to offer sugar wafers to the patient to help offset the bitter taste, although most Chinese welcome a bitter taste as a normal part of Asian cuisine. The prepared medicines offer an alternative to the traditional preparations. A number of companies, particularly in Taiwan and California, have begun to popularize the manufacture and sale of powder and tincture formulas in single herb form to help “bridge” the traditional form and the prepared, more palatable, forms of medicine. This allows the practitioner to still use the traditional approach, that of mixing and adjusting the formulas tailored to the patient’s individual diagnosis. Prepared formulas are fixed, of course, and do not allow any adjustments in the ingredients. Before the mid-l970s, the U.S. Food and Drug Administration (FDA) restricted the import and sale of traditional medicines by ethnic groups. New legislation and court rulings since then have lifted these restrictions, which, coupled with the explosion of acupuncture on

the American health scene, has opened the door to the spread of prepared medicines.* Now, due to this rapid growth in the sale and use of prepared medicines, problems with adulterants and false labeling are increasing, especially in California, where a multiagency herbal medicine task force involving numerous California and federal government agencies was formed in response. In fact, California Department of Health Services documents state that ”most imported Asian patent medicines do not fully comply with California laws.”10Although some of these violations are indeed potentially dangerous and may involve toxic ingredients and the inclusion of endangered species, many involve labeling issues and can often be sorted out by revising the labeling at the company of origin.

FORMULATIONS AND PREPARATIONS CPMs are prepared in numerous different forms. As far back as 200 BC, Chinese pharmaceutics had already developed a surprising level of sophistication. Pills were bound together using a wide variety of animal and human substances.” Box 79-1 lists 15 of the most common dosage forms of CPM. In China, the prepared medicines are produced at factories located throughout the country. Reputation and awards are important to these mainland Chinese operations. Factories such as the Chongqing Tong Jun Ge Medicine Works in Sichuan province, built in 1908, are proud of their products. This factory produces more than 200 medicines in 14 therapeutic categories.’* Roadside and rooftop billboards across China extol the benefits of ”famous” CPM, as well as displaying the awards various formulas have received over the years. Longevity is an important virtue attributed to specific herbs and formulas in Asian medicine. Ginseng, in all its many species and preparations, is surely the most

Pills Honeyed Watered Pasted Concentrated Powders Medicinal granules Tablets Troches Concentrated decoctions Glues Syrups Mixtures Dripping pills

Capsules Hard Soft Enteric Medicinal wines Tinctures Liquid extracts Plasters Adhesive plasters Ointments Medicinal distillates Medicinal teas Injections Suppositories

-

Modified from the Pharmacopeia Commission of PRC. Pharmacopeia of the People’s Republic of China (English edition 1997). VOI 1. Beijing: Chemical Industry Press, 1997:A3-A14.

revered and used herb in China. The pursuit of longevity is central to its popularity, aside from the fact that it is a highly useful and effective herb. An interesting side note is that the American species of ginseng, Panax quinquefolius,is exported in great quantitiesto China, only to be repackaged and exported back to Western markets. American ginseng is considered a milder, more "supportive" ginseng in action, making it more suitable for the elderly and weak. Ginsengs are part of the tonic herb family, a major classification that does not exist in the conventional Western pharmacy. The most famous factory for herbal medicine products in China is the Tong Ren Tang Pharmacy in Beijing. The Tong Ren Tang Pharmacy, first established in 1669, has been operated by the same family for more than 317 years. Prepared medicines produced in this factory have generally been held in the highest reputation in China, where the factory has supplied medicines to Chinese royalty over several centuries. The drug control acts implemented by the Chinese government in the 1970sand 1980s have helped to further guarantee quality control of prepared medicines in China, and companies such as the Tong Ren Tang pride themselves on following these ~tandards.'~

ADULTERANTSyENDANGERED SPECIES, AND STANDARDS The issue of adulterants and endangered species has increasingly threatened the reputation of CPM as safe and effective. The massive historical and growing contemporary usage of these products in Asia and indeed the world often obscures these quality and ethical realities. The use of tiger bone, rhino horn, bear gallbladder, and seahorse are realities in a system of medicine that spans the centuries. Raising the consciousness of practitioners who grew up in that culture is really a task of education and reshaping that culture. Trafficking of illegal products is tied to big money, and separation between this practice and the legitimate market can be challenging. Western pharmaceutics find their way into "herbal" products as "secret" ingredients that boost the effectiveness of the actions. Government control in the countries of origin is one thing, but ControlLing this globally given widespread corruption and conflicting priorities is a difficult task. The fundamental question remains: "Is the product purchased today in the Asian supermarket or local health food store free of adulterants and endangered species?" Many prepared medicines made outside mainland China lack the same quality controlsas the factories within China. Factories and sellers within China can indeed be visited and found to have goodquality products determined to be safe and free of adulterants. In 1975 an herbal-based preparation called Toukuwan was manufactured in Hong Kong by the Nan-Lien Pharmaceutical

Company and widely promoted in the United States as a treatment for rheumatism and arthritis. The FDA banned the import of Toukuwan after it discovered four drugs including Valium in the Chuifong preparation. Various prescription drugs have also been discovered in other prepared medicines. The Journal of the American Medical Association also reported four cases of agranulocytosis caused by prepared medicines in 1975 before the FDA ban. The Chuifong product has continued to appear under various names such as "miracle herb" since 1975.14J5Caution must be used when purchasing and prescribing prepared herbal medicines, and we recommend using only well-known and reputable manufacturers. If consumers are in doubt, we recommend using products produced at American companies, which typically are subject to far more quality-control standards than those in Asia, and always consulting practitioners who research the origins of various products they use and recommend. In May 1994 Traffic USA and the World Wildlife Fund published Prescription for Extinction: Endangered Species and Patented Oriental Medicines in Trade.I5 This report gave insight into the vast number of endangered species being used in natural medicine. The report indicates which products and traditional formulas contain endangered or threatened species, according to Appendices I, 11, and I11 of the Convention on International Trade in Endangered Species of Wild Fauna and Flora.16J7 Lu,18 writing in the China Daily, described new European regulations in 2004 regarding the importation of Chinese herbal medicines into the European market. He stated the following: The directive regulates that manufacturers who export herbal medicines to the EU market must get the union's GMP (Good Manufacturing Product) certificate, products quality must comply with EU phannacopoeia, and importers should have import licenses. . . . But generally speaking, the directive, which for the first time grants TCM legal status as medicines, will benefit Chinese medicine makers to explore the European market in the future.Currently, most of the TCM products exported to the EU market are under the category of food, native produce, health products, or pharmaceutical ingredients, instead of medicine. Industry experts said that when one TCM product is registered as traditional herbal medicine in the EU, it indicates great market potentials. First, the market value of TCM will be greatly lifted compared to being sold as food or pharmaceutical ingredients. Second, the legal status as medicine would allow TCM join EU countries' hospitalization insurance system. And EU's recognition of TCM will help reduce possible unfair treatment of Chinese medicines from other countries. . . . Meanwhile, domestic makers should strengthen research and development, dismiss some ingredients which are unacceptableto western people, and develop products to cater for the huge European market.

Hong Kong, long a stronghold of TCM despite a restrictive anti-TCM atmosphere under British rule, has

Pharmacology of Natural Medicines upgraded its standards for Chinese herbs. The Chinese Medicine Council of Hong Kong was formed in 1999 to protect public health and consumers’ rights and to ensure the professional standard of Chinese medicine practitioners and the trade of Chinese medicines. On the council’s website, Shawl9discusses the trailblazing approach Australia has taken to create standards for the practice and sale of Chinese herbal medicines: In that country (Australia),products were either “listed” or ”registered.” Listed products were of certified quality and were required to have supporting evidence of safety from the literature. No claims regarding efficacy could be made. Registered products equated to those with a license in the UK.

Shaw also referred to the 1996 report “Towards a Safer Choice,” which resulted from a review of the practice of TCM in Australia. The report concluded that regulation of Chinese herbal medicine and acupuncture practitioners was necessary and led to the Chinese Medicine Regulation Act 1999, which set out statutory regulation for such practitioners in the state of Victoria. The intention was that regulation would eventually be brought in on a national scale. Shaw emphasized that this was being done for the benefit of the public, not practitioners. Summing up, Shaw listed five elements for improving the safety of Chinese herbal medicines: Research into efficacy and safety Training of practitioners Quality herbs Adverse-effect monitoring Appropriate regulation

Also on the council’s website is a valuable list of safety concerns raised by AndersonI9 of the Hong Kong Medicines Control Agency, listed as follows: Lack of adequate authentication Intentional or accidental substitution Use of toxic substances and heavy metals (e.g., arsenic disulphide) Use of toxic animal materials (e.g., Bufo secretions) Use of synthetic drugs (e.g., corticosteroids, nonsteroidal antiinflammatory drugs) Inadequate or inaccurate labeling

DISPENSARY GUIDE CPM serves a number of different therapeutic purposes in and out of the practitioner’s office. First and foremost, it is best prescribed within the principles of prescribing of traditional Chinese herbal medicine. For example, clearing heat or dispelling dampness formulas require some understanding of the philosophy underlying these principles. If just prescribed cookbook style, then individual patient reactions cannot be understood and

tracked properly and the full effect of the formulas will not be appreciated. Secondly, CPM can augment and support traditional decoction-style prescribing. Thirdly, CPM is most valuable in acute prescribing and generally lends itself to OTC use. OTC use is best with input from trained Chinese medicine practitioners. In the case of Yin Chiao, described later, this widely used effective formula is most often prescribed at the onset of colds. And then there is the formula called Chuan Xin Lian (Androgrophis antiinflammatory tablets), which has tremendous effectiveness in inhibiting common bacterial infections, almost an “herbal antibiotic.”*OA final example of useful CPM in acute prescribing is the famous formula called Y m a n Baiyao. This is the most important CPM one should have at hand, at home and on the road. It is an emergency medicine useful in all cases of injury. The signature of Yunnan Baiyao as traditionally dispensed involves little bottles of yellow powder with a tiny red “emergency” pill that is said to help revive critically injured individuals. Yang and Liar@ described it as follows: Yunnan Baiyao, literally meaning Yunnan White medicine, smells like a walk through an exotic forest. That’s a clue to its composition: a dozen or so herbs from the Southwestern flora-abundant province of Yunnan-but exactly which herbs remains a state secret. Successfully used for more than 80 years, Yunnan Baiyao, now available in several forms, is a veritable cure all and an essential, trusty family medicine in China.

The 10 Chinese prepared medicines described in Table 79-1 represent a small sample of the most common and therapeutically effective formulations. Several common varieties of preparations such as pills, tablets, oral liquids, tinctures, and plasters are included. An attempt has been made to introduce preparations for cardiovascular, respiratory, central nervous system, urinary, female, and dermatological conditions. This approach of focusing on major human systems is a common method of teaching prepared medicines. Ingredients are listed with their Chinese (Pinyin) name, botanical name, and percentage in formula. Actions are listed in terms of TCM with Western activities when pertinent. Indications are given according to major Chinese sources. Administration and dosage information is provided with specific directions for adult, as well as pediatric, use. Packing information is also provided to help ensure proper recognition and dosage.A special notes section is included to highlight unique uses, cautions, and contraindications of the preparations. Due to the questionable standards of prepared medicines manufactured in Asia and generally outside China, only mainland Chinese sources known to us are listed. We also urge practitioners to scrutinize the labels of products from unknown sources. With correct labeling,

Allergic rhinitis Sinusitis Chronic rhinitis Nasal obstruction Rhinorrhea Sneezing Cough Asthma Bronchitis

Antiinflammatory Anodyne Antiasthmatic

Xanthium fruit (Cang Er Zi) Magnolia flower (Xin Yi) Angelica root (Bai Zhi) Chrysanthemum (Ju Hua) Lonicera flower (Jin Yin Hua) Pogostemon herb (Huo Xiang) Ox gallstone (Niu Huang) Bear bile (Xiong Dan Zhi) Other herbal extracts This is a widely known and used formula that is accepted as an herbal combination whose manufacturer maintains a patent on its exact formulation

Pe Min Kan Wan (nasal allergy pills)

Indications Common cold and flu Fever and sensation of chill Pain and weariness of limbs Headache Cough Swelling sore throat Mumps Parotitis

Antiphlogistic Disinfectant Carminative Refrigerant

Loniceral flower (Jin Yin Hua), 17.85% Forsythia fruit (Lian Qiao), 17.85% Arctium fruit (Niu Bang Zi), 10.72% Platycodon root (Jie Geng), 10.72% Mentha herb (Bo He), 10.72% Soja seed (Dan Dou Chi), 8.93% Licorice root (Gan Cao), 8.93% Lophaterum leaf (ZhuYe), 7.14% Scizonepeta herb (Jing Jie), 7.14%

Actions

Ingredients

Formula name

Yin Chiao Chieh Tu Pien (Lonicera and Forsythia dispel heat tablets)

Bottle of 50 tablets

Two to three tablets each dose, bid or tid Taking this medicine consistently for 30 days is considered one course of treatment

Continued

Pe Min Kan Wan is an effective remedy for the treatment of acute or chronic sinusitis and rhinitis. It is particularly effective for hypersensitive sinusitis. In hypertrophic rhinitis, it will gradually reduce the size of the polyps in the nose. Marked amelioration of the symptoms can be seen after the patient has taken this medicine for 1 week in mild cases, and one or two courses of treatment are sufficient for recovery. In serious cases, several courses of treatment should be given. Manufactured by the Fu Shan United Pharmaceutical Manufactory, Guang Dong, People’s Republic of China

Notes This formula was made for wind heat invasion of the exterior in traditional Chinese medicine. It is a very popular and commonly used medicine throughout China for early stages of common cold and flu. The Chinese hold that it is the best medicine for common cold and flu. It is most effective when taken immediately or in the first day or two after onset of cold or flu. It may also produce a diaphoretic effect, so monitor use carefully. Produced by Tien Jin Drug Manufactory, Tianjin, People’s Republic of China

Packaging 0.6 g each tablet, eight tablets per tube, 12 tubes per box

Dosage Two to four tablets bid or tid

Salviae multiorrhiza (Dan Shen) Promotes blood fanax notoginseng(San Qi) circulation Borneolum (Bing Pian) Limits blood stasis Induces resuscitation by means of aromatics Regulates the blood flow of Qi to alleviate pain

€leutherocomus senticosus (Ci Wu Jia), 100%

Dan Shen Pian (Salvia miltorrhiza compound tablets)

Wu Cha Seng tablet (Eleutherococcus senticosus tablets) Accelerates the function of the brain and kidney Improves the appetite Improves eyesight and hearing Sedative effect on the central nervous system

Strengthen vital energy Tonify the digestive system Nourish the entire system

Panax ginseng (Ren Shen) Royal Jelly (Feng Wang Jiang) In a base of honey

Renshenfengwanaiang (ginseng and Royal jelly oral liquid)

Actions

Ingredients

Formula name

Ten Chinese prepared medkines--cont’d

Bottle of 50 tablets

Clinical research in China suggested that this herb is especially effective for relieving fatigue and increasing the immune function. It can also reduce anxiety, mental depression and irritation. In China, anthropanax is preferred over ginseng in the treatment of cancer. Produced by Harbin Chinese Medicine Factory, Heilongjiang, People’s Republic of China

The most popular heart remedy in China. Laboratory and clinical research in China has shown that this remedy is able to improve heart muscle contractions, invigorate the blood, increase the blood supply to the coronary artery circulation, and regulate the heart function. This medicine may cause stomach irritation. Produced by China National Chemicals Import & Export Company, Shanghai Branch, People’s Republic of China

This is a general tonic prepared medicine and is used to treat general weakness and to strengthen the immune system. Produced by China National Medicine and Health Products Import and Export Corporation, Harbin Branch, Harbin, People’s Republic of China

Oral liquid, 10 ml each vial, 10 vials per box

Notes

Packaging

Three to four Box of 60 tablets twice tablets daily, to be taken in the morning and evening with warm boiled water Desired effect is brought about in 2-3 Weeks Of administration. Prolonged administration will give better effects.

Three tablets tid

Coronary heart disease Angina pectoris Oppressed feeling in the chest

It has therapeutic effects for coronary heart symptoms such as dyspnea, dizziness, angina pectoris, etc. Satisfactory results for general debilitation, senility, sore limbs or arthritic pains This preparation also helps stimulate and restore the functions of the organs of the infirm or aged, and of those weakened after illness or childbirth. According to the manufacturer, it is effective in curing leukopenia.

To be taken orally, one vial each time, in the morning and in the evening

Dosage

Fatigue Poor constitution Malnutrition Also used as supplementary treatment of coronary artery disease, chronic hepatitis, neurasthenia, arthritis, gastritis, stomach and duodenal ulcer, impotence, lower sexual drive

Indications

Bupleurum chinense (Chai Hu), 14.3% Angelica sinensis (Dang Gui), 14.3% Paeonia lactiflora (Bai Shao), 14.3% Atractylodes rnacrocephala (Bai Zhu), 14.3% Poria cocus (Fu Ling), 14.3% Glycyrrhiza oralensis (Gan Cao), 115% Zingiber (Sheng Jiang), 14.3% Herba rnentha (Bo He), 2.9%

Rehmannia glutinosa (Di Huang), 12% Cornus officinalis (Shan Zhu Yu), 16% Diosmrea opposita (Shan Yao), 16% Alisrna plantago (Ze Xie), 12% Poria cocas (Fu Ling), 12% Paeonia sufutricosa (Mu Dan Pi), 12%

Angelica sinensis (Dang Gui), 12.12% Ligusticum wallichii (Chuan Xiong), 9.10% White Paaeonia lactiflora (Bai ShaoYao), 12.12%

Hsiao Yao Wan (Free and Easy pill)

Liu Wei Di Huang Wan (Rehmannia six formula)

Fu Ke Ba Zhen Wan (women’s precious pills)

Continued

Produced by Lanzhou Fo Ci Pharmaceutical Factory, Lanzhou, People’s Republic of China

Gynecological disorders with loss of Mood, and deficiency of Qi and blood including pale face, fatigue, dizziness, vertigo, shortness of breath, irregular menstruation,

Replenishingboth Qi and blood

Bottle of 200 pills

Produced by Lanzhou Fo Ci Pharmaceutical Factory, Lanzhou, People’s Republic of China

Eight to 10 pills Bottle of tid, taken 200 pills with warm water

Traditionally this remedy is used to treat deficiency of kidney yin, flaming up of deficient fire, with sore and weak back and knees, feverish and painful body, dizziness, tinnitus or deafness, spontaneous or night sweating, nocturnal emission with dream, thirst, dribbling of urine, dry tongue and soreness of throat, unstable teeth, and heel pain Modern use includes treatment of nephritis, diabetes, tuberculosis, hyperthyroidism, and hypertension.

Nourishing yin Tonifying the kidney

Eight to 10 pills tid, taken with warm water

Produced by Lanzhou Fo Ci Pharmaceutical Factory, Lanzhou, People’s Republic of China

Eight to 10 pills, Bottle of tid taken 200 pills with warm water

Traditionally this remedy is used to treat depression of the liver Qi and deficiency of the liver blood which manifest as pain in the hypochondria1region, alternative fever and chills, headache, vertigo or dizziness, dry mouth and throat, fatigue, anorexia, irregular menstruation, distention of the breasts, wiry and weak pulse. Modern use includes treatment of anxiety, depression, irritability, dizziness, vertigo, PMS, and irregular menses.

Circulating the liver Qi and relieving depression of the liver; invigorating the spleen and regulating the nutrient system

Skin infections caused by fungus, tinea, or scabies Itch of toes and skin Athlete’s foot, etc.

Arthralgia Soreness of waist and pain of the back Sprain and local pain caused by rheumatism It also is used for acute bruises, sprains, fractures, and traumatic swelling.

Eliminates damp and heat in the skin: stops itching

Promotes the flow of Qi and blood circulation Dispels pathogenic factor Alleviates pain

Cortex hibisci (Tu Jin Pi), 6 cc Benzoic acid, 1.8 g Salicylic acid, 0.9 g Alcohol, suitable amount Also contains safflower, dandelion and rhubarb extracts as inert ingredients for flavor and adjuvant in a base of myrrh gum mass

Menthol, 16% Methyl salicylate, 10%

Medicated herbal plaster

Indications

Tu Jin Liniment (complex hibisci tincture)

Actions hypermenorrhea, hypomenorrhea, dysmenorrhea, general deficiency during pregnancy, general deficiency in the postpartum period, chills and fever, restlessness and thirst

Ingredients

Rehmannia glutinosa (Shou Di Huang), 18.18% Codonopis pilosulae (Dang Shen), 12.12% Atractylodes macroephala (Bai Zhu), 12.12% Poria cows (Fu Ling), 12.12% Glycyrrhiza uralensis (Gan Cao), 6.06%

Formula name

Ten Chinese prepared medicines-cont’d

Rub on the skin (it is not necessary to cover the skin), and the liquid will dry quickly. Tighten the lid after use. Not to be taken orally or dropped into eyes. Produced by The United Pharmaceutical Manufactory, Guangzhou, People’s Republic of China Administer with care to pregnant women. Contraindicated for patients with local ulceration. If skin irritation occurs, move to adjoining area or discontinue use. In the case of an allergic reaction, immediately discontinue use. Manufactured by the United Pharmaceutical Manufactory, Guang Zhong, People’s Republic of China

3.9 x 11 inches, 10 pieces per box Remove attached film and apply to affected area. For adults and children 2 years of age and older. Apply to affected area not more than three or four times daily. It will remain effective for 24 hours; more effective if used after a bath. Remove patches while bathing. If needed, cut sheet into smaller patches to save plaster.

Notes

In bottles of 15 ml: 12 bottles to a paper box

Packaging

External application one to two times a day

Dosage

Chinese Prepared Medicines

ingredients of prepared medicines should be obvious to anyone who can read Latin or Chinese herbal names. In recent years, prepared medicine companies have become well established in the United States. Several

high-quality manufacturersare now producing formulas in forms more suitable. These tinctures, powders, and capsules are usually based on the same classical formulas described in this chapter.

1.The Pharmacopeia Commission of PRC. Pharmacopeia of the People’s Republic of China (English Edition 1993, vol 1. Beijing: Chemical Industry Press, 1997162. 2.Zhu CH. Clinical handbook of Chinese prepared medicines. Brookline, MA: Paradigm Publications, 1989:77. 3.Zhu CH. Clinical handbook of Chinese prepared medicines. Brookline, MA: Paradigm Publications, 1989:2. 4. State Administration of Traditional Chinese Medicine. Advanced textbook on traditional Chinese medicine and pharmacology, vol 1. Beijing: New World Press, 1995139. 5. California Department of Health. Asian patent medicines, questions and answers. Sacramento, C A California Department of Health Food & Drug Branch, 1991. 6. Buell P. Chinese medicine on the golden mountah an interpretive guide. Seattle: Wing Luke Memorial Museum, 1984. 7. Barlow J, Richardson C. China doctor of John Day. Portland, OR Binford & Mort Publishing, 1979. 8. Traditional Chinese medicines: The Chinese market and intemational opportunities, London: Natural Medicine Marketing in Collaborationwith Sin0 European Clinics Limited, 1996. 9. Li S. Tong Ren Tang goes international: An interview with Ding Yongling, general manager of Beijing Tong Ren Tang International Co, Ltd and deputy general manager of Beijing Tong Ren Tang Group Co, Ltd. China Today, October 2003. Available online at wvw.chinatoday.corn.cn [accessedAugust 27,20041. 10. State of California, Department of Health Services. Important information for the sellers of Asian patent medicines. Sacramento, CA State of California, Department of Health Services, 1991.

11. Fu WK. Traditional Chinese medicine and pharmacology. Beijing: Foreign Languages Press, 1985. 12. Product catalog. Chongqing, Sichuan, China: Chongqing Tong Jun Ge Medicine Works, 1985. 13.Zhu CH. Clinical handbook of Chinese prepared medicines. Brookline, MA: Paradigm Publications, 1989:6. 14.Rics CA, Sahud MA. Agranulqtosis caused by Chinese herbal medicines. JAMA 1975;23352-355. 15. McCaleb R, Blumenthal M. Black pearls lose luster. HerbalGram 1990;22:45,38-39. 16. Gaski AL, Johnson KA. Prescription for extinction: endangered species and patented oriental medicines in trade. Washington, DC: Traffic USA, 1994. 17. CITES Secretariat,Convention Documents. Geneva: Conventionon InternationalTrade in Endangered Species of Wild Fauna and Flora (CITES), September 1997. 18. Yu Lu. EU regulation affects TCM exports. China Daily. Available online at zvww.ChinadaiZy.corn.cn[accessed August 7,20041. 19. Chinese Medicine Council of Hong Kong. Regulation of Chinese medicine. Available online at vwwcrnchk.org.hk (accessed August 12, 20041. 20. Zhu C-H. Clinical handbook of Chinese prepared medicines. Brookline, MA: Paradigm Publications, 1989:189. 21. Unbelievable cures and medicines from China. Beijing: New World Press, 199761-67. 22. The Pharmacopeia Commission of PRC. Pharmacopeia of the People’s Republic of China (English edition 1993, vol 1. Beijing: Chemical Industry Press, 1997A3-Al4.

Chinese Herbal Patent Formulas: APractical Guide by Jake Fratkin, 1985

Encyclopedia of Chinese and U.S. Patent Herbal Medicines by Chongyun Liu, 1999 Outline Guide to Chinese Herbal Patent Medicines in Pill Form-with Sample Pictures of the Boxes by Margaret Naeser, 1989

Chinese Patent Medicines: A Beginner’s Guide by Mark Taylor, 1998 Clinical Handbook of Chinese Prepared Medicinesby Chun-Han Zhu, 1989 The Clinical Manual of Chinese Herbal Patent Medicines by Will MacLean, 2003, ed 2

Cimicihga racemosa (Black Cohosh) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 847

Dosage 850

Chemical Composition 847

Toxicology 850

History and Folk Use 847

Drug Interactions 851

Pharmacology 848 Clinical Applications 848 Menopause 848 Effects on Bone Resorption 850

Cimicifuga racemosa (family: Ranunculaceae) Common names: black cohosh, macrotys, rattleweed, black snake root

GENERAL DESCRIPTION Cirniczfuga racemosa is a perennial herb native to North America that grows on hillsides and in woods at higher elevations from Maine and Ontario to Wisconsin, Georgia, and Missouri. The large, creeping rhizome produces stems up to 9 feet high. The ovate or oblong leaflets are 1 to 6 inches long and 4 inches wide, while the smaller leaflets are ternate, then pinnate, and sometimes even further divided. Small, white, fetid flowers grow in long racemes from May to August. The rhizome is the portion of the plant used for medicinal purposes.

CHEMICAL COMPOSITION C. racemosa contains at least three important natural product groups that contribute to its pharmacology: cycloartane triterpene glycosides such as actein, 26-deoxyactein; phenylpropanoid esters; and phenolic compounds such as caffeic acid derivatives including ferulic acid and isoferulic acid (Figures 80-1 and 80-2).’” Early reports showed that it also contained the phytoestrogen flavonoid formononetin, but more recent analysis demonstrates that this compound is not contained in

either the crude herb or standardized extracts. At this point, despite extensive chemical, biologic, and clinical studies, neither the active constituents nor the exact mode of action of black cohosh has been determined! Currently, the standardization of cimicifuga preparations is based on the content of triterpene glycosides, calculated as 26-deoxyactein. Other important triterpene glycosides include actein and cimicifugoside (aglycone cimegenol).

HISTORY AND FOLK USE The generic name cimicifuga comes from the Latin cimex, a bug, andfugo, to drive away, alluding to its use as a vermifuge. Native Americans used cimicifuga rhizomes for the relief of pain during menses and childbirth, as well as snakebite. The rhizome of C. racemosa was listed in the National Formulary from 1936 to 1950 and in the U.S. Pharmacopeia from 1820 to 1936. Eclectic physicians in the early part of the twentieth century used cimicifuga in gynecologic disorders, as well as rheumatoid and myalgic pain. Although use in the United States declined dramatically from 1950 to 1995, cimicifuga preparations have been used extensively in Europe during this same period primarily as a natural alternative to hormone replacement therapy (HRT) during menopause. This popularity is based on substantial empiric and clinical evidence. 847

Pharmacology of Natural Medicines

Constituents able to bind to estrogen receptor sites and to inhibit LH secretion Compounds that bound to estrogen receptors but did not inhibit LH secretion

Flgutr, 80-1 Cimigenol.

Flgure a 2 Formononetin.

PHARMACOLOGY The primary pharmacologic effects of cimicifuga appear to revolve around its ability to impact endocrine regulatory mechanisms.= In the past, this activity was thought to be related to various phytoestrogenic components of cimicifuga, with formononetin perhaps being the most sisrUficant-9However, thisline of reasoning has been questioned by the lack of formononetin in clinically studied cimicifuga extracts, as well as equivocal reports on phytoestrogen activity. Current thinking is that certain cimicifuga components exert selective estrogen receptor modulator (SERM) activity with no action in the uterus but beneficial effects in the hypothalamo/pituitary unit and in the b ~ n e . ~ J ~ J ~ Cimicifuga’s primary effect on endocrine regulatory mechanisms appears to be the result of complex synergistic actions of its key ingredients. Evidence suggests that these compounds act on both the hypothalamus and vasomotor centers to produce sigruficantclinical benefits in menopause. For example, one study to determine the endocrhologic actions of cimicifuga extract involved treating 110 women with either cimicifuga extract (supplying a total daily dosage of 8 mg of 27-deoxyactein) or placebo.EAfter 2 months of treatment, luteinizing hormone (LH) decreased by 20% in the cimicifugagroup compared with the placebo group. Unlike estrogens, cimicifuga does not affect the release of prolactin and folliclestimulating hormone (FSH). Researchers then divided the extract into three distinct types of active compounds on the basis of their ability to reduce LH secretion in ovariectomized rats and to compete in vitro with 17-beta-estradiol for estrogen receptor binding sites, as follows: Constituents that did not bind to estrogen receptors but did suppress LH secretion

The authors concluded that ”the LH suppressive effect of C. racemosa extracts observed in menopausal women and ovariectomized rats is caused by at least threedifferent synergistically acting compounds.” Apparently, one of cimicifuga’s key pharmacologic effects is inhibition of the secretion of LH by the pituitary gland. This effect is accomplished equally by components that do and do not bind to estrogen receptors. If cimicifuga was simply mimicking the effects of estrogen, it would certainly alter the secretion of other pituitary hormones just like estrogen, but it does not. It appears that enhancement of dopaminergic activity is the responsible mechanism for some of these central effects on menopausal symptoms.5J2 C i m i h g a extracts also appear to exert some benefiaal effects on preventing bone loss. In an experiment carried out on ovariectomized rats, cimicifuga extract increased the expression of collagen I and osteocalcin. Similarly, other animal studies have demonstrated that cimicifuga extract significantly reduces the urinary parameters of increased bone metabolism and bone loss. The effects in these animal models were similar to raloxifene, a wellconfirmed S E W . Importantly, although early studies reported a direct estrogenic effect with cimicifuga, the current perspective is that ethanol and isopropanol extracts of black cohosh do not contain formononetin or other estrogenic flavonoids and therefore do not bind to the estrogen receptor, upregdate estrogen-dependentgenes, or stimulate the growth of estrogen-dependent tumors in in vitro and animal m~dels.~J~J~

CLINICAL APPLICATIONS C. racmosu extracts are by far the most widely used and thoroughly studied natural alternatives to HRT in menopause. Clinical studies have shown cimicifuga extracts to relieve not only hot flashes but also depression and vaginal a t r ~ p h y . ~ , ’ ~ ~ ~ Although evidence indicates that cimicifuga may provide benefit in other gynecologic complaints such as premenstrual syndrome, amenorrhea (both primary and secondary), dysmenorrhea, polymenorrhea, uterine fibroids, and fibrocysticbreast disease, its primary clinical application is menopause.”-26

Menopause In one of the first clinical studies, a large open study involving 131 doctors and 629 female patients, cimicifuga extract (two tablets twice daily providing a daily

Cimicifuga racemosa (Black Cohosh)

Cimicifuga in the treatment of menopause SvmDtom

Percentaae no longer present

Percentage improved

Total Dercentaae improved

~~~~

Hot flashes

43.3 38.6 36.2 35.2 35.2 38.1 43.2 30.7 36.5

43.3 49.9 45.7 51.6 54.6 54.8 42.4 46.1 46.0

Profuse perspiration Headache Vertigo Heart palpitation Ringing in the ears Nervousnesdirritability Sleep disturbances Depressive moods

Effect on Kupperman Menopausal Index of cimicifuga compared with conjugated estrogens and diazepam Treatment group Cimicifuga Conjugated estrogens Diazepam

Beginning

At 12 wk

35 35 35

14 16 20

dosage of 4 mg 27-deoxyactein)produced clear improvement of menopausal symptoms in more than 80% of patients within 6 to 8 weeks.I8 As shown in Table 80-1, both physical and psychologic symptoms improved. Most patients reported noticeable benefits within 4 weeks after the onset of cimicifuga therapy. After 6 to 8 weeks, complete resolution of symptoms was achieved in a large percentage of patients. Cimicifuga was well tolerated, as there was no discontinuation of therapy and only 7% of patients reported mild transitory stomach complaints. In one of the first double-blind studies, 60 patients were given cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein), conjugated estrogens (0.625 mg daily), or diazepam (2 mg daily) for 12 weeks.19Results from standard indexes of menopausal symptoms indicated a clear advantage of cimicifuga extract over both drugs. Cimicifuga’s effect on relieving the depressive mood and anxiety associated with menopause was far superior to either diazepam or conjugated estrogens, as shown in Table 80-2. One of the most used assessments in clinical studies in menopause is the Kupperman Menopausal Index. This quantitative assessment of menopausal symptoms is achieved by grading in severity: severe = 3, moderate = 2, mild = 1,not present = 0. The symptoms assessed are the following: Hot flashes Depressive moods

9

86.6 88.5 81.9 86.8 90.4 92.9 85.6 76.8 82.5

Profuse perspiration Feelings of vertigo Sleep disturbances Loss of concentration Headache Joint pain Nervousness/irri tability Heart palpitation

The results of the Kupperman Menopausal Index from this trial clearly demonstrate cimicifuga extract’s superiority over conjugated estrogens and diazepam, especially when safety and side effects are taken into consideration. In another early double-blind study, 80 patients were given cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein), conjugated estrogens (0.625 mg daily), or placebo for 12 weeks.2O Cimicifuga produced better results in the Kupperman Menopausal Index, the Hamilton anxiety test, and the vaginal lining than estrogens or placebo. The number of hot flashes experienced each day dropped from an average of five to fewer than one in the cimicifuga group. In comparison, the estrogen group only dropped from 5 to 3.5. Even more impressive was the effect of cimicifuga on the vaginal lining.Although both conjugated estrogens and the placebo produced little effect, a dramatic increase in the number of superficial cells was noted in cimicifuga €PUP* In a double-blind study of 110 women, cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein) was shown to exert significant improvements in menopausal symptoms.8In addition to providing relief of hot flashes, cimicifuga once again demonstrated impressive results on the vaginal lining, as confirmed by vaginal smear. In one study, 60 women younger than the age of 40 who had hysterectomiesleaving at least one intact ovary received one of the following: cimicifuga extract (two tablets twice daily providing a daily dosage of 4 mg 27-deoxyactein),estriol(1 mg daily), conjugated estrogens

Pharmacology of Natural Medicines (1.25 mg daily), or estrogen-progestin combination (Tiisequens, one tablet daily).21Although the hormone therapies produced better results as determined by a modified Kuppeman’s Menopausal Index, cimicifuga still displayed signhcant effects in relieving the symptoms of “surgical menopause.” These results indicate that cimicifuga can be a suitable alternative to estrogens in women having partial, and possibly even complete, hysterectomies. In perhaps the most detailed double-blind study to date, cimicifuga extract was evaluated for its effect on menopausal symptoms, bone metabolism and on the endometrium compared with those of conjugated estrogen (CE) and placebo.” The 62 postmenopausal women were treated either with black cohosh extract (daily dose 40 mg), 0.6 mg CE, or matching placebo for 3 months. Results indicated that the black cohosh extract was equipotent to CE and superior to placebo in reducing menopausal complaints. Both black cohosh extract and CE produced beneficial effects on bone metabolism, but the black cohosh extract had no effect on endometrial thickness, which was signrficantly increased by CE. Vaginal superficial cells were increased with cimicifuga and CE treatment. These results seem to confirm that cimicifuga extracts contain substances with SERM activity (i.e., with desired effects in the brain/hypothalamus, bone, and the vagina but without exerting uterotropic effects). Women being treated with tamoxifen most often experience symptoms similar to menopause. To examine the effect of cimicifuga extract on hot flashes caused by tamoxifen adjuvant therapy in young premenopausal breast cancer survivors, 136breast cancer survivors aged 35 to 52 years who had been treated with segmental or total mastectomy, radiation therapy, and adjuvant chemotherapywere randomly assigned to receive tamoxifen 20 mg per day orally or tamoxifen plus black cohosh extract (20 mg daily).23The duration of treatment was 5 years for tamoxifen, according to international standards for adjuvant therapies, and 12 months for the black cohosh extract. Follow-up included clinical assessment every 2 months; the primary endpoint was to record the number and intensity of hot flashes. Results indicated that almost half of the patients getting the black cohosh extract were free of hot flashes. Only 24.4% of patients taking black cohosh extract experienced severe hot flashes compared with 73.9% of the women taking tamoxifen alone.

Effects on Bone Resorption On the basis of cimicifuga’s mechanism of action, pre-

liminary experimental and clinical research, and longterm clinical experience, many experts believe it will be shown to positively influencebone resorption. In patients at high risk for osteoporosisor those with confirmed low

bone density, physicians should monitor therapy with cimicifuga by using the Osteomark-NTXor other suitable indicator of bone res0rption.2~

DOSAGE The dosage of cimicifuga is based on its content of 27-deoxyactein,which serves as an important biochemical marker to indicate therapeutic effect. The dosage of the cimicifuga extract used in the majority of clinical studies has been 40 mg of black cohosh extract supplying 2 mg of 27-deoxyacteine twice daily. Approximate dosage recommendations using other (nonstandardized) forms of C. rucmosu are as follows: Powdered rhizome: 1to 2 g Tincture (1:5): 4 to 6 ml Fluid extract (1:l):3 to 4 ml(1 tsp) Solid (dry powdered) extract (41): 250 to 500 mg The German Commission E has recommended that treatment with cimicifuga be limited to 6 months (which is also the standard recommendation for HRT); however, thisrecommendation was made before detailed toxicology studies, discussed next. Based on currently available data, cimicifuga is appropriate for long-term continued use.

TOXICOLOGY The standardized extract of C. ~ u c m o s uproviding 1 mg of 27-deoxyactein in 40 mg of extract per tablet has been used in Germany since 1956 and has a remarkable safety record. A comprehensive review including preclinical and clinical research in estrogen-sensitive populations, including women at risk for breast cancer and breast cancer survivors, as well as human cell lines most relevant to breast cancer, confirmed this safety record. No serious side effects have ever been reported.28 Cimicifuga offers a suitable natural alternative to HRT for menopause, especially where HRT is contraindicated (e.g., in women with a history of cancer, unexplained uterine bleeding, liver and gall bladder disease, pancreatitis, endometriosis, uterine fibroids, and fibrocystic breast disease). Since cimicifuga extract shows some, albeit weak, estrogenic activity, researchers have sought to determine Remefemin’s effect on an established breast tumor cell line whose growth in vitro depends on the presence of estrogens. The results from these experiments show no stimulatory effects, but rather inhibitory effects as well as an ability to promote apoptosis in these cell^.^^"^ Furthermore, combining black cohosh with tamoxifen was shown to potentiate the inhibitory effects of tamoxifen.

Cimicifuga racernosa (Black Cohosh)

Detailed toxicology studies have also been performed on black cohosh extracts. No teratogenic, mutagenic, or carcinogenic side effects have been noted. The no-effect dosage in studies in a 6-month chroNc toxicity study in rats was at 1800 mg/kg body weigh-roughly 90 times the therapeutic dose.31A 6-month toxicologic study in rats is comparable to an unlimited treatment time in humans.

Although clinical evidence is lacking, there is some theoretic concern that L-carnitine 1 g daily potentiates the anticoagulant effects of aceno~ournarol.~~

1. Chen SN, Fabricant DS,Lu ZZ, et al. Cimiracemates A-D, phenylpropanoid esters from the rhizomes of Cimicifigu racemosa. Phytochemistry 2002;61:409-413. 2. Li WK, Chen SN, Fabricant D, et al. High-performance liquid chromatographic analysis of black cohosh (Cirnicifigu rucemosa) constituents with in-line evaporative light scattering and photodiode array detection. Anal Chim Acta 2002;471:61-75. 3.Shao Y, Harris A, Wang M, et al. Triterpene glycosides from Cimicifugu racemosu. J Nat Prod 2O00;63:905-910. 4. Kennelly EJ, Baggett S, Nuntanakom P, et al. Analysis of thirteen populations of black cohosh for formononetin. Phytomediche 2002; 9~461-467. 5. Borrelli F, Izzo AA, Emst E. Pharmacological effects of Cirnicifuga rucemosa. Life Sci 2003;731215-1229. 6. Jarry H, Hamischfeger G. [Endocrine effects of constituents of Cimicifuga rucemosu. 1. The effect on serum levels of pituitary hormones in ovariectomized rats]. Planta Med 1985;1:4649. 7. Jarry H, Hamischfeger G, Duker E. [The endocrine effects of constituents of Cimicifigu rucemosa. 2. In vitro binding of constituents to estrogen receptors]. Planta Med 1985;4316-319. 8. Duker EM, Kopnski L, Jarry H, Wuttke W. Effects of extracts from Cimicifuga rucemosa on gonadotropin release in menopausal women and ovariectomized rats. Planta Med 1991;57420424. 9. Mksicek RJ. Commonly occurring plant flavonoids have estrogenic activity. Mol Pharmacol 1993;443743. 10. Seidlova-Wuttke D, Hesse 0, Jarry H, et al. Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifigu racemosa) extract: comparison with estradiol-17beta. Eur J Endocrinol2003;149:351-362. 11. Nisslein T, Freudenstein J. Effects of an isopropanolic extract of Cimicifigu rucemosu on urinary crosslinks and other parameters of bone quality in an ovariectomized rat model of osteoporosis. J Bone Miner Metab 2003;21:370-376. 12.Jarry H, Metten M, Spengler B, et al. In vitro effects of the Cimicifuga rucemosu extract BNO 1055. Maturitas 2003;44:531-538. 13. Mahady GB. Is black cohosh estrogenic? Nutr Rev 2003;61:183-186. 14. Zierau 0, Bodinet C, Kolba S, et al. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol 2002; 80:125-130. 15. Kligler B. Black cohosh. Am Fam Physician 2003;68:114-116. 16. Borrelli F, Ernst E. Cimicifigu racemosu: a systematic review of its clinical efficacy. Eur J Clin Pharmacol2002;58235-241. 17. McKenna DJ,Jones K, Humphrey S, Hughes K. Black cohosh efficacy, safety, and use in clinical and preclinical applications. Altem Ther Health Med 2001;793-100.

18. Stolze H. An alternative to treat menopausal complaints. Gynecology 1982;3:14-16. 19. Wamecke G. Influencing menopausal symptoms with a phytotherapeutic agent. Med Welt 1985;36:871-874. 20. Stoll W. Phytopharmacon influences atrophic vaginal epithelium. Double-blind study-cimicifuga vs. estrogenic substances. Therapeuticum 1987;1:23-31. 21. Lehmann-Willenbrock E, Riedel HH. [Clinical and endocrinologic studies of the treatment of ovarian insufficiency manifestations following hysterectomy with intact adnexa]. Zentralbl Gynakol 1988; 110:611-618. 22. Wuttke W, Seidlova-WuttkeD, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebocontrolled study: effects on menopause symptoms and bone markers. Maturitas 2003;44:%7-S77. 23. Hernandez Munoz G, Pluchino S. Cimiczfigu racemom for the treatment of hot flashes in women surviving breast cancer. Maturitas 2003;44:S59-565. 24. Bruker A. Essay on the phytotherapy of hormonal disorders in women. Med Welt 1960;44:2331-2333. 25. Schildge E. Essay on the treatment of premenstrual and menopausal moods swings and depressive states. Rigelh Biol Umsch 1964;19: 18-22. 26. Gorlich N. Treatment of ovarian disorders in general practice. Arztl Prax 1962;141742-1743. 27. Nisslein T, Freudenstein J. Effects of an isopropanolic extract of Cimicifiga rucemosa on urinary crosslinks and other parameters of bone quality in an ovariectomized rat model of osteoporosis. J Bone Miner Metab 2003;21:370-376. 28. Dog TL, Powell KL, Weisman SM. Critical evaluation of the safety of Cimicifuga racemosu in menopause symptom relief. Menopause 2003;10299-313. 29. Hostanska K, Nisslein T, Freudenstein J, et al. Cimicifrcga racemosa extract inhibits proliferation of estrogen receptor-positive and negative human breast carcinoma cell Lines by induction of apoptosis. Breast Cancer Res Treat 2004;84:151-160. 30.Nesselhut T, Borth S, Kuhn W. Influence of Cimicifigu rucemosa extracts with estrogen-like activity on the in vitro proliferation of mammary carcinoma cells. Arch Gynecol Obstet 1993;254: 817-818. 31. Kom WD. Six-month oral toxicity study with Remefemin-granulate in rats followed by an 8-week recovery period. Hannover, Germany: International Bioresearch, 1991. 32. Martinez E, Doming0 P, Roca-Cusachs A. Potentiation of acenocoumarol action by L-carnitine. J Intem Med 1993;233:94.

DRUG INTERACTIONS

Citicoline (CDP-Choline) Alexander G. Schauss, PhD, FACN CHAPTER CONTENTS Introduction 853

Alzheimer's Disease 856

Pharmacokinetics 853

BrainTrauma 856

Mechanisms of Action Plasma Choline Levels Acetylcholinesterase Production 854 Phospholipase Activity Beta-amyloid Inhibition

854 854

Glaucoma 856 Amblyopia 857

854 854

Dosage 857 Toxicology 857

Elevation of Neurotransmitters 855 Drug Interactions 857 Clinical Applications 855 Age-Related Cognitive Deficiencies 855

Summary 857

StrokeTherapy 855 Memory-Impaired Elderly 856

INTRODUCTION

PHARMACOKINETICS

Citicoline (cytidine Y-diphosphocholine)is an important organic molecule that functions as an intermediate in the biosynthesis of cell membrane phospholipids. Taken at therapeutic levels as a supplement, it is hydrolyzed in the small intestine and readily absorbed as choline and cytidine, resulting in a sparing effect on systemic choline reserves. As a choline donor, it serves as an intermediate in the biosynthesis of phospholipids and acetylcholine. At the same time, its breakdown products enter into circulation and prevent undesired loss of membrane phospholipids. In situ, citicoline is the rate-limiting step in the synthesis of phosphatidylcholine from choline.' For this reason, supplementationwith citicoline can be a useful therapeutic adjunct to practitioners treating stroke victims, in improving cognitive function in patients experiencing mild cognitive impairment, and in the treatment of senile dementia of the Alzheimer type, and memory loss. Evidence that citicoline can also play a role in the treatment and prevention of vision disorders such as glaucoma and amblyopia is growing (Figure 81-1).

A water-soluble compound, citicoline is rapidly absorbed and highly bioavailable (>90%). It is metabolized in the gut and liver via hydrolysis to choline and cytidine. After ingestion, plasma levels peak within 1 hour, followed by a second larger peak 24 hours after intake. Once absorbed, choline and cytidine enter systemic circulation; contribute to various biosynthetic pathways; and cross through the blood-brain barrier, where they are resynthesized into citicoline in the brain? Citicoline elimination occurs by respiration and urinary excretion as biphasic eliminatory peaks. Using carbon-14 radiopharmacokinetic studies, it has been determined that the half-life of citicoline is 56 hours via carbon dioxide and 71 hours via urinary e~cretion.~ The first peak and decline in plasma concentration occurs 4 to 10 hours after ingestion. The second peak occurs about 12 hours after ingestion and declines more slowly until the majority is eliminated by the twenty-fourth hour? 853

the structural and functional integrity of brain neuronal membranes by serving as a precursor for acetyl~holine.~

Acetylcholinesterase Production

OH

II,

OH

,\."'

HO

4%

OH

Figure 81-1 CDP-Ciicoline.

Another mechanism of action suggests that citicoline stimulates production of acetylcholinesterase (AChE) and Na+ATPaseand K+ATPase.In vitro work indicates that citicoline bioconverts to phosphatidylcholinewithin external leaflets of the neuronal membrane where AChE activity occurs.1oHowever, since citicoline is not known to serve as an AChE inhibitor in humans, the significance of this finding remains unknown.

Phospholipase Activity MECHANISMS OF ACTION Prolonged oral administration of citicoline for 42 to 90 days has been shown in animals to increase brain levels of phosphatidylserine, phosphatidylcholine, and phospha tidylethanolamine, three critical phospholipids found in brain cell membranes." In aged rats it has been shown that citicoline activates phosphocholine cytidylyltransferase (CTP), the rate-limiting enzyme in the citicoline to phosphatidylcholine synthesis pathway?

Plasma Choline Levels Even a single dose of citicoline has been shown by protein magnetic resonance spectroscopy to raise plasma choline levels in young and old subjects6These studies have also determined that the cytidine moiety of citicoline is responsible for stimulating phosphatidylcholine. The strongest evidence of citicoline's ability to reverse age-related cognitive deficits comes from a protein decoupled phosphorus magnetic resonance spectroscopy study that followed administration of the agent for 6 weeks, after which it was seen that brain levels of phosphodiesters, byproducts of phospholipid metabolism, increased.' However, there are other mechanisms of action of citicoline. The metabolites of citicoline metabolism including choline, methionine, betaine, and cytidine-derived nucleotides enter several metabolic pathways that are of sigruficance to cognitive and neuronal function. Degeneration of cholinergic neurons is one of the sigruficant markers associated with Alzheimer disease. If the demand for acetylcholine increases or if choline levels in the brain decrease, catabolism of neuronal membranes may scavenge yield choline from phospholipids within those membranes. Since citicoline serves as a precursor for acetylcholine, it has been demonstrated in animals that administration of citicoline can result in a modest improvement in cognitive function.s Hence regular administration of citicoline could preserve

Alteration of phospholipase activity by citicoline has also been shown. Some evidence indicates that citicoline can restore sphingornyelin levels after ischemic reperfusion, thus protecting hippocampal neurons." During brain ischemia, hydrolysis of sphingomyelin occurs due to increased production of sphingomyelinase.Citicoline's effect on phospholipase A2,combined with its inhibition of sphingomyelinaseproduction, would suggest another route providing neuroprotection, especially when administered immediately after a cerebral stroke-induced ischemic episode. Citicoline's modulation of phospholipase A2 activity contributes to yet another potential mechanism of action. The inner mitochondria1 membrane contains a phospholipid component known as cardiolipin. Studies have shown that citicoline inhibits enzymatic hydrolysis of cardiolipin by phospholipase A2 via inhibition of arachidonic acid, a substrate for phospholipaseA2.12This mechanism of action is quite interesting. The arachidonic acid content of phosphatidylcholine has been shown to decrease after postischemic reperfusion due to hydrolysis of phospholipids. Because citicoline can restore the arachidonic acid content of phosphatidylcholine, it can prevent activation of phospholipase A2.An animal study supports this mode of action by demonstrating that citicoline decreases phospholipase A2 ~timu1ation.l~

Beta-amyloid Inhibition Of particular interest to clinicians seeking to arrest the pathophysiology associated with Alzheimer's disease is the finding that citicoline counteracts the deposition of beta-amyloid,a neurotoxicprotein involved in Alzheimer's disease. A body of evidence agrees that the degree of cognitive dysfunction and neurodegeneration associated with Alzheimer's disease is proportionate to the buildup of beta-amyloid in certain brain c e l l ~ . ' ~InJ one ~ rat study it has been demonstrated that intrahippocampalinjection of beta-amyloid protein did not impair memory retention, as measured by passive avoidance learning tasks, when concurrent citicoline was administered. Not only

Citicoline (CDP-Choline) did citicoline counteract neuronal degeneration in rat hippocampus, induced by the injection of beta-amyloid protein, but the number of apoptotic cells was also reduced.16 Amyloid precursor protein (APP) contains the pep tide that forms amyloid deposits. Abnormal cleavage of APP occurs when phosphatidylcholine and phosphatidylethanolamine content is decreased, resulting in destabilization of the cell membrane. The resultant formation of amyloidogenic APP fragments is considered abnormal. It is found in older adults with Alzheimer's disease. Ordinarily,APP is cleaved in such a way that the amyloidogenic peptide is broken down and excreted as nonplaque-forming fragments. Since citicoline has been shown to maintain or restore depleted phospholipid levels in neuronal cell membranes, it may thus promote normal APP cleavage by excretion of nonplaque-forming APP fragments. In vitro work has provided some support for this hypothesis by showing an increase in the levels of phospholipids in rat brain cells induced by choline and cytidine, followed by excretion of the APP found in the lipid bilayer of neuronal mernbrane~.'~

ELEVATION OF NEUROTRANSMllTERS Evidence also indicates that citicoline can increase the levels of several neurotransmitters. In one study in rats, a dose of 100 mg/kilo of citicoline administered for 7 days resulted in an increase in norepinephrine levels in the cerebral cortex and hypothalamus, an increase in dopamine in the corpus striatum, and a concomitant increase in serotonin in the cerebral cortex, striatum and hypothalamus.16In a different study, citicoline was found to activate dopamine synthesis via stimulation of tyrosine hydroxylase activity.19 This finding may explain anecdotal reports of benefits in patients with parkinsonism following citicoline administration?O That citicoline could enhance norepinephrine release has been demonstrated in humans as well. In one study, it was shown that following citicoline administration, urinary levels of 3-methoxy4hydroxyphenylglycol (MHPG), a norepinephrine metabolite, increased.21 Further work in rats found evidence that citicoline potentiates brain dopamine synthesis by stimulating release of acetylcholine.22 A more detailed review of the mechanisms of action and therapeutic benefits of aticoline has been published.=

CLINICAL APPLICATIONS Age-Related Cognitive Deficiencies Normal cognitive function relies on the ability of neurons to transmit impulses along neuronal membranes. Agerelated cognitive deficits are associated with decreased brain cell membrane phospholipid levels. Several animal

studies have shown broad spectrum benefits in cognitive function and memory performance using various active and passive avoidance tests and via artificially induced hypoxia, electric shock, or scopolamine administration, in young and old r a t ~ ? ~ Z

STROKE THERAPY Most of the well-controlled clinical trials of citicoline involve administering it intravenously in patients in the acute stage of moderate to severe cerebral infarction with mild to moderate disturbance in consciousness.26~27 However, some studies of oral administration are available. The Citicoline Stroke Study Group, a multicentered, double-blind controlled trial conducted in the United States, examined the effects of oral citicoline on 259 stroke patients given 500,1000, or 2000 mg of citicoline within 24 hours of a stroke, continued by daily oral administration for 6 weeks?* Using any change in the Barthal Index of Neurological Function (Barthal Index) as the primary clinical endpoint and the National Institutes of Health Stroke Scale (NIHSS)score as a second variable to determine changes between baseline and follow up, patients receiving 500 or 2000 mg of citicoline were found to have twice the chance of stroke recovery compared with patients on placebo. No difference was seen in the group receiving 1000 mg of citicoline compared with placebo. Because the 2000 mg group had a higher incidence of dizziness and accidental injury, the authors concluded that the 500 mg/day dose might be the most optimal for these patients. A second controlled clinical trial was subsequently conducted by the Citicoline Stroke Study Group. This study enrolled 394 patients with acute ischemic stroke, randomly assigned to the treatment or placebo groups on a two-to-one ba~is.2~ Given the earlier advice to use a 500-mg daily dose, only this dosage level was given to the treatment group. The Barthel Index and NIHSS were used to assess efficacy.No differences were found between the treatment and placebo groups after 6 weeks of treatment and an equal 6-week follow-up period. However, the investigators noted that an inequality in baseline stroke severity was found between the two groups; 34% of the patients in the placebo group had had a mild stroke, compared with 22% in the citicoline group. The authors concluded that the baseline imbalances could have affected the overall results of the trial. The two aforementioned Citicoline Stroke Study Group trials led to a third multicentered, double-blind clinical trial. This trial enrolled 899 patients with acute stroke that occurred in the middle cerebral artery region.3oSubjects were given either 1000 mg of citicoline twice daily or placebo for 6 weeks, followed by a 6-week posttreatment follow-up. The outcome was virtually the

same for both groups. As judged by the NIHSS, 52% of subjects in the aticoline group and 51% in the placebo p u p achieved a seven-point improvement. The citicoline p u p showed a signhcant improvement on the Barthe1 Index after 6 weeks, but it was not evident at the end of 12weeks. The investigators concluded that the use of more traditional analyses might have revealed modest benefits.

Memory-Impaired Elderly A study of 95 healthy volunteers, 50 to 86 years old, looked at the effect of citicoline on verbal memoryY The study was conducted in two phases. In the first phase, all subjects took 10oO mg of citicoline or placebo daily for 3 months. Among this group of 95 subjects, a subgroup that had relatively poor memory function was identified. Those subjects identified with poor memory function were recruited for a second cross-over trial phase and given either 2000 mg of citicolineor placebo for 3 months. After the initial phase of the study, improvement was only seen in the poor memory subgroup, which found improvement in delayed recall and logical memory. At the end of the second phase of the study, a greater improvement was seen in the 2000 mg group, but then only for those with age-associated memory impairment. Another study involved 24 memory-impaired elderly subjects who were given citicoline at 500 or 1000 mg with the calcium channel blocker nimodipine, which is used to treat neurologic deficits in brain hemorrhagic patients. Pretreatment and posttreatment memory performance was In tests of recognition, no improvement was observed. However, improvements were seen in word and object recall. Positive results occurred in both treatment groups. On the basis of the role of citicoline as an intermediate in phosphatidylcholine biosynthesis, a study was carried out on 84 elderly patients with mild to moderate memory loss.% Study participants were given either loo0 mg of citicoline or placebo for 6 weeks. All subjects exhibited memory loss on the basis of their score on the Mini Mental State Examination ( M E ) and the Randt Memory Test (RMT). The FMT was only given 3 weeks into the study and again at end of treatment 3 weeks later. The RMT measures threecognitive functions: encoding and organization, cognitive efficiency, and acquisition efficiency. At the end of the study it was found that on the RMT, the citicoline group had only improved in acquisition efficiency, which is specifically related to attention skills, suggesting a dopaminergic effect of citicoline. This is because dopaminergic stimulation and improvement has been shown to be associated with attention-related cognitive mechanisms. In addition, the study showed improvements in global memory efficiency in subjects given aticoline compared with placebo. To date there is limited evidence supporting the use of citicoline to improve memory in individuals unless they have measurable deficits in memory. A study conducted

with young, 1-year-old, healthy dogs that were given citicoline over a 42-day period found that compared with control animals, the citicoline group showed superior memory processes (acquisition, retention, and retrieval) as demonstrated by a series of operant, conditionedlearning experiments.M A meta-analysis of controlled clinical trials has concluded that citicoline administration contributes to modest improvements in memory and behavioral outcomes.35Human studies of the effect of citicoline in healthy adults without cognitive impairment remains a fertile area for further investigation.

ALZHEIMER’S DISEASE Besides studies showing benefits associated with the administrationof citicoline given to Alzheimer patients%% and those suffering from age-related deficits in memory, other brain-related disorders or conditions have also been shown improvement. Citicoline may improve cognitive performance in Alzheimer patients. A 1994 double-blind study evaluated 1-month treatment with citicoline (1000 mg/day orally) on cognition in 20 Alzheimer patients. Cognitive function assessment using W E improved slightly in an early onset subgroup. MMSE scores decreased in patients in later stages of the disease. Spatial-temporal orientation improved in the total group, with a more marked difference in early-onset patients.% A later double-blind, placebo-controlled trial tested the effect of citicoline (1000 mg/day) on 30 patients with mild-to-moderate senile dementia. The overall results showed differences between the citicoline and placebo groups in the 12-week study, but the changes did not reach statistical ~igruficance.~~

BRAIN TRAUMA In a double-blind study in patients going through rehabilitation following brain trauma to restore blood flow to the site of lesion, 1month of 1000mg of citicoline administered orally was found to significantly improve recall of designs compared with placeb0.3~ However, there was no significant difference seen in either group in word recall, recall of locations, or verbal fluency. Interestingly, a greater trend was seen in patients on placebo regarding complaints of postconcussional symptoms such as headache, tinnitus, and dizziness at follow-up than among the citicoline group.

GLAUCOMA Two open clinical trials suggest that citicoline may repair damage to the optic nerve in glaucoma.40The mechanism of action appears to be related to citicoline’s ability to provide neuroprotection by enhancing

Citicoline (CDP-Choline) phosphatidylcholine synthesis. As is well known, glaucoma is the leading cause of age-related blindness and is characterized by apoptosis of retinal ganglion cells (well before visual loss is detected)!l In a double-blind, placebo-controlled trial, 1000 mg of citicoline was administered by intramuscular injection, resulting in improvement in retinal and visual function in openangle glaucoma patients." In glaucoma, as intraocular pressure builds up to abnormal levels, the resultant effect is damage to the optic disc. Continued damage to this area causes visual defects, most notably the progressive loss of peripheral vision, sometimes called "tunnel vision." If this progressive loss of vision is detected too late, it can eventually lead to permanent loss of vision.

administration by gavage of 150 mg/kg SW, 350 mg/kg BW, and 1000 mg/kg BW in 160 rats followed by histopathologies of all organs and assessment of blood, urine, ophthamology, and behavior reported no mortality, adverse events, or sigruhcant differences compared with the control ("0"dose) group.&Citicoline appears to show a low risk of toxicity in humans. One small, short-term human study did report headaches at 600mg and lo00 mg dosages in a few subjects, but this proved to be of a transient nature. No hematologic, clinical biochemistry, or neurologic abnormities were reported.44In some clinical studies, transient diarrhea and stomach pain was reported in about 5% of subjects.

DRUG INTERACTIONS AMBLYOPIA Additional research on citicoline and vision has been conducted on adults with amblyopia. In amblyopia, the condition is characterized by dimness of light entering the eye without apparent structural damage to the eye. In one small open t i a l reported by the University of Bologna, Italy, adult patients with amblyopia given citicoline showed improvement in visual acuity, contrast sensitivity, and visually evoked potentials, in addition to improved vision.

Theoretic concern has been raised over combining nootropic drugs such as citicoline with central stimul a n t ~ ?However, ~ no adverse clinical effects have been reported.

SUMMARY

Large oral dosages in animal studies have not shown toxicity. I am a co-investigator in two completed good laboratory practice (GLP)-compliantnonclinical toxicology studies in the rat. No mortality or adverse events were reported following an acute oral dose by gavage of 2000 mg/kg of body weight (BW) followed by a 14-day postadministration observation period and gross pathology on day 15 ("the limit test"). A subsequent GLP subacute toxicology study over 90 days involving daily

Citicoline appears to be a useful adjunct for improving both the structural integrity and functionality of the neuronal membrane that assists in membrane repair, particularly of brain neuron membranes. This qualifies citicoline as a nootropic agent. Its application in the treatment and possible prevention of a range of neurodegenerative diseases is apparent, especially given the many mechanisms of action of citicoline discovered to date and discussed herein. The suggestive evidence that citicoline improves performance in old but not young rats is consistent with the conception that citicoline corrects impaired phospholipid metabolism. Most likely, citicoline may also contibute to a reduction in oxidative stress by increasing glutathione, another fertile area for research on this increasingly recognized agent in the management and treatment of cognitive dysfunction, neurodegenerative diseases, and visual health. A citicoline-free base is available as an oral dietary supplement in the United States or as a drug for intravenous or intramuscular injection and oral use in other countries.

1. Weiss GB. Metabolism and actionsof CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci 1995; 56637-660. 2. Rao AM,Hatcher JF, Dempsey RJ. CDP-choline: neuroprotedion in transient forebrain ischemia of gerbils.J Neurosci Res 199958697-705. 3. Dinsdale JR, Griffiths GK, Rowlands C, et al. Pharmacokinetics of 14C CDP-choline. Arzneimittelforschung1983;33.1066-1070. 4. Lopez-Coviella I, Agut J, Savci V, et al. Evidence that 5'cytidinediphosphocholinecan affect brain phospholipid composition

by increasing choline and cytidine plasma levels. J Neurochem 1995;65:889-894. 5. Gimenez R, Soler S, Aguilar J. Cytidine diphosphate cholie administration activates brain cytidine triphosphate: phosphocholine cytidylytransferase in aged rats. Neurosci Lett 1999;273163-166. 6. Babb SM, Appelmans KE, Renshaw PF, et al. Differentialeffect of CDPcholine on brain cytosolic levels in younger and older subjects as measured by protein magnetic rrsonanm spectroscopy. Psychopharmacol 1996;12788-94.

DOSAGE The typical dosage of citicoline in clinical students is 500 to 2000 mg/day.

TOXICOLOGY

Pharmacology of Natural Medicines 7. Babb SM, Wald LL, Cohen BM, et al. Chronic aticoline inaeasesphosphodiesten in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study. Psychopharmacol 2002; 161:248-254. 8. de la Morena E. Efficacy of CDP-choline in the treatment of senile alterations in memory. Ann N Y Acad Sci 1991;640:233-236. 9. Amenta F, Di Tullio MA, Tomassoni D. The cholinergic approach for the treatment of vascular dementia: evidence from pre-clinical and clinical studies. Clin Exp Hypertens 2002;24697-713. 10. Plataras C, Tsakiris S, Angelogianni P. Effect of CDP choline on brain acetylcholinesterase and Na’, K+-ATPase in adult rats. CLin Biochem 200033351-357. 11. Adibhatla RM, Hatcher JF, Dempsey RJ. Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem 2002;80 12-13. 12. Rao AM, Hatcher JF, Dempsey RJ. Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain Res 2001;893268-272. 13.Adibhatla RM, Hatcher JF. Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia. J Neurosci Res 2003;73:308-315. 14. Nitta A, Itoh A, Hasegawa T, et al. beta-Amyloid protein-induced Alzhemer’s disease animal model. Neurosci Lett 1994;17063-66. 15. Nitta A, Fukuta T, Hasegawa T, et al. Continuous infusion of betaamyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration. Jpn J Pharmacol1997;7351-57. 16. Alvarez XA, k p e d r o C, Lozano R, et al. Citicoline protects hip pocampal neurons against apoptosis induced by brain beta-amyloid deposits plus cerebral hypofusion in rats. Methods Find Exp Clin Pharmacol1999;21:535-540. 17. Wang CS, Lee RK. Choline plus cytidine stimulate phospholipid production, and the expression and secretion of amyloid precursor protein in rat PC12 cells. Neurosci Lett 2000;283:25-28. 18.Petkov VD, Stancheva SL, Tocuschieva L, et al. Changes in brain biogenic monoamines induced by the nootropic drugs adafenoxate and meclofenoxate and by citicoline (experiments on rats). Gen Pharmacol1990;21:71-75. 19. Martinet M, Fonlupt P, Pacheco H. Effects of cytidine-5’ diphosphocholine on noreinephrine, dopamine and serotonin synthesis in various regions of the rat brain. Arch Int Pharmaccdyn Ther 1979; 23952-61. 20. Martinet M, Fonlupt P,Pacheco H. Interaction of CDP-choline with synaptosomal transport of biogenic amines and their precursors in vitro and in vivo in the rat corpus striaturn. Experientia 1978;34:1197-1199. 21. Lopez I, Coviella G, Agut J, et al. Effect of cytidine(5’)diphosphocholine (CDP-choline) on the total urinary excretion of 3-methoxy4hydrophenylglycol (MHPG)by rats and humans. J Neural Transm 1986;66:129-134. 22. Agut J, Coviella IL, Wurtman RJ. Cytidine(5’)diphosphocholine enhances the ability of haloperidol to increase dopamine metabolites in the striaturn of the rat and to diminish stereotyped behavior induced by apomorphine. Neuropharmacology 1984;23:1403-1406. 23. Conant R, Schauss AG. Therapeutic applications of citicoline for stroke and cognitive dysfunction in the elderly: a review of the literature. Altem Med Rev 2004;9:17-31. 24. Drago F, Mauceri F, Nardo L, et al. Effects of cytidine-diphosphocholine on acetylcholine-mediated behaviors in the rat. Brain Res Bull 199331:485-489. 25. Petkov VD, Kehayov RA, Mosharrof AH, et al. Effects of cytidine diphosphate choline on rats with memory deficits. Arzneimittelforschung 1993;43822-828. 26. Tazaki Y, Sakai F, Otomo E, et al. Treatment of acute cerebral infarction with a choline precursor in a multicentered doubleblind placebo- controlled study. Stroke 1988;19:211-216.

27. Davalos A, Castillo J, Alvarez-Sabin J, et al. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke 2002;33:2850-2857. 28. Clark WM, Warach SJ, Pettigrew LC, et al. A randomized doseresponse trial of citicoline in acute ischemic stroke patients. Neurology 1997;49:671-678. 29. Clark WM, Williams BJ, Selzer KA, et al. A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke 1999; 30:2592-2597. 30. Clark WM, Wechsler LR, Sabounjian LA, et al. A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients. Neurology 2001;571595-1602. 31.Spiers PA, Myers D, Hochanadel GS, et al. Citicoline improves verbal memory in aging. Arch Neurol1996;53441-448. 32. Alvarez XA, Laredo M, Corzo D, et al. Citicoline improves memory performance in elderly subjects. Methods Find Exp Clin Pharmacol 1997;19201-210. 33. Agnoli A, Bruno G, Fioravanti M, et al. Therapeutic approach to senile memory impairment: a double-blind clinical trial with CDP choline. In Wurtman RJ, Corkin S, Growden JH,eds. Alzheimer’s disease: proceedings of the fifth meeting of the International Study Group on the Pharmacology of Memory Disorders Associated with Aging. Boston: Birkhauser, 1989:649-654. 34. Bruhwyler J, Liegeois JF, Geczy J. Facilitatory effects of chronically administered citicoline on learning and memory processes in the dog. Prog Neuropsychopharmacol Biol Psychiatr 1998;22: 115-128. 35. Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP choline) for cognitive and behavioral disturbances associated with chronic cerebral disorders in the elderly (Cochrane Review). In The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, 2004. 36.Caamano J, Gomez MJ, Franco A, et al. Effects of CDP-choline on cognition and cerebral hemodynamics in patients with Alzheimer’s disease. Methods Find Exp Clin Pharmacol 1994; 16~211-218. 37. Alvarez XA, Mouzo R, Pichel V, et al. Double-blind placebo controlled study with citicoline in APOE genotyped Alzheimer‘s disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Methods Find Exp Clin

Pharrnacol1999;21:633-644. 38. Cacabelos R, Alvarez XA, Franco-Maside A, et al. Effect of CDPcholine on cognition and immune function in Alzheimer’s disease and multi-infarct dementia. Ann N Y Acad Sci 1993;695: 321-323. 39. Levin HS. Treatment of postconcussional symptoms with CDPcholine. J Neurol Sci 1991;103S39-S42. 40.Grieb P, Rejdak R. Pharmacodynamics of citicoline relevant to the treatment of glaucoma. J Neurosci Res 2002;67143-148. 41. Quigley HA, Addicks EM, Green WR. Optic nerve damage in human glaucoma: III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic optic neuropathy, papilledema, and toxic neuropathy. Arch Opthalmol1992;100:135-146. 42. Parisi V, Manni G, Colacino G, et al. Cytidine-5’-diphosphocholiie (citicoline) improves retinal and cortical responses in patients with glaucoma. Opthalmology 1999;1061126-1134. 43. Horvath K, Schauss AG, Somfai-RelleS, et al. Acute and subchronic toxicity of citicoline-free base administered orally to the rat. Manuscript submitted for publication, 2005. 44.Dinsdale JR, Griffiths GK, Castello J, et al. CDP-choline: repeated oral dose tolerance studies in adult healthy volunteers. Arzneimittelforschung 198333:lMl-1065. 45. Petkov VD, Konstantinova E, Petkov W, et al. Modulation of the effects on learning and memory of nootropic drugs and central stimulants when applied together. Acta Physiol Pharmacol Bulg 1991; 1717-26.

Coenzyme Qo Alan R.Gaby, MD Laurie K.Mischley, ND CHAPTER CONTENTS Introduction 859 Coenzyme QtoDeficiency 860 Clinical Applications 860 Mitochondria1 Diseases 860 Parkinson Disease 860 Friedrich Ataxia 860 Immune Function 860 Acquired Immunodeficiency Syndrome (AIDS) 861 Aging 861 Cancer 861 Periodontal Disease 861 Gastric Ulcer 862 Physical Performance 862 Muscular Dystrophy 862 Asthma 863 Cardiovascular Disease-General Considerations 863

INTRODUCTION Coenzyme Qlo(CoQlo)is a compound found naturally in the human body. Because of its ubiquitous presence in nature and its quinone structure (similar to that of vitamin K), CoQlois also known as ubiquinone (Figure 82-1). The primary biochemical action of CoQlois as a cofactor in the mitochondria1 electron-transport chain, the series of redox reactions that are involved in the synthesis of ATP. Since most cellular functions depend on an adequate supply of ATP, CoQlois essential for the health of virtually all human tissues and organs. In addition to its significant role in the mitochondria, CoQlois an important scavenger of reactive oxygen species. CoQlo is one of the few antioxidants that can readily regenerate to its reduced form after utilization.] Although CoQlo can be synthesized from phenylalanine or tyrosine, situations may arise in which the body’s synthetic capacity is insufficient to meet CoQlorequirements. Susceptibility to CoQlodeficiency appears to be greatest in cells that are the most metabolically active (such as those in the heart, brain, immune system, gingiva,

Cardiac Disease 863 Cardiomyopathy 863 Congestive Heart Failure 864 Angina 864 Arrhythmias 864 Prevention of Adriamycin Toxicity 864 Protection during Cardiac Surgery 865 Mitral Valve Prolapse 865 Hypertension 865 Diabetes Mellitus 865 Infertility 865 Toxicant Exposure 866 Drug Interactions 866 Dosage

866

Toxicology 867

and gastric mucosa), since these cells presumably have the highest requirements for CoQlo.Tissue deficiencies or subnormal serum levels of CoQlohave been reported to occur in a wide range of medical conditions including cardiovascular disease, hypertension, periodontal disease, asthma, Parkinson disease, and acquired immunodeficiency syndrome (AIDS).In addition, CoQlolevels decline with advancing age and this decline might contribute in part to some manifestations of aging. A need for supplemental CoQlo could theoretically result from the following: Impaired CoQlosynthesis due to nutritional deficiencies A genetic or acquired defect in CoQlo synthesis or utilization Increased tissue needs resulting from a particular illness The requirement to prevent the side effects of medical intervention Because oral administration of CoQlo can increase tissue levels of the nutrient, it is possible to correct CoQlo deficiency and its associated metabolic consequences by supplementation? 859

Pharmacology of Natural Medicines

CH20

+Fi2-

CH - C - CH2--),oH

0 Flgum 82-1 Coenzyme Qto.

Coenzyme Qlo Deficiency CoQlo participates in the citric acid cycle (Krebs cycle) enzyme known as succinate dehydrogenase-CoQlo reductase. An assay of the activity of this enzyme has been used to detect deficiencies of C0QlP3If the enzyme is fully saturated with CoQloin vivo, addition of exogenous CoQlo does not increase enzyme activity. On the other hand, exogenous CoQlo increases activity appreciably when tissue levels of CoQlo are low. Other CoQlodependent enzymes can also be measured using a similar approach? More recently, measurements of both serum and whole blood CoQlolevels have been used to detect deficiencies. Plasma CoQloreference ranges were determined to be 0.42 to 1.14mmol/Lon the basis of data for 50 healthy persons aged 20 to 64 years old. A recent study demonstrated ubiquinone-10 status was below the reference range in 40% of healthy women and 24% of men (p = 0.02):

CLINICAL APPLICATIONS Mitochondria1 Diseases Although rare, congenitalCoQlodeficiency has been documented in a few cases of mitochondrial encephalomyopathy characterized by recurrent myoglobinuria and brain involvement (seizures, ataxia, and mental retardation). Additionally, several cases of muscle C0Ql0 deficiency have been documented in patients with familial cerebellar ataxia, pyramidal signs, and seizures. In one study, all six patients determined to have low muscle CoQlo concentrations showed a clinical response to CoQlosupplementation. Clinical improvements included improvement of strength, improved ataxia, and less frequent seizures. Primary CoQlodeficiency is a potentially important and treatable cause of familial ataxia and should be considered in the differential diagnosis of this condition.

Parkinson Disease Excessive freeradical production is largely responsible for dopaminergic cell death seen in Parkinson's disease (PD). Both as a cause and an effect of the excessive oxidative stress, there is reduced activity of complex I of the mitochondrial electron transport chain. Given that CoQlo is

essential for the function of complex I and is also a powerful antioxidant, it holds therapeutic potential in the treatment of PD. Reduced levels of CoQlohave been demonstrated in the platelets of individuals with PD, and CoQlolevels were strongly correlated with activity in complexes I and II/III. Clinically, it has been demonstrated that oral CoQlo increases complex I a~tivity.~ A recent study suggests that a dose of 1200 mg/day was substantially more effective at slowing PD progression than 300 or 600 mg/day doses; indicating adequate plasma levels may need to be reached before a clinical effect is observed. Treatment is more effective if initiated early in the course of the disease.

Friedreich Ataxia Friedrich ataxia is a progressive neurologic disease characterized by loss of myelin in the central nervous system. Evidence indicates that mitochondrial oxidative stress in Friedreich ataxia may be responsible for the cardiomyocyte hypertrophy associated with this disease.' In a placebo-controlled trial, idebenone (a synthetic CoQlo analog) sigruficantly decreased heart hypertrophy (>20% decrease) in about 50% of study participants, with no adverse effects?Jo A second study combined CoQlowith vitamin E in an attempt to address two of the key features of Friedreich ataxia4ecreased mitochondrial respiratory chain function and increased oxidative stress. This therapy resulted in a rapid and sustained increase in the amount of energy generated by the diseased heart muscle, nearly returning to normal levels. The improvements in skeletal muscle energy generation paralleled those of the heart but were less substantial."

Immune Function At the mitochondrial level, CoQlo is essential for the optimal function of the immune system,12and several studies have demonstrated immune-enhancing effects of CoQlo or its analog^.^"'^ These immune-enhancing effects included increased phagocytic activity of macrophages, increased proliferation of granulocytes in response to experimental infections, and prolonged survival in mice infected with Pseudornonas ueruginosa, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, or Candida aZbicuns. Inoculation of animals with Friend leukemia virus reduced CoQlolevels in the blood and spleen,'6 whereas treatment of infected animals with CoQlo increased the survival rate and decreased the severity of hepatomegaly and ~plenomegaly.'~ Lmmune function tends to decline with advancing age. In a study of elderly mice, suppression of the immune response was associated with a marked decline of CoQlo levels in thymic tissue.18 This immune suppression was partly reversed by treatment with C0Q10.19In a study of eight chronically ill patients, administration of 60 mg/day

Coenzyme Qlo

of CoQlo was associated with si&cant increases in serum levels of immunoglobulin G (I&) after 27 to 98 days of treatment.20These studies suggest that CoQlo may help to prevent or reverse the immunosuppression that is associated with aging or chronic disease.

Acquired Immunodeficiency Syndrome AIDS is a complex disease associated with a wide range of nutritional defiaenaes and immunologic disorders. Although correction of nutritional defiaenaes does not cure AIDS, appropriatenutritional interventionsmay help to prevent weight loss and enhance overall immune function. In addition, since oxidative stress is believed to be involved in the pathogenesis of AIDS-related diseases, the antioxidant activity of CoQlo may be of value for individuals with AIDS.2l The T4/T8 ratios of lymphocytes are known to be low in patients with AIDS and -related complex (ARC). Several studies have demonstrated that CoQlo increases T4/T8 ratios of lymphocytes.22,23In one study, blood levels of CoQlowere sigruficantly lower in patients with ARC than in a control group and were signrficantly Six lower in patients with AIDS than in those with patients withor ARC were treated with 200 mg/day of CoQlo. T-cell helper/suppressor ratios increased in three patients, becoming normal in one case. Five patients reported symptomatic improvement, which was dramatic in some cases. Furthermore, none of the patients developed opportunistic infectionsduring a 4- to 7-month follow-up period. This study demonstrates that CoQlo deficiency is common in patients with HIV infection and that supplementation with CoQlomay improve immune function and reduce the incidence of opportunistic infections.

Aging CoQlo levels in human organs peak at 20 years of age except in the pancreas and adrenal, in which the levels seem to be highest at 1year of age. Once the peak level is achieved, levels decrease continuously with advancing age. After the age of 35 to 40, humans begin to lose their ability to synthesize CoQlo.25It has been proposed that the increase in age-associated diseases is due in part to decreased protection afforded by CoQlo as both an antioxidant and a facilitator of energy production at a cellular level. In recent years, makers of several over-the-counter skin creams have begun advertising the addition of Qlo as an ingredient capable of curbing the aging process. Research suggests there may be some truth to this claim, demonstrating topical CoQlo applied to the skin can reduce the level of oxidation normally associated with the photoaging. CoQlowas able to protect against ultraviolet A-mediated oxidative stress, suppress the expression of collagenase, and cause a reduction in wrinkle depth.26

Cancer Because of its role in enhancing immune function, CoQlo has been considered as a possible anticancer agent. Administration of CoQlo reduced tumor size and increased survival in mice exposed to a chemical carcinogen." Preliminq studies in humans, though uncontrolled, are promising. In one study, 32 women with breast cancer who were classified as "high r i s k because of tumor spread to the axillary lymph nodes received 90 mg/day of CoQlo,along with vitamins C and E, betacarotene, and essential fatty acids. In six of these women, the tumor became smaller. During the 18-month treatment period, none of the patients died (the expected number of deaths was four) and none showed signs of further distant metastases. Six patients had an apparent partial remission. In addition, patients receiving CoQlorequired fewer pain killers.27 In another report, two women with metastatic breast cancer received 390 mg/day of CoQlo.One was a 44-yearold woman with numerous liver metastases. After treatment with CoQlofor 11months, all of the liver metastases had disappeared and the patient was reported to be in excellent health. The other patient was a 49-year-old woman with breast cancer that had metastasized to the pleural cavity. After 6 months of CoQlotherapy, the pleural fluid had completely resolved and the patient was reported to be in excellent health.= Although these reports are anecdotal, the results are far better than would normally be expected. Preliminary results suggest that CoQlo might inhibit tumor-associated cyt0kines.2~Considering that CoQlois virtually free of side effects, empirical treatment of breast cancer with CoQloseems justified.

Periodontal Disease Periodontal disease affects about 60% of young adults and 90% of individuals older than the age of 65. Although proper oral hygiene is helpful, many people suffer from intractable gingivitis, often requiring surgery and resulting in eventual loss of teeth. Because periodontal disease is so common, the costs of periodontal surgery and other treatments contribute a significant amount to the overall cost of health care in the United States. Healing and repair of periodontal tissues require efficient energy production, which depends on an adequate supply of CoQlo. However, gingival biopsies revealed subnormal tissue levels of CoQloin 60% to 96% of patients with periodontal disease and low levels of CoQloin leukocytes in 86% of c a ~ e s . These 3 ~ ~findings ~ indicate that periodontal disease is frequently associated with CoQlodeficiency. Eighteen patients with periodontal disease received either 50 mg/day of CoQlo or a placebo in a 3-week double-blind tria1.3 Results were assessed according to

Pharmacology of Natural Medicines a "periodontal score," which included gingival-pocket depth, swelling, bleeding, redness, pain, exudate, and loosenessof teeth. All 8 patients receiving CoQlo improved, compared with only 3 of 10 receiving the placebo (p < 0.01). The treating dentists, who were unaware that a .study was being conducted, consistently remarked about the "very impressive" rate of healing in patients treated with CoQlo. One prosthodontist commented that the amount of healing that occurred in 3 weeks in patients receiving CoQlowould normally require about 6 months. In an open trial, administration of CoQlo produced "extraordinary postsurgical healing" (two to three times as fast as usual) in seven patients with advanced periodontal disease.34

Gastric Ulcer Susceptibility to gastric ulceration is related to the balance between ulcer-promoting factors (e.g., excessive gastric acidity, infection with Helicobucter pylori) and resistance factors (e.g., tissue integrity, production of protective mucus, repair mechanisms). Free radical damage is believed to be one of the primary mechanisms by which external factors induce gastric injury and peptic ulcerat i ~ n Since . ~ ~ CoQlo possesses antioxidant activity, it may be capable of preventing ulceration by reducing the amount of free radical damage. In addition, the production of protective mucus and the rapid cell turnover of gastric mucosa are highly energy-dependent processes requiring the presence of adequate amounts of CoQlo. The efficiency of these protective and reparative processes may be compromised in some patients with gastric ulcers. With advancing age, the fundic mucosa and its rich blood supply are gradually replaced by pyloric tissue, which has poor vascularity. This change in cell type may result in hypoxia in certain portions of the stomach. The hypoxic state of gastric tissue could explain why gastric ulcers frequently become intractable in elderly patients or in those with chronic heart or lung disease. At least one study has documented low levels of CoQloin humans with peptic ulcer disease.%The importance of CoQlo for healing of gastric ulcers has been demonstrated in animals?7Gastric ulcers were induced in mice by the application of acetic acid. The mice were then maintained either in room air (20% oxygen) or under mild hypoxic conditions (17% oxygen). Ulcers healed normally in mice exposed to room air but increased in size under hypoxic conditions. However, in hypoxic mice treated with CoQlo (50 mg/kg per day) the ulcers healed normally. This study demonstrates that hypoxia has an adverse effect on the healing of gastric ulcers in animals and that the effect of hypoxia can be prevented by administration of CoQlo.Although human studies have not been done, empirical use of CoQlo seems to be a reasonable option for elderly patients with intractable gastric ulcers,

particularly those who also have diseases likely to produce hypoxia.

Physical Performance Because CoQlo is involved in energy production and its concentration in muscle is correlated with performance, it is theoretically possible that supplementation could enhance aerobic capacity and muscle performance. In one study, six healthy sedentary men (mean age, 21.5 years) performed a bicycle ergometer test before and after taking CoQlo(60 mg/day) for 4 to 8 weeks.%CoQlotreatment improved certain performance parameters, including work capacity at submaximal heart rate, maximal work load, maximal oxygen consumption, and oxygen transport. These improvements ranged from 3% to 12% and were evident after about 4 weeks of supplementation. Although this study suggests that administration of CoQlo improves physical performance in sedentary individuals, other publications are conflicting. Until larger studies are done, the use of CoQlofor the purpose of performance enhancement cannot be considered proven.39

Muscular Dystrophy The muscular dystrophies are a group of hereditary diseases characterized by the progressive loss of muscle cells. In some types of muscular dystrophy an impairment of mitochondria1 function may contribute to the pathogenesis of the disease. Several studies have demonstrated a deficiency of CoQlo in muscle mitochondria of humans with muscular dystrophy.40In addition, serum CoQlo levels were sigruficantly (p < 0.05) inversely correlated with the degree of genetic defect.4lSQ The first double-blind trial of CoQlo in the treatment of individuals with muscular dystrophies and neurogenic atrophies concluded, "Patients suffering from these muscle dystrophies and the like should be treated with vitamin CoQloindefinitel~."~~ The same group conducted two studies on patients between 7 and 69 years of age who had diseases associated with cardiac diseases, including the Duchenne, Becker, and the limb-girdle dystrophies; myotonic dystrophy; Charcot-Marie-Tooth disease; and the Welander disease. Individuals were treated for 3 months with 100 mg daily of CoQlo or a matching placebo. In both trials, definitely improved physical performance was recorded in the groups receiving CoQlo. Cardiac function was monitored by technicians who were unaware of which treatment the patients were receiving. In each case they correctly identified the treatment group to which the patient had been assigned, on the basis of the improvement or lack of improvement in cardiac function. In a smaller double-blind study, 100 mg of CoQlo was given daily for 3 months to 12 patients with progressive muscular dystrophy. CoQlotreatment resulted in

significant improvements in cardiac output and stroke volume, as well as increased physical well-being in four of eight patients.4O Subjective improvements included increased exercise tolerance, reduced leg pain, better control of leg function, and less fatigue. Presumably, the mechanism by which CoQlo improves the symptoms of muscular dystrophies is related to an improvement in energy production in muscle cells.

Asthma The contribution of oxygen free radicals to the pathogenesis of asthma is widely k n ~ w n The . ~ modulation of antioxidant defenses by antioxidant supplementation represents a potentially important therapeutic approach. CoQlo levels, in addition to the levels of a number of other antioxidants,are decreased in asthmatics compared with c0ntrols,4~and supplementation with antioxidants including CoQlohas been shown to decrease both oxidative stress and asthma symptom^.^*^^ Results of a recent study demonstrated low concentrations of CoQloin 56 asthmatic patients compared with 25 healthy controls. In the study, mean concentrationsof CoQlo both in plasma and whole blood were significantly lower than in healthy volunteers (p < 0.001).48In a case report of a patient with chronic asthma treated with glucocorticoid for 45 years, symptoms of glucocorticoidinduced myopathy were attenuated by the administration of C O Q ~ , ,This . ~ ~ report suggests that CoQlo may decrease some long-term side effects in glucocorticoidtreated asthmatics, in addition to providing the aforementioned antioxidant protection. In a 1-year double-blind trial involving 322 patients with congestive heart failure, supplementation with CoQlo at a dose of 2 mg/kg/day for 1year decreased episodes of cardiac asthma compared with a placebo ( p < 0.001).46

Cardiovascular Disease-General Considerations Enhancing myocardial function is an important, though frequently overlooked, component of the overall prevention and treatment of cardiovascular disease. CoQlo plays a key role in energy production and is therefore essential for all energy-dependent processes including heart muscle contraction. CoQlo deficiency has been documented in patients with various types of cardiovascular disease. Whether a decline in CoQlo levels is a primary cause or a consequence of heart disease is unclear. However, given the fundamental involvement of CoQloin myocardial function, it is not unlikely that CoQlo deficiency would exacerbate heart disease and that correction of such a deficiency would have therapeutic value. In addition, CoQlo has been shown to be a potent antioxidant. In fact, ubiquinol-10, the reduced form of CoQlo,protected human low-density lipoproteins (LDLs)

more efficiently against lipid peroxidation than did vitamin E.50 Because oxidation of LDL is believed to be an initiating factor in the development of atherosclerosis, CoQlowould appear to be a preventive factor.

Cardiac Disease Circulating levels of CoQlo were significantly lower in patients with ischemic heart disease and in those with dilated cardiomyopathy (mostly New York Heart Association [NYHA] functional class I11 or IV) than in healthy c o n t r ~ l sIn . ~another ~ ~ ~ study, CoQlo levels in myocardial tissue (estimated by enzymatic methods) were low in approximately 75% of patients undergoing cardiac surgery. Concentrations of CoQlo declined progressively in both blood and myocardial tissue with increasing severity of heart disease.% Myocardial deficiencies of CoQlo were also found in the majority of patients with aortic stenosis or insufficiency, mitral stenosis or insufficiency,diabetic cardiomyopathy,tetralogy of Fallot, atrial septal defects, and ventricular septal defects.%In patients with cardiomyopathy and myocardial deficiency of CoQlo, oral administration of 100 mg/ day of CoQlofor 2 to 8 months resulted in an increase in myocardial CoQlo levels ranging from 20% to 85Y0.~~ These findings suggest that CoQlodeficiency is common in patients with various types of cardiovascular disease and that oral administration of CoQlocan increase tissue levels of this nutrient.

Cardiomyopathy In one study, 126 patients with dilated cardiomyopathy (98% of whom were in NYHA functional class I11 or IV) received 100 mg/day of CoQlo for periods of up to 66 months. After 6 months of treatment, the mean ejection fraction increased from 41% to 59% (p < 0.001) and remained stable thereafter with continued treatment. After 2 years, 84% of the patients were still alive, and at 5.5 years 52% were alive.5zThese survival rates are considerably better than the published survival statistics of patients given conventional therapy (i.e., 2-year survival rate of 50”/0for symptomatic cardiomyopathy, and 1-year survival rate of 50%for decompensated cardiomyopathy). In another study, 88 patients with cardiomyopathy received 100 mg/day of CoQlo for periods of 1 to 24 months. Significant improvements in at least two of three cardiac parameters (ejection fraction, cardiac output, and NYHA class) were seen in 75% to 85% of the patients. Approximately 80% of the patients improved to a lower (i.e., more favorable) NYHA functional class.56 In a double-blind, cross-over trial, 19 patients with cardiomyopathy (NYHA classes III and IV) received 100 mg/day of CoQlo or a placebo, each for 12 weeks. Compared with placebo, CoQlo treatment significantly increased cardiac stroke volume and ejection fraction.

Eighteen patients reported improvement in activity while taking CoQ10.57

Congestive Heart Failure The potential of CoQlo as a treatment for congestive heart failure (CHF) was suggested as early as 1967 by Japanese researchers.%In 1976 these same investigators administered 30 mg/day of CoQlo to 17 patients with CI-IF.All of the patients improved, and nine (53%)became asymptomatic after 4 weeks of treatment.59 In an open trial of 34 patients with refractory NYHA class IV CHF, administration of 100 mg/day of CoQlo resulted in sustained improvement in cardiac function in 28 cases (82%).The survival rate after 2 years was 62%' compared with an expected 2-year survival rate of less than 25% for similar patients.@ In another study, 12 patients with advanced CHF who had failed to respond adequately to digitalis and diuretics received 100 mg/day of CoQlofor 7 months. Two thirdsof the patients showed definite clinical improvement after a mean treatment period of 30 days. In these patients, dyspnea at rest disappeared and energy level and tolerance for activity increased. Objective improvements included decreased hepatic congestion, reductions in heart rate and heart volume, and a decline in systolic time intervals (suggesting improved myocardial performance). Withdrawal of CoQlowas followed by severe clinical relapse, with subsequent improvement on resumption of treatment.6l In a large multicenter trial, 1113 CHF patients received 50 to 150 mg/day of CoQlofor 3 months (78% of the patients received 100 mg/day). The proportion of patients with improvements in clinical signs and symptoms were as follows62: Cyanosis, 81% Edema, 76.9% Pulmonary rales, 78.4% Enlargement of the liver area, 49.3% Jugular reflux, 81.5% Dyspnea, 54.2% Palpitations, 75.7% Sweating, 82.4% Arrhythmia, 62% Insomnia, 60.2% Vertigo, 73% Noduria, 50.7% The results of these uncontrolled studies were confirmed more recently in a double-blind trial. Some 641 patients with CHF (NYHA classes lll or IV)were randomly assigned to receive placebo or CoQlo (2 mg/ kg/day) for 1 year. Conventional therapy was continued in both groups. The number of patients requiring hospitalization during the study for worsening heart

failure was 38% less in the CoQlo group than in the placebo group (p < 0.001). Episodes of pulmonary edema were reduced by about 60% in the CoQlo group, compared with the placebo group (p < 0.001).46

Angina Twelve patients with stable angina pectoris were randomly assigned to receive 150 mg/day of CoQlo or a placebo in a Cweek, double-blind, cross-over trial. CoQlo treatment sigruficantly increased exercise tolerance on a treadmill (time before onset of chest pain) and sigruficantly increased the time until ST-segment depression occurred. Compared with placebo, there was a 53% reduction in the frequency of anginal episodes and a 54% reduction in the number of nitroglycerin tablets needed during CoQlotreatment; however, these differences were not statistically significant.63 These results suggest that CoQlois a safe and effective treatment for angina pectoris. Although the amelioration of anginal attacks was not statistically sigruficant, the magnitude of the effect was large. It would therefore be worthwhile to perform a similar study with a larger number of patients.

Arrhythmias Twenty-seven patients with ventricular premature beats (VPBs) and no evidence of organic heart disease received a placebo for 3 to 4 weeks, followed by 60 mg/day of CoQlofor 4 to 5 weeks. The reduction in VPBs was significantly greater after CoQlo than after placebo. The beneficial effect of CoQlowas seen primarily in diabetics, in whom the mean reduction in VPB frequency was 85.7V0.A sigruficant reduction in VPBs also occurred in 1 (11%) of 9 otherwise healthy patients and in 4 (36%) of 11 patients with hypertension.@

Prevention of Adriamycin Toxicity The clinical value of Adriamycin as an anticancer agent is limited by its toxicity, which includes cardiomyopathy and irreversible heart failure. Adriamycin-induced cardiotoxicity is believed to be caused, at least in part, by a reduction in CoQlo levels and by inhibition of CoQlodependent enzymes. In rats treated with Adriamycin, administration of CoQlorestored the levels of thisnutrient to normal and prevented Adriamycin-induced morphologic changes in the heart.65Treatment with CoQlo also prevented Adriamycin-induced cardiotoxiaty in rabbits.% Cancer patients receiving Adriamycin had lower myocardial levels of CoQlothan did controls. The magnitude of CoQlo depletion was directly related to the severity of cardiac im~airment.6~ To determine the effect of CoQlosupplementation on Adriamycin cardiotoxicity, seven patients receiving Adriamycin were also given 100 mg/day of CoQlo, beginning 3 to 5 days before

Coenzyme Qto

Adriamycin was started. Another seven patients (control group) received Adriamycin without CoQlo. Cardiac function deteriorated significantly in the control group, whereas patients given CoQlo had little or no cardiotoxicity, even though the cumulative dose of Adriamycin in the CoQlogroup was 50% greater than that in the control group.@Despite the small number of patients in thisstudy, the results are highly encouraging.Because administration of CoQlodoes not appear to affect the antitumor activity of Adriamycin, CoQloprophylaxis seems appropriate for all patients receiving Adriamy~in.6~

Protection during Cardiac Surgery Postoperative low cardiac output is a major cause of early death following cardiac surgery. Fdty patients undergoing cardiac surgery for acquired valvular lesions were randomly assigned to receive 30 to 60 mg/day of CoQlo for 6 days before surgery or to a control group that did not receive CoQlo.Postoperatively, a state of severe low cardiac output developed in 48% of the patients in the control group, compared with only 12% of those in the CoQlo group. These results suggest that preoperative administration of CoQlo increases the tolerance of the heart to ischemia during aortic cross-clamping.7°

Mitral Valve Prolapse Cardiac performance was evaluated using an isometric hand-grip test in 194 children with symptomatic mitral valve prolapse. Before treatment, all patients had an abnormal hand-grip test. Sixteen children received 2 mg/ kg/day of CoQlo or a placebo for 6 weeks in a singleblind trial. Hand-grip strength became normal in seven of the patients receiving CoQloand in none of the placebotreated patients.71 However, the relevance of this study to the treatment of mitral valve prolapse in adults is doubtful. Aside from the study's inadequate blinding, isometrichand-grip may not be a reliable test of cardiac function. Furthermore, impaired cardiac function is not typical of mitral valve prolapse in adults, and the symptoms associated with this condition do not appear to be caused by diminished cardiac function.

Hypertension Enzymatic assays revealed a deficiency of CoQloin 39% of 59 patients with essential hypertension, compared with only 6% of healthy controls. In animal models of hypertension including spontaneously hypertensive rats, uninephrectomized rats treated with saline and deoxycorticosterone, and experimentally hypertensive dogs, orally administered CoQlo significantly lowered blood Twenty-six patients with essential hypertension received 50 mg of CoQlo twice daily. After 10 weeks of

treatment, mean systolic blood pressure decreased from 164.5 to 146.7 mmHg and mean diastolic blood pressure decreased from 98.1 to 86.1 mmHg (p < 0.001). The fall in blood pressure was associated with a sigruficant reduction in peripheral resistance, but there were no changes in plasma renin activity, serum and urinary sodium and potassium, and urinary aldosterone. These results suggest that treatment with CoQlo decreases blood pressure in patients with essential hypertension, possibly because of a reduction in peripheral resistanceT6 In another study, 109patients with essential hypertension received CoQlo(average dose, 225 mg/day) in addition to their usual antihypertensive regimen. The dosage of CoQlowas adjusted according to clinical response and blood CoQlo levels (the aim was to attain blood levels >2 pg/ml). The need for antihypertensive medication declined gradually, and after a mean treatment period of 4.4 months, about half of the patients were able to discontinue between one and three drugs." Similar results have been reported by others.76 It should be noted that the effect of CoQlo on blood pressure was usually not seen until after 4 to 12 weeks of therapy. That observation is consistent with the delayed increase in enzyme activity that results from administration of CoQlo.Thus CoQlois not a typical antihypertensive drug; rather, it s e e m to correct some metabolic abnormality involved in the pathogenesis of hypertension.

Diabetes Mellitus Low tissue levels of CoQlo have been consistently reported in diabetic patients. There are several mechanisms by which CoQlo may be of therapeutic value in Improved blood pressure and long-term glycemic control have been reported with CoQlosupplementation (100 mg twice Enhancement of endothelial function may offer some protection against arteriopathies.84A recent study of 80 dyslipidemic type 2 diabetics found that CoQlo (200 mg/day) in combination with fenofibrate (200 mg/day) sigruficantly improved endothelial and nonendothelial forearm vasodilatory functi011.8~This effect was not found with either therapy alone or in a placebo group. An accumulating body of research demonstrates a link between mitochondria1 dysfunction and type 2 diabetes. The mitochondrial enhancement offered by supplemental CoQloappears to offer some therapeutic value against a defect in cellular energy p r o d u ~ t i o n . ~ ~ , ~ f i ~

InfertiI ity Peroxidation in sperm cells is an important factor associated with male infertility. Sperm function in infertile men has been associated with lipid peroxidation and decreased antioxidant defenses in spermatozoa.88

A statistically significant correlationbetween CoQlolevels and sperm count was found in 32 patients with a history of infertility. The association was direct for reduced (p < 0.05) CoQloand indirect for oxidized (p < 0.01) CoQ10.88 Recent research suggests that sperm cells with low motility and abnormal morphology have low levels of CoQ10.2 Consequently, sperm cells with low CoQlo concentrations might be less capable of quenching free radicals. Some authors have suggested using the reduced-to-oxidized CoQloratio as a diagnostic test for asthenozoospennia.@ In a &month, uncontrolled open trial, in which infertile men were supplemented orally with CoQlo,sperm cells demonstrated a sigruficant increase in motility and both seminal plasma and sperm cell quantity of CoQlo increased.g0 This supports previous studies on both sperm motility and fertilization rates?l

Toxicant Exposure Many ambient and occupational exposures to environmental toxicants affect the mitochondrial respiratory chain.92-%Damage to the respiratory chain can decrease mitochondrial membrane potential, leading to upregulated apoptosis; CoQlohas demonstrated the ability to reduce thismembrane-potential damage.97-101 Although current diagnosis and treatment of environmentally related illnesses remain controversial, cytoprotection with CoQlo may be an effective therapeutic method to reduce mitochondrial damage due to toxicants, both acute and chronic, and should be a focus of further research.Io2

Drug Interactions Cholesterol-lowering Statin drugs such as lovastatin and pravastatin inhibit the enzyme 3-hydroxy-3-methylglutaryl(HMG)-CoA reductase, which is required for biosynthesis of both cholesterol and CoQlo.Thus administration of these drugs might compromise CoQlostatus by decreasing its synthesis. Supplementation of the diet of rats with lovastatin (400 mg/kg of diet) for 4 weeks reduced the concentration of CoQlo in the heart, liver, and blood.Io3In another study, administration of lovastatin to five patients receiving CoQlo for heart failure was followed by a reduction in blood levels of CoQloand a sigruficant deterioration of clinical status. Some of these patients improved after the dosage of CoQlowas increased or the lovastatin was discontinued.lap These results suggest that people who have low CoQlo levels and suboptimal cardiac function might develop clinically sigruficant CoQlo depletion after taking an HMG-CoA reductase inhibitor. Although individuals with high CoQlolevels and good cardiac function may be more resistant to this side effect, it is recommended that all patients being treated with HMG-CoA reductase inhibitors also receive CoQloprophylactically.

The beta-blockers propranolol and metoprolol have been shown to inhibit CoQlo-dependentenzymes.lo5The antihypertensive effect of these drugs might therefore be compromised in the long run by the development of CoQlo deficiency. In one study, administration of 60 mg/day of CoQlo reduced the incidence of druginduced malaise in patients receiving propranolol.106 A number of phenothiazines and tricyclic antidepressants have also been shown to inhibit CoQlo-dependent enzymes. It is therefore possible that CoQlo deficiency may be a contributing factor to the cardiac side effects that are frequently seen with these drugs. In two clinical studies, supplementation with CoQlo improved electrocardiographic changes in patients on psychotropic dmgs.lo7 Several case reports describing potential interactions between CoQloand warfarin have been reported. CoQlo is structurally related to menaquinone (vitamin K2)and may have procoagulant effects." In each of these patients the international normalized ratio (INR),which had been stable and therapeutic, fell below the therapeutic range within 2 weeks of beginning CoQlosupplementation (as low as 30 mg/day).lm The INR returned to the therapeutic range after CoQlo was discontinued. It is recommended that the INR be monitored closely if these agents are to be used concomitantly. See also the earlier discussion on prevention of Adriamycin toxicity.

DOSAGE The optimal dose of CoQlo is not known and probably varies according to the severity of the condition being treated. For example, 30 mg/day of CoQlo was reportedly effective in the treatment of mild congestive heart failure, 90 mg/day resulted in improvements in some cases of cancer, 390 mg/day was associated with complete regression of liver metastases in a patient with breast cancer, and 1200 mg/day proved the most advantageous dose for slowing the progression of Parkinson disease. The plasma and presumably brain levels of CoQlo may be the primary determinant of efficacy, rather than the dose.8J10Research indicates that therapeutic blood levels of CoQlo should be at least 2.5 pg/mL to elicit a therapeutic result56 and that optimum improvement in neurodegenerative diseases and myocardial function may occur at plasma levels greater than 3 pg/mL.8Jl0 Unfortunately, few laboratories offer plasma analysis of CoQloat this time. The usual dosage of CoQlois 60 mg/day, with a range of 30 to 1200 mg/day. The dosage of CoQlo should be adjusted according to the response of the patient. Because the synthesis of new CoQlo-dependentenzymes is a slow process, a clinical response might not occur until 8 or more weeks after therapy is begun."'

Coenzyme Qlo

TOXICOLOGY CoQlois generally well tolerated, and no serious adverse effects have been reported with long-term use. Because safety during pregnancy and lactation has not been proven, CoQlo should not be used during these times unless the potential clinical benefit outweighs the risks. CoQlo is contraindicated in cases of known

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hypersensitivity. In a series of 5143 patients treated with 30 mg/day of CoQlo, the following incidence of side effects was reported70: Epigastric discomfort, 0.39% Loss of appetite, 0.23% Nausea, 0.16% Diarrhea, 0.12%

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56. Langsjoen PH, Folkers K, Lyson K, et al. Effective and safe therapy with coenzyme QlO for cardiomyopathy. Klin Wochenschr 1988;66:583-590. 57. Langsjoen PH, Vadhanavikit S, Folkers K. Effective treatment with coenzyme QlO of patients with chronic myocardial disease. Drugs Exp Clin Res 1985;11:577-579. 58.Ymamura Y, Ishiyama T, Yamagami T, et al. Clinical use of c0enzyme-Q for treatment of cardiovascular disease. Jpn Circ J 1967; 31:168. 59. Ishiyama T, Morita Y, Toyama S, et al. A clinical study of the effect of coenzyme Q on congestive heart failure. Jpn Heart J 1976;17 32-42. 60.Anonymous. Coenzyme aids cardiomyopathy. Med World News 19852669. 61. Mortensen SA, Vadhanavikit S, Baandrup, et al. Long-term coenzyme QlO therapy: a major advance in the management of resistant myocardial failure. Drugs Exp Clin Res 1985;11:581-593. 62. Baggio E, Gandini R, Plancher AC, et al. Italian multicenter study on the safety and efficacy of coenzyme QlO as adjunctivetherapy in heart failure (interim analysis). The CoQlO Drug Surveillance Investigators.Clin Investig 1993;71(suppl8):S145-S149. 63. Kamikawa T, Kobayashi A, Yamashita T, et al. Effects of coenzyme QlO on exercise tolerance in chronic stable angina pectoris. Am J Cadi01 198556247-251. 64.Fujioka T, Sakamoto Y, Mimura G. Clinical study of cardiac arrhythmias using a 24-hour continuous electrocardiographicrecorder (5th report)-antiarrhythmic action of coenzyme QlO in diabetics. Tohoku J Exp Med 1983;141(suppl):453-463. 65. Ogura R, Toyama H, Shimada T, et al. The role of ubiquinone (coenzyme QlO) in preventing Adriamycin-induced mitochondrial disorders in rat heart. J Appl Biochem 1979;1:325-335. 66. Domae N, Sawada H, Matsuyama E, et al. Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possible prevention by coenzyme QlO. Cancer Treat Rep 1981; 65:79-91. 67. Karlsson J, Astrum H, et al. Effect of Adriamycin on heart and skeletal muscle coenzyme Q (CoQlO) in man. In Folkers K, ed. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1986. 68. Judy WV, Dugan W, et al. Coenzyme QlO reduction of Adriamycin cardiotoxicity. In Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1984: 231-241. 69. Cortes EP, Gupta M, Chou C, et al. Adriamycin cardiotoxicity: early detectionby systolic time interval and possible prevention by coenzyme QlO. Cancer Treat Rep 1978;62:887-891. 70. Tanaka J, Tominaga R, Yohitoshi M, et al. Coenzyme Q10 the prophylactic effect on low cardiac output following cardiac valve replacement. Ann Thorac Surg 1982;33145-151. 71. Oda T, Hamamoto K. Effect of coenzyme QlO on the stress-induced decrease of cardiac performance in pediatric patients with mitral valve prolapse. Jpn Circ J 1984;48:1387. 72. Yamagami T, Iwamoto Y, Folkers K, et al. Reduction by coenzyme QlO of hypertension induced by deoxycorticosterone and saline in rats. Int J Vitam Nutr Res 1974;44:487-496. 73. Igarashi T, Nakajima Y, Tanaka M, et al. Effect of coenzyme QlO on experimental hypertension in rats and dogs. J Pharmacol Exp Ther 1974;189:149-156. 74. Iwamoto Y, Yamagami T, Folkers K, et al. Deficiency of coenzyme QlO in hypertensive rats and reduction of deficiency by treatment with coenzyme QlO. Biochem Biophys Res Commun 1974;58:743-748. 75. Okamoto H, Kawaguchi H, Togashi H, et al. Effect of coenzyme QlO on structural alterations in the renal membrane of stroke-prone spontaneously hypertensive rats. Biochem Med Metab Biol 1991;45:216-226.

76. Digiesi V, Cantini F, Oradei A, et al. Coenzyme QlO in essential hypertension.Mol Aspects Med 1994;15(suppl):S257-S263. 77. Langsjoen P, Langsjoen P, Willis R, et al. Treatment of essential hypertension with coenzyme QlO. Mol Aspects Med 1994;(suppl 15):5265-5272. 78. Kishi T, &hi H, Watanabe T, et al. Bioenergetics in clinical medicine. XI. Studies on coenzyme Q and diabetes mefitus. J Med 1976;7307-321. 79. Kucharska J, Braunova Z, Ulicna 0, et al. Deficit of coenzyme Q in heart and liver mitochondria of rats with streptozotocin-induced diabetes. Physiol Res 2000;49411-418. 80. Eriksson JG, Forsen TJ, Mortensen SA, et al. The effect of coenzyme QlO administration on metabolic control in patients with type 2 diabetes mellitus. Biofactors 1999;9:315-318. 81. Hodgson JM, Watts GF, Playford DA, et al. Coenzyme QlO improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr 2002;561137-1142. 82. McCarty ME Toward practical prevention of type 2 diabetes. Med Hypotheses 2000;51:786-793. 83. McCarty MF. Toward a wholly nutritional therapy for type 2 diabetes. Med Hypotheses 2000;54:483-487. 84. Watts GF, Playford DA, Croft KD, et al. Coenzyme Q(l0) improves endothelial dysfunction of the brachial artery in type II diabetes mellitus. Diabetologia 2002;45420-426. 85. Playford DA, Watts GF, Croft KD, et al. Combined effect of coenzyme QlO and fenofibrate on forearm microcirmlatoIy function in type 2 diabetes. Atherosderosis 2003;168:169-179. 86. Lamson DW, Plaza SM. Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment. Altem Med Rev 2002;7 94-111. 87. Silvestre-Aillaud P, BenDahan D, Paquis-Fluckinger V, et al. Could coenzyme QlO and L-camitine be a treatment for diabetes secondary to 3243 mutation of mtDNA? Diabetologia 1995;38: 1485-1486. 88. Alleva R, Scaramucci A, Mantero F, et al. The protective role of ubiquinol-10 against formation of lipid hydroperoxides in human seminal fluid. Mol Aspects Med 1997;(suppl18):S221-S228. 89.Balercia G, Amaldi G, Fazioli F, et al. Coenzyme QlO levels in idiopathic and varicmle-associated asthenomspermia. Andrologia 2OO2;M107-111. 90. Balemia G, Mosca F, Mantero F, et al. Coenzyme Q(l0) supplementation in infertile men with idiopathicasthenozoospermk an open, uncontrolled pilot study. Fertil Steril2004;81:93-98. 91. Lewin A, Lavon H. The effect of coenzyme QlO on sperm motility and function. Mol Aspects Med 1997;(suppl18):S213-S219. 92.Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson’s disease: genes, environment and mitochondria. Parkinsonism Relat W o r d 2003;(suppl9)2S59-S64. 93. Dorta DJ, Leite S, DeMarco KC, et al. A proposed sequence of events for cadmium-induced mitochondrial impairment. J Inorg Biochem 200397251-257. 94. Peraza MA, Carter DE, Gandolfi AJ. Toxicity and metabolism of subcytotoxic inorganic arsenic in human renal proximal tubule epithelial cells (HK-2).Cell Biol Toxicol 2003;19:253-264.

95. Robertson JD, OrreniUs S. Molecular mechanisms of apoptosis induced by cytotoxic chemicals. Crit Rev Toxicol 2000;30609-627. 96. Robertson JD, OrreniUs S. Role of mitochondria in toxiccell death. Toxicology 2002;181:491496. 97. Femandez-Ayah DJ, Martin SF, Barroso MP, et al. Coenzyme Q protects cells against serum withdrawal-induced apoptosis by inhibition of ceramide release and caspase-3 activation. Antioxid Redox Signal 2OOO;2263-275. 98. Kagan T, Davis C, LinL, et al. Coenzyme QlO can in some circumstances block apoptosis, and this effect is mediated through mitochondria. Ann N Y Acad Sci 1999;88731-47. 99. Menke T, Gille G, Reber F, et al. Coenzyme QlO reduces the toxicity of rotenone in neuronal cultures by pmerving the mitochondrial membrane potential. Biofactors 2003;1865-72. 100. Papucci L, Schiavone N, Witort E, et al. Coenzyme q10 prevents apoptosis by inhibiting mitochondria1 depolarization independently of its free radical scavenging property. J Biol Chem 2003; 27828220-28228. 101. Merlo Pich M, Castagnoli A, Biondi, et al. ubiquinol and a coenzyme Q reducing system protect platelet mitochondrial function of transfusional buffy coats from oxidative stress. Free Radic Res 2002;36:429-436. 102. Piotrowska D, Dlugosz A, Pajak J. Antioxidative properties of coenzyme QlO and vitamin E in exposure to xylene and gawline and their mixture with methanol. Acta Pol Pharm 200259: 427432. 103. Willis RA, Folkers K, Tucker JL, et al. Lovastatin decreases c m zyme Q levels in rats. Proc Natl Acad Sci U S A 1990;87:892& 8930. 104. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci U S A 1990;8789318934. 105. Kishi T, F o k K. Inhibition of cardiac CoQlO-enzymesby clinically used drugs and possible prevention. In Folkers K, ed. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1977. 106. Hamada M, Ochi T, et al. Correlation between serum CoQlO level and myocardial contractility in hypertensive patients. In Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1984. 107. Kishi T, Okamoto T, et al. Inhibition of myocardial respiration by psychotherapeutic drugs and prevention by coenzyme Q. In Folkers K, Yamamura Y, eds. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 1984A39-154. 108. Morton RA. Ubiquinones, plastoquinones and vitamins K. Biol Rev Camb PMOSSoc 1971;46:47-96. 109. Spigset 0. Reduced effect of warfarin caused by ubidecmone. Lancet 1994;344:1372-1373. 110. Sinatra ST. Coenzyme QlO and congestive heart failure. Ann Intern Med 2000;133745-746. 111. Kishi T, Okamoto T. Metabolism of exogenous coenzyme QlO in vivo and the bioavailability of coenzyme QlO preparations in Japan. In Follcers K, ed. Biomedical and clinical aspects of coenzyme Q. Amsterdam: Elsevier Scientific, 19M131-142.

Coleus forskohlii Michael T. Murray, NI) Joseph E. Pizzorno J r , ND CHAPTER CONTENTS General Description 871 Chemical Composition 871 History and Folk Use

871

Hypothyroidism 874 Malabsorption and Digestive Disorders 874 Depression 874 Cancer Metastases 874 Immune System Enhancement 874

Pharmacology 872

Dosage 874

Clinical Applications 872 Inflammatory Conditions 872 Cardiovascular Effects 873

Toxicology

874

Drug Interactions 874

Other Clinical Applications 874 Glaucoma 874 Weight Loss Programs 874

Coleusforskohlii (family: Labiatae) Synonyms: Coleus barbatus, Plectranthus barbatus, I? forskohlii Common name: coleus

GENERAL DESCRIPTION Coleus forskohlii, a perennial, is a small member of the mint (Labiatae)family. It grows on sun-exposed, dry hill slopes between an altitude of 1000 and 6000 feet in the subtropical, temperate climactic zone. Thus it is found in India, Nepal, Sri Lanka, and Thailand. Its Latin name comes from the word coleos, which means "sheath" and refers to the fused filaments that form a sheath around the stylus of the flower. The epithet, forskohlii, commemorates the Finnish botanist Forskal, who traveled extensively in Egypt and Arabia in the eighteenth century. The radially spread rootstock is the portion of the plant that has been used for medicinal purposes. The rootstock is also the source of a compound of unique biologic importance, forskolin. No other species of Coleus contains forskolin.

CHEMICAL COMPOSITION The primary chemical of clinical interest contained in C. forskohlii is the diterpine forskolin (Figure 83-1). In 1974 forskolin was discovered during a large-scale screening of medicinal plants by the Indian Central Drug Research Institute. The screening revealed the presence of a hypotensive and spasmolytic component, which was initially named coleanol.' Additional investigation determined the exact chemical structure, and the name was changed to forskolin. From 1981 to 2003, forskolin was used in more than 13,000 in vitro and in vivo experimental studies designed to better understand the cellular processes governed by CAMP(discussed later). Although most of these studies have used this isolated constituent, there is evidence that other components within the plant extract enhance the absorption and biologic activity of forskolin. However, no detailed analysis of the chemical composition of C. forskohlii could be found.

HISTORY AND FOLK USE C. forskohlii has a long history of use in Ayurvedic, Siddha, and Unani systems of medicine. Studies of the 871

Pharmacology of Natural Medicines

OCOCH, OH Flgum 83-1 Forskolin.

pharmacologic activity of forskolin substantiate the traditional uses of C. forskohlii in such conditions as': Cardiovascular disease Eczema Abdominal colic Respiratory disorders Painful urination himnnia Convulsions

PHARMACOLOGY As noted in a landmark experiment in 1981, the basic mechanism of action of forskolin is the activation of adenylate cyclase, which increases cyclic adenosine monophosphate (CAMP)in cells? CAMPis perhaps the most important cell-regulating compound. Once formed, it activates many other enzymes involved in diverse cellular function^.^ Under normal situations, CAMP is formed when an activating hormone (e.g., epinephrine) binds to a receptor site on the cell membrane and stimulates the activation of adenylate cyclase. This enzyme is found in all cellular membranes, and only the specificity of the receptor site determines which hormone will activate it in a particular cell. In contrast, forskolin appears to directly activate adenylate cyclase, bypassing hormonal transmembrane activation of adenylate cyclase. The physiologic and biochemical effects of a raised intracellular CAMPlevel include the following: Inhibition of platelet activation and degranulation Inhibition of mast cell degranulation and histamine release Increased force of contraction of heart muscle Relaxation of the arteries and other smooth muscles Increased insulin secretion Increased thyroid function Lipolysis Forskolin possesses additional mechanisms of action independent of its ability to directly stimulate adenylate cyclase and CAMP-dependent physiologic responses! Specifically, forskolin has been shown to inhibit a number of membrane transport proteins and channel proteins through a mechanism that does not involve the

production of CAMP. The result is again a transmembrane signaling that results in activation of other cellular enzymes. Research is under way to determine the exact receptors to which forskolin is binding. Another action of forskolin is the inhibition of platelet-activating factor (PAF) by interfering with PAF binding to receptor sites? PAF plays a central role in many inflammatory and allergic processes including neutrophil activation, increasing vascular permeability, smooth muscle contraction such as bronchoconstriction, and reduction in coronary blood flow. Treatment of platelets with forskolin before PAF exposure results in a 30% to 40% decrease in PAF binding. This decrease in PAF binding caused by forskolin was concomitant with a decrease in the physiologic responses of platelets induced by PAF. However, this forskolin-induced decrease in PAF binding was not a consequence of CAMPformation, as the addition of a CAMPantagonist did not inhibit the action of forskolin. In addition, the inactive analog of forskolin, dideoxyforskolin, which does not activate adenyl cyclase, also reduced PAF binding to its receptor. Researchers speculate that the action of forskolin on PAF binding is due to a direct effect of this molecule and its analog on the PAF receptor itself or to components of the postreceptor signaling for PAF.

CLINICAL APPLICATIONS The therapeutic ramifications of C.forskoh2ii based on the pharmacology of forskolin are immense. In many conditions a decreased intracellular CAMPlevel is thought to be a major factor in the development of the disease process. C. forskohlii appears to be especially well indicated in the following types of conditions: Atopic dermatitis Asthma Psoriasis Angina Hypertension Although C. forskohlii can be used alone, it may prove to be most useful when combined with other botanicals or measures, or both, in the treatment of these disorders.

Inflammatory Conditions Allergic conditions such as asthma and eczema are characterized by a relative decrease in CAMPin both the bronchial smooth muscle and the skin. As a result, mast cells degranulate and smooth muscle cells contract more readily. In addition, these allergic conditions are also characterized by excessive levels of PAF.

Asthma and Eczema Current drug therapy for allergic conditions like asthma and eczema is largely designed to increase CAMPlevels

Coleus forskohlii

by using substances that either bind to receptors to stimulate adenylate cyclase (e.g., corticosteroids) or inhibit the enzyme phosphodiesterase,which breaks down CAMP once it is formed (e.g., methylxanthines). These actions are different than forskolin's ability to increase the production of CAMPvia transmembraneactivation of adenylate cyclase. The CAMP-elevating action of forskolin supports the use of C. forskohlii extracts alone or in combination with standard drug therapy in the treatment of virtually all allergic conditions. C. forskohlii extracts may be particularly useful in asthma, as increasing intracellular levels of cAMP result in relaxation of bronchial muscles and relief of respiratory symptoms. Forskolin has been shown to have remarkable effects in relaxing constricted bronchial muscles in asthmatics.G8This type of smooth muscle is also found in the gastrointestinal tract, uterus, bladder, and arteries. Forskolin has been shown to have tremendous antispasmodic action on these various smooth muscles. This antispasmodic action of forskolin supports the folk medicine use of C. forskohlii in the treatment of not only asthma, but also intestinal colic, uterine cramps (menstrual cramps), painful urination, angina, and hypertension. In addition to forskolin's ability to relax smooth muscle, its other antiallergic activities, such as inhibiting the release of histamine and synthesis of allergic compounds, are also beneficial in treating asthma? One double-blind clinical study sought to compare the antiasthmatic effects of forskolin with the drug fenoterol. Sixteen patients with asthma were studied using three different preparations: Single inhalation doses of fenoterol Dry powder capsules of fenoterol(O.4 mg) Metered doses of fenoterol (0.4 mg) and forskolin dry powder capsules (10 mg) All three preparations caused sigrufrcant improvement in respiratory function and bronchodilation. However, while the fenoterol preparations caused tremors and decreased blood potassium levels, no such negative effects were seen with forskolin. In another study, the bronchodilating effect (after 5 minutes) of forskolin was as good as that produced by fenoterol in 12 healthy volunteers (nonsmokers),as determined by whole body plethysmography.lo Both substances were administered by metered dose inhalers. At the beginning (after 3 and 5 minutes), the protective effect of forskolin against inhaled acetylcholine was as good as that produced by fenoterol, while later on (after 15 and 30 minutes), fenoterol provided stronger protection. Whether orally administered forskolin in the form of C. forskohlii extract would produce similar bronchodilatory effects is yet to be determined. However, based on the plant's historical use and additional mechanisms of action, it appears likely.

Psoriasis Psoriasis is a common skin disorder that seems to be caused by a relative decrease in cAMP as compared with cyclic guanine monophosphate (cGMP). The result is a tremendous increase in cell division. In fact, cells divide in psoriasis at a rate 1000 times greater than normal. Preliminary studies have indicated that forskolin may be of great benefit to individuals with psoriasis via its ability to reestablish the normal balance between cAMP and cGMP.'

Cardiovascular Effects Perhaps the most useful clinical applications of C. forskohlii extracts will be for cardiovascular diseases such as hypertension, congestive heart failure, and angina. The cardiovascular effects of C. forskohIii and its components have been studied in great detail.'J1J2 Its basic cardiovascular actions involve lowering of blood pressure along with improving contractility of the heart. Again, this is related to increasing cAMP levels throughout the cardiovascular system, which results in relaxation of the arteries and increased force of contraction. The net effect is sigruficant improvement of cardiovascular function.

Hypertension and Cardiac Failure Several clinical and animal studies have supported the use of forskolin in hypertension and cardiac failure."-14In one human study involving seven patients with dilated cardiomyopathy, forskolin was shown to improve left ventricular function primarily via reduction of preload and without raising metabolic costs.I3 This study confirmed earlier animal studies showing forskolin increases the contractile force of heart muscle.12 In another human study, the hernodynamic effects of intravenous (3 pg/kg/min) forskolin given to patients with dilated cardiomyopathy was e~a1uated.l~ Although systemic vascular resistance and diastolic pressure fell, forskolin had no effect on cardiac index, ejection fraction, or myocardial oxygen consumption at this low dosage. However, when a small dosage of dobutamine was given along with the forskolin, an increase of all four parameters was observed. At a higher dosage (4 pg/kg/min), forskolin increased heart function by 19% and produced a 16% rise in heart rate. However, these changes were associated with symptomatic flush syndromes. These results indicate that forskolin may best be used in congestive heart failure in combination with other botanicals such as Crutaegus (see Chapter 85). Forskolin has also been shown to be a direct cerebral vasodilator, indicating that it may prove to be useful in cerebral vascular insufficiency and poststroke re~overy.'~

An additional mechanism of action particularly beneficial in a wide range of cardiovascularconditions is inhibition of platelet aggregation. In this area, the evidence indicates that the standardized C. forskohlii extract is superior to pure forskolin.16 In an animal model for evaluating in vivo inhibition of platelet aggregation, rats were divided into four groups: Group 1 received C. forskohlii extract (480 mg/kg supplying 20 mg/kg of forskolin);group 2 received forskolin (20 mg/kg); group 3 received dipyridamole; and group 4 served as the control. All treatments were given orally once daily. ADPinduced platelet aggregation was measured on odd days 1 through 15. All three treatments produced signhcant inhibition of platelet aggregation. On day 15, the inhibitions were approximately 42% for group 1, 37% for group 2, and 52% for group 3. Hence the extract of C. forskohlii produced greater inhibition than the pure forskolin.

OTHER CLINICAL APPLICATIONS C.forskohlii extracts concentrated and standardized for forskolin content may prove to be useful in a number of other clinical applications, including the following: Weight loss programs Hypothyroidism Malabsorption and digestive disorders Depression Prevention of cancer metastases Immune system enhancement

Glaucoma In clinical studies, forskolin has been shown to greatly reduce intraocular pressure (IOP) when it is applied This effect indicates that topical directly to the eye~.'~-~O forskolin preparations may be of benefit in the treatment of glaucoma. Unlike current drug therapy, forskolin actually increases intraocular blood flow, has no side effects, and does not induce miosis.

Malabsorption and Digestive Disorders Forskolin stimulates digestive secretions including the release of hydrochloric acid, pepsin, amylase, and pancreatic e n z y r n e ~ Forskolin . ~ ~ ~ ~ has been shown to promote nutrient absorption in the small intestine.29 C.forskohliiextracts may prove to be quite useful in treating dry mouth, as forskolin increases salivation.30

Depression Forskolin has been shown to exert antidepressant activity in animal studies.31

Cancer Metastases Forskolin has been shown to be a potent inhibitor of cancer metastasis in mice injected with malignant cells.32 As little as 82 mcg administered to mice inhibited metastasis by over 70%.

Immune System Enhancement Forskolin exhibits potent immune system enhancement (primarily through activation of macrophages and lymphocytes) in several m ~ d e l s . ~ - ~ ~

DOSAGE The recommended dosage should be based on the level of forskolin. As the forskolin content of coleus root is typically only 0.2% to 0.3%,crude coleus products may not be sufficient to produce a pharmacologic effect. The safety of the whole root at high dosages is not as well studied. It is best to use standardized extracts that have known forskolin content. Daily dosages follow: Forskolin: 5 to 10 mg two to three times daily Standardized extract (18% forskolin): 50 mg two to three times daily Dried root: 2 to 5 g two to three times daily

Weight Loss Programs

TOXIC0LOGY

Lipolysis, the breakdown of stored fat, is regulated by CAMP.Forskolin has been shown to stimulate lipolysis, as well as inhibit the synthesis of fat in adipocytes?l-" Forskolin has also been shown to counteract the agerelated decreased response of fat cells to lipolytic hormones like epinephrine.25

The animal studies on forskolin indicate low toxicity. The pharmacology of forskolin suggests it would be wise to restrict the use C.forskohlii preparations in patients with low blood pressure and peptic ulcers.

Hypothyroidism

C.forskohlii preparations should be used cautiously in patients on prescription medications, especially antiasthmatics and antihypertensives, due to its ability to potentiate these and other drugs' effects.

Forskolin has been shown to increase thyroid hormone production, as well as stimulate thyroid hormone release.26

DRUG INTERACTIONS

Coleus forskohlii

1.Ammon HIT, Muller AB. Forskoh. from ayurvedic remedy to a modem agent. Planta Med 1985;51:473-477. 2. Seamon KB, Daly JW. Forskolin: a unique diterpene activator of cyclic AMP-generating systems. J Cyclic Nucleotide Res 1981;7 201-224. 3. Insel PA, Ostrom RS. Forskolin as a tool for examining adenylyl cyclase expression, regulation, and G protein signaling. Cell Mol Neurobiol2003;23:305-314. 4. Laurenza A, Sutkowski EM, Seamon KB. Forskolin. A specific stimulator of adenyl cyclase or a diterpene with multiple sites of action. Trends Pharmacol Sci 1989;10442-447. 5. Wong S, Mok W, Phaneuf S, et al. Forskolin inhibits platelet-activating factor binding to platelet receptors independently of adenylyl cyclase activation. Eur J Pharmacol1993;245:55-61. 6. Wong S, Mok W, Phaneuf S. Forskolin inhibits platelet-activating factor binding to platelet receptors independently of adenylyl cyclase activation. Eur J Pharmacol1993;24555-61. 7. Lichey J, Friedrich T, Priesnitz M, et al. Effect of forskolin on methacholine-induced bronchoconstridion in extrinsic asthmatics. Lancet 1984;2167. 8. Bauer K, Dietersdorfer F, Sertl K, et al. Phannacodynamic effects of inhaled dry powder formulations of fenoterol and colforsin in asthma. Clin Pharmacol Ther 1993;5376-83. 9. Marone G, Columbo M, Triggiani M, et al. Forskolin inhibits the release of histamine from human basophils and mast cells. Agents Actions 1986;18:96-99. 10. Kaik G, Witte PU. Protective effect of forskolin in acetylcholine provocation in healthy probands. Comparison of 2 doses with fenoterol and placebo. Wien Med Wochenschr 1986;136637-641. 11. Dubey MP, Srimal RC, Nityand S, Dhawan BN. Pharmacological studies on coleonol, a hypotensive diterpene from Coleus forskohlii. J Ethnopharmacology 1981;31-13. 12. Lindner E, Dohadwalla AN, Bhattacharya BK. Positive inotropic and blood pressure lowering activity of a diterpene derivative isolated from Coleus forskohlii. Forskolin. Arzneimittelforschung 1978; 28284-289. 13.Kramer W, Thormann J, Kinder M, Schlepper M. Effects of forskolin on left ventricular function in dilated cardiomyopathy. Arzneimittelforschung 1987;37364-367. 14. Schlepper M, Thormann J, Mitrovic V. Cardiovascular effects of forskolin and phosphodiesterase-III inhibitors. Basic Res Cardiol 1989;84:197-212. 15. Wysham DG, Brotherton AF, Heistad DD. Effects of forskolin on cerebral blood flow. Implications for a role of adenylate cyclase. Stroke 1986;171299-1303. 16. Wysham DG, Brotherton AF, Heistad DD. Effects of forskolin on cerebral blood flow. Implications for a role of adenylate cyclase. Stroke 1986;171299-1303. 17. Potter DE, Burke JA, Temple JR. Forskolin suppresses sympathetic neuron function and causes ocular hypotension. Curr Eye Res 1985;487-96. 18. Caprioli J, Sears M. Forskolin lowers intraocular pressure in rabbits, monkeys, and man. Lancet 1983;1:958-960.

19. Meyer BH, Stulting AA, Muller FO. The effects of forskolin eye drops on intra-ocular pressure. S Afr Med J 1987;71:570-571. 20. Seto C, Eguchi S, Araie M, et al. Acute effects of topical forskolin on aqueous humor dynamics in man. Jpn J Ophthalmol 1986;30: 238-244. 21. Allen DO, Quesenberry JT.Quantitative differences in the cyclic AMP-lipolysis relationships for isoproterenol and forskolin. J Pharmacol Exp Ther 1988;244%52-858. 22. Allen DO, b e d B, Naseer K. Relationships between cyclic AMP levels and lipolysis in fat cells after isoproterenol and forskolin stimulation. J Pharmacol Exp Ther 1986;238:659-664. 23. Okuda H, Morimoto C, Tsujita T. Relationship between cyclic AMP production and lipolysis induced by forskolin in rat fat cells. J Lipid Res 1992;33225-231. 24. Bianco AC, Kieffer JD, Silva JE. Adenosine 3’,5’-monophosphate and thyroid hormone control of uncoupling protein messenger ribonucleic acid in freshly dispersed brown adipocytes. Endocrinology 1992;1302625-2633. 25. Hoffman BB, Chang H, Reaven GM. Stimulation and inhibition of lipolysis in isolated rat adipocytes. Evidence for age-related changes in responses to forskolin and PGEl. Horm Metab Res 1987;19:358-360. 26. Saunier B, Dib K, Delemer B, et al. Cyclic AMP regulation of Gs protein. Thyrotropin and forskolin increase the quantity of stimulatory guanine nucleotide-binding proteins in cultured thyroid follicles. J Biol Chem 1990;265:19942-19946. 27. Roger PP,Servais P,Dumont JE. Regulation of dog thyroid epithelial cell cycle by forskolin, an adenylate cyclase activator. Exp Cell Res 1987;172282-292. 28. Haye B, Aublin JL, Champion S, et al. Chronic and acute effects of forskolin on isolated thyroid cell metabolism. Mol Cell Endocrinol 1990;43:41-50. 29.Reymann A, Braun W, Woermann C. Proabsorptive properties of forskolin. Disposition of glycine, leucine and lysine in rat jejunum. Naunyn W e d e b e r g s Arch Pharmacol1986;334:110-115. 30.Larsson 0, Detsch T, Fredholm BB. VIP and forskolin enhance carbachol-induced K+ efflux from rat salivary gland fragments by a Ca2(+)-sensitive mechanism. Am J Physiol 1990;259: C904C910. 31. Wachtel H, Loschmann PA. Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressant activity. Interactions with rolipram. Psychopharmacol (Berl) 1986;90: 430-435. 32. Agarwal KC, Parks RE Jr. Forskolin: a potential antimetastatic agent. Int J Cancer 1983;32:801-804. 33. Schorlemmer HU. Forskolin for immune stimulation. Chem Abstr 1985;1021009. 34. KraU JE Femandey EI, Connolly-Filtingoff M. Human aging: effect on the activation of lymphocyte cyclic AMP-dependent protein kinase by forskolin. Proc Soc Exp Biol Med 1987;184:396-402. 35. Chang J, Chemey ML, Moyer JA. Effect of forskolinon prostaglandin synthesis by mouse resident peritoneal macrophages. Eur J Pharmacol1984;103:303-312.

c0mrm;ohora mukd (Mukul Myrrh Tree) Michael T. Murray. NI) Joseph E. I'izzorno Jr. XI) CHAPTER CONTENTS General Description 877

Additional Antiatherosclerotic Effects 879 Antiinflammatory Effects 879

Chemical Composition 877 Dosage 879 History and Folk Use 877

Toxicology 879 Pharmacology 878 Lipid Disorders 878

Commiphora mukul (family: Burseraceae) Common name: mukul myrrh tree

GENERAL DESCRIPTION Commiphoru mukul, a small, thorny tree that grows 4 to 6 feet tall, is native to Saudi Arabia and India. In its natural setting, the tree remains essentially free of foliage for most of the year. Its bark is ash colored and comes off in rough flakes, exposing the under-bark, which also peels off. When injured, the tree exudes a yellowish gum resin that has a balsamic odor. This oleoresin is referred to as "gum guggul" or "guggulu." This resin is used for medicinal purposes. When tapped during the winter, the average tree yields 1.5 to 2 lb of resin.'

CHEMICAL COMPOSITION Guggulu contains a mixture of diverse chemical constituents that can be separated into several fractions.' The first step in the fractionation process involves mixing guggulu with ethyl acetate to yield soluble and insoluble fractions (Figure &I-1).The insoluble fraction, containing the carbohydrate constituents, is regarded as toxic and is the major reason why extracts of the soluble portion are preferred to crude gum guggul for medical use. The insoluble portion has no demonstrable pharmacologic activity other than toxicity.' In contrast, the soluble portion possesses sigruficant cholesterol-lowering and antiinflammatory activity. The soluble portion can be further separated into base, acid,

and neutral fractions. The neutral portion possesses almost all of the cholesterol-loweringactivity, while the acid portion possesses the antiinflammatory components.' On further purification of the neutral portion, it was determined that the ketone fraction contains the most potent cholesterol-lowering components. The ketone fraction is composed of Czl or Cz7steroids, with the major components being Z- and E-guggulsterone (Figure 84-2). These compounds are considered the major active components of gum guggul and its extracts.' For medicinal purposes, a standardized extract known as gugdipid, which is standardized to contain a minimum of 50 mg of guggulsterones/g, is regarded as the most beneficial in terms of safety and effectiveness.'P2 In addition to guggulsterones, gugullpid contains various diterpenes, sterols, esters, and fatty alcohols. These accessory components appear to exert a synergistic effect.'tZ

HISTORY AND FOLK USE Guggulu is a highly valued botanical medicine in the Indian system of medicine, Ayurveda. It is included in formulas for various health conditions including rheumatoid arthritis and lipid disorders. The classic Ayurvedic medical text, the Sushru tusumhitu, describes in detail the usefulness of guggul in the treatment of obesity and other disorders of fat metabolism including "coating and obstruction of channels."',2 Inspired by thisdescription, researchers began examining, in well-designed scientific studies, the clinical effectiveness of gum guggul and its extracts in disorders of 877

Insoluble (55%) gum carbohydrates

D

Bases (.3%)

Soluble (45%') gugulipid (antiinflammatory and hypocholesterolemic activities) Guggulsterones

\ Diterpenes, lignans,

Figure 84-1 Chemical segregation of gum guggulu.

Guggul preparations appear most indicated in type IIb (increased LDL, VLDL, and triglycerides) and type IV (increased VLDL and triglycerides) hyperlipidemias. Preliminary human clinical trials using gugulipid found that cholesterol levels showed typical reductions of 14% to 27"/0 in total cholesterol levels in a 4- to 12-week period, while triglyceride levels dropped Figure 84-2 Guggulsterone. from 22 to 30Y0.'~-'~ However, a larger double-blind study did not show either of two doses of a standardized guggul extract (guggulipid, containing 2.5% guggulslipid metabolism-specifically, its ability to lower cholesterol and triglyceride levels and promote weight terones) in lowering LDL-C levels healthy adults with hyperli~idemia.'~ loss. This research resulted in the development of a natSubjects received either standard-dose guggulipid ural cholesterol-lowering substance that is safer and more effective than many cholesterol-lowering drugs (1000 mg), high-dose guggulipid (2000 mg), or matching placebo three times daily for 8 weeks. LDL-C levels including niacin. Gugulipid was granted approval in India for marketing as a lipid-lowering drug in 1986.'~~ decreased by 5% in the placebo group. Both standarddose guggulipid and high-dose guggulipid raised levels of LDL-C by 4%, respectively. There were no significant PHARMACOLOGY changes in levels of total cholesterol, HDL-C, triglycerides, Lipid Disorders or VLDL-C in response to treatment with guggulipid in Numerous studies in humans and animals have shown the intention-to-treat analysis. Although guggulipid was that gum guggul (both crude and purified alcohol generally well tolerated, six participants treated with guggulipid developed a hypersensitivity rash compared extract),37its petroleum ether extract (referred to asfmcwith none in the placebo group. These results call into tion A)?-" and gugulipid (standardized ethyl acetate question the clinical effectiveness of guggulipid despite extract)'*J3all exert effective lipid-lowering activity. All plausible mechanisms of action. lower both elevated cholesterol and triglyceride levels. The effect on cholesterol is particularly beneficial, as In vitro studies have shown that the primary mechaguggul lowers very low-density lipoprotein cholesterol nism of action involves guggulsterones acting as an (VLDL-C) and low-density lipoprotein cholesterol antagonist ligand for the farnesoid X receptor (FXR)(i.e., (LDL-C), while simultaneously elevating high-density guggulsterones promote the conversion of cholesterol to lipoprotein cholesterol (HDL-C),thus offering protection bile acids and increase the uptake of LDL-C from the against heart disease due to atherosclerosis. blood by the li~er).'~*"j-'~ Another possible action of

Cornrniphora rnukul (Mukul Myrrh Tree) guggulsterones in affecting lipid levels is their ability to stimulate thyroid fun~tion.'~

Additional Antiat herosclerotic Effects In addition to lowering lipid levels, gum guggul and its extracts including gugulipid have been shown to prevent the formation of atherosclerosis and aid in the regression of preexisting atherosclerotic plaques in animals. This implies that they may have similar effects in humans. Gum guggul and gugulipid have also been shown to prevent the heart from being damaged by freeradicals and to improve the metabolism of the heart?J4 Gum guggul and its extracts have a mild effect in inhibiting platelet aggregation and promoting fibrinolysis, implying that it may also prevent the development of a stroke or ernboli~m.~J~ This research indicates that guguhpid offers considerable benefit for preventing and treating atherosclerotic vascular disease, the leading cause of death in the United States.

Antiinflammatory Effects The guggulsterone fraction of gum guggul has been shown to exhibit sigruficant antiinflammatory action in experimental models of inflammation (e.g., raw paw edema and adjuvant arthritis method).20-22 Its activity in models of acute inflammation is comparable to approximately one fifth that of hydrocortisone and equal to phenylbutazone and ibuprofen.2O In models of chronic inflammation, it was shown to be more effective than hydrocortisone, phenylbutazone, and ibuprofen in reducing the severity of secondary lesions. The antiinflammatory action is thought to be due to inhibition of delayed hypersensitivity reactions.21,22 The clinical application of these effects may include osteoarthritis. In an open trial of 30 patients with osteoarthritis of the knee, 500 mg of the concentrated exact three times daily produced significant improvements in the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Total Score and subscales, visual analog scale (VAS), and 6-minute

1. Satyavati GV. Gugulipid. A promising hypolipidaemic agent from gum guggul (Cornrniphora wightii). Econ Med Plant Res 1991; 547-82. 2. Satyavati GV. Gum guggul (Cornrniphoru rnukul)-The success story of an ancient insight leading to a modem discovery. Indian J Med Res 1988;87327-335. 3. Satyavati GV, Dwarakanath C, Tripathi SN. Experimental studies of the hypocholesterolemic effect of Cornrniphoru rnukul. Indian J Med Res 1969371950-1962. 4. Khana DS, Agarwal OP, Gupta SK, Arora RB. A biochemical approach to anti-atherosclerotic action of Comrniphoru-rnukul.

walk-test. WOMAC subscales were used as outcome mea~ures.2~

DOSAGE Although the crude oleoresin (gum guggul), alcohol extract, and petroleum ether extract all exert lipid-lowering and antjinflammatory action, they are associated with side effects (e.g., skin rashes, diarrhea) at the doses required to produce a clinical effect. Interestingly, in classic Ayurvedic texts the purification of crude guggul in Triphala kashaya is recommended to eliminate these side effects2 Guguhpid, the standardized ethyl acetate extract of the gum guggul, has demonstrated not only greater clinical efficacy but also much greater patient tolerance than crude or purified gum guggul. The dosage of guguhpid is based on its guggulsterone content. The typical dosage, 25 mg of guggulsterone three times per day, is an effective treatment for elevated cholesterol levels, elevated triglyceride levels, or both. For a 2.5% guggulsterone content extract, this translates to an effective dose of 1000 mg three times/day. For comparison, the daily dosages of the other forms follow: Crude gum guggul-10 g Alcoholic extract-4.5 g Petroleum ether extract-1.5 g

TOXICOLOGY ~~~~

The side effects of crude gum guggul and alcoholic and petroleum ether extracts were discussed earlier. In clinical studies, gugulipid has not displayed any untoward side effects, nor has it adversely affected liver function, blood sugar control, kidney function, or hematologic parameters.11-13 Safety studies in rats, rabbits, and monkeys have demonstrated gugulipid to be n0nt0xic.l~It does not possess any embryotoxic, fetotoxic effects and is therefore considered safe to use in pregnancy. In mice the oral and intraperitoneal LDS0values are 1600 mg/kg.'

An Indian indigenous drug in Indian domestic pigs. Indian J Med

Res 1969;57900-906. 5. Nityand S, Kapoor NK. Hypocholesterolemic effect of Cornrniphoru mukul resin (guggal). Indian J Exp Biol1971;9:376-377. 6. Kuppurajan K, RajagopalanSS, Koteswara RT, SitaramanR. Effect of guggul (Cornrniphora rnukul-Engl.) on serum lipids in obese, hypercholesterolemic and hyperlipidemic cases. J Assoc Physicians India 1978;26367-371. 7. Baldwa VS, Bhasin V, Ranka PC, Mathur KM. Effects of Comrniphora rnukul (Guggul) in experimentally induced hyperlipidernia and atherosclerosis.J Assoc Physicians India 1981;29:13-17.

8. Malhotra SC, Ahuja Mh4S Comparative hypolipidaemic effectiveness of gum guggulu (Cornmiphoru mukill) fraction "A," ethylp-chlorophenoxyisobutyrate and Ciba-13437-Su. Indian J Med Res 1971;101621-1632. 9. Arora RB, Das D, Kapoor SC,Sharma RC. Effect of some fractions of Comrniphora rnukul on various serum lipid levels in hypercholesterolemic chicks and their effectiveness in myocardial infarction in rats. Indian J Exp Biol1973;11:166-168. 10. Malhotra SC, Ahuja MMS, Sundaram KR. Long term clinical studies on the hypolipidaemic effect of Commiphoru mukul (guggulu) and clofibrate. Ind J Med Res 1977;65390-395. 11. Vema SK, Bordia A. Effect of Cornrniphoru mukul (gum guggulu) in patients of hyperlipidemia with special reference to HDL-cholesterol. Indian J Med Res 1988;87356-360. 12. Agarwal RC, Singh SP, Saran RK, et al. Clinical trial of guguhpida new hypolipidemic agent of plant origin in primary hyperlipidemia. Ind J Med Res 1986;&4:626-634. 13. Nityanand S, Srivastava JS, Asthana OF'. Clinical trials with guguhpid. A new hypolipidaemic agent. J Assoc Physicians India 198937323-328. 14. [No authors listed]. Gugulipid. Drugs Fuhire 1988;13:618-619. 15.Szapary PO, Wolfe ML, Bloedon LT, et al. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial. JAMA 2003;290:765-772. 16. Singh V, Kaul S, Chander R, Kapoor NK. Stimulation of low density lipoprotein receptor activity in liver membrane of guggulsterone treated rats. Pharmacol Res 1990;22:37-44.

17. Cui J, Huang L, Zhao A, et al. Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump. J Biol Chem 2003;278 1021410220. 18. Urizar NL, Liverman AB, Dodds DT, et al. A natural product that lowers cholesterol as an antagonist ligand for FXR. Science 2002;2961703-1706. 19. Tripathi YB, Tripathi P, Malhorta OF,' Tripathi SN. Thyroid stirnulatory action of (Z)-guggulsterone: mechanism of action. Planta Med 1988;54:271-277. 20.Arora RB, Kapoor V, Gupta SK, Sharma RC. Isolation of a crystalline steroidal compound from Cornmiphora rnukul and its anti-inflammatory activity. Indian J Exp Biol1971;9:403-404. 21.Arora RB, Taneja V, Sharma RC, Gupta SK. Anti-inflammatory studies on a crystalline steroid isolated from Cornmiphoru mukul. Indian J Med Res 1972;60:929-931. 22. Sharma JN, Sharma JN. Comparison of the anti-inflammatory activity of Cornmiphoru mukul (an indigenous drug) with those of phenylbutazone and ibuprofen in experimental arthritis induced by mycobacterial adjuvant. Arzneimittelforschung 1977;271455-1457. 2 3 . S i g h BB, Mishra LC, Viijamury SP, et al. The effectiveness of Cornmiphoru mukul for osteoarthritis of the knee:an outcomes study. Altem Ther Health Med 2003;974-79.

Crataegus oxyacantha (Hawthorn) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S General Description 881 Chemical Composition 881

Clinical Applications 883 Atherosclerosis 883 Hypertension 883 Congestive Heart Failure 883

History and Folk Use 881 Dosage 884 Pharmacology 882 Synergism with Vitamin C 882 Collagen-Stabilizing Action 882 Cardiovascular Effects 882

Crutuegus oxyucuntha (family: Rosacea) Synonym: Crutuegus luevigitu Common names: hawthorn, may bush, whitethorn, haw

GENERAL DESCRIPTION Crutuegus oxyucunthu is a spiny tree or shrub that is native to Europe. It may reach a height of 30 feet but is often grown as a hedge plant. Its common name, hawthorn, is actually a corruption of ”hedgethorn,” as it was used in Germany to divide plots of land. Its botanical name, C. oxyucuntha, is from the Greek krutos, meaning hardness (of the wood); oxus, meaning sharp; and ukunthu, meaning a thorn. The fruit and blossoms are used medicinally.’ Other species of Crataegus (e.g., Crutuegus rnonogyna, Crutuegus pentugynu) contain similar constituents and likely have similar pharmacologic actions to C. oxyucunthu, so they may be suitable alternatives?J

Side Effects and Drug Interactions 884 Toxicology

884

but also of blackberries, cherries, blueberries, grapes, and many flowers as well. These compounds are highly concentrated in hawthorn berry and flower extracts. High-performance liquid chromatography and thin-layer chromatography (of crataegus extracts) have demonstrated that extracts of the flowers are particularly rich in flavonoids (e.g., quercetin, quercetin3-galactosidefvitexin, vitexin-4’-rhamnoside),procyanidins (Figure 85-2),and oligomers of procyanidins.5T6 In addition to flavonoids, crataegus extracts also contain7: Cardiotonic amjnes (e.g., phenylethylamine, o-methoxyphenylethylamine, tyramine, isobutylamine) Choline and acetylcholine Purine derivatives (e.g., adenosine, adenine, guanine, caffeic acid) Amygdalin Pectins Triterpene acids (ursolic, oleonolic, and crategolic acids)

CHEMICAL COMPOSITION Hawthorn leaves, berries, and blossoms contain many biologically active flavonoid compounds, particularly anthocyanidins and proanthocyanidins (polymers of anthocyanidins, also known as bifluvuns or procyanidins) (Figure 85-1).2-5These flavonoids are responsible for the red to blue colors not only of hawthorn berries,

HISTORY AND FOLK USE Crataegus flowers and berries have been used primarily as cardiac tonics and mild diuretics in organic and functional heart disorders. They are also used for their astringent qualities to relieve sore throat pain.’ 881

The prevention of free radical damage, due to potent antioxidant and free radical scavenging action2,4,810 The inhibition of enzymatic cleavage by enzymes secreted by leukocytes during infla~~tmation~ The prevention of the release and synthesis of compounds that promote inflammation, such as histamine, serine proteases, prostaglandins, and leukotrienes4

OH Flgure 851 Proanthocyanidin 82.

rhamnoside

These effects on collagen and their potent antioxidant activity make hawthorn extracts extremely useful in the treatment of a wide variety of inflammatory conditions. Hawthorn berries, like cherries," are particularly effective in the treatment of gout, as their flavonoid components reduce uric acid levels, as well as reduce tissue destruction.

Cardiovascular Effects The beneficial effects of crataegus in the treatment of cardiovascular conditions appear to be a result of the following pharmacologic actions:

HowoH

I

I OH

OH

0

Figure 85-2 Vitexin4-rhamnoside.

PHARMACOLOGY The pharmacology of crataegus centers on its flavonoid components.23 The proanthocyanidins in crataegus are largely responsible for its cardiovascular activities.

Synergism with Vitamin C As stated earlier, crataegus is particularly rich in anthocyanidins and proanthocyanidins. These flavonoids have strong "vitamin P" activity. Included in their effects are the abilities to increase intracellular vitamin C levels, stabilize vitamin C (by protecting it from oxidation), and decrease capillary permeability and frag~lity.~,~-~

Collagen-Stabilizing Action Crataegus's flavonoid components possess significant collagen-stabilizing action. Collagen is the most abundant protein of the body and is responsible for maintaining the integrity of ground substance, tendons, ligaments, and cartilage. Collagen is destroyed during inflammatory processes that occur in rheumatoid arthritis, periodontal disease, and other inflammatory conditions involving bones, joints, cartilage, and other connective tissue. Crataegus procyanidins affect collagen metabolism in many ways including the following: Reinforcement of the natural cross-linking of collagen that forms the collagen matrix of connective tissue (e.g., ground substance, cartilage, tendon)2A

Improvement of the blood supply to the heart by dilating the coronary v e ~ s e l s ~ * ~ J * - ~ ~ Improvement of the metabolic processes in the heart, which results in an increase in the force of contraction of the heart muscle and elimination of some types of rhythm d i ~ t u r b a n c e s ~ , ~ J ~ J ~ - ' ~ Inhibition of angiotensin-converting enzyme (ACE)20 Crataegus's ability to dilate coronary blood vessels has been repeatedly demonstrated in experimental studies. This effect appears to be due to relaxation of vascular smooth muscle by a combination of direct effects on both the vascular endothelium and smooth muscle. In addition, various flavonoid components in crataegus have been shown to inhibit vasoconstriction by various substances including hypophysin, histamine, and acetylcholine. In addition, procyanidins have been shown to inhibit ACE (discussed later).2*3"1 Improvement in cardiac metabolism has been demonstrated in humans and animalswho have received crataegus extracts2J The improvement is not only a result of increased blood and oxygen supply to the myocardium, but also a result of flavonoid-enzyme interactions. In particular, crataegus extracts and various flavonoid components in crataegus have been shown to inhibit cyclic AMP phosphodiesterase (CAMP-PDE).~ This results in increased levels of CAMPwithin the myocardium, leading to a positive inotropic effect (i.e., an increase in the force of contraction). This is particularly beneficial in cases of congestive heart failure (discussed later). The procyanidins of crataegus have demonstrated a specific inhibition of ACE similar to synthetic ACE inhibitors widely used in the treatment of hypertension.2I The proanthocyanidins that appear to have the highest activity are proanthocyanidins 8-5 3,3'-di-O-gallate and C-1 3,3',3''-tri-O-gallate. It is not surprising that

Crataegus oxyacantha (Hawthorn)

these proanthocyanidins are found in relatively high concentrations in hawthorn berries, flowers, and their extract^.^,^

CLINICAL APPLICATIONS The clinical use of crataegus revolves around its cardiovascular effects. Its use in atherosclerosis, hypertension, congestive heart failure, and arrhythmias is discussed as follows.

Atherosclerosis Crataegus preparations, although in a supplement form, should be thought of as a necessary food in the prevention and treatment of atherosclerosis. Increasing the intake of flavonoid compounds by taking crataegus extracts has numerous health-promoting effects including reducing cholesterol levels and decreasing the size of existing atherosclerotic plaques.= This effect is probably a result of collagen stabilization. A decrease in the integrity of the collagen matrix of the artery results in cholesterol deposition. Many researchers believe that if the collagen matrix of the artery remains strong, the atherosclerotic plaque will never develop. Crataegus flavonoids, by increasing the integrity of collagen structures, may offer sigruficant protection against atherosclerosis. In addition, feeding proanthocyanidin extracts to animals has resulted in reversal of atherosclerotic lesions, as well as decreased serum cholesterol levels. Flavonoids contained in hawthorn extracts appear to offer significant prevention, as well as potential reversing effects, in the treatment of atherosclerotic processes, which are still the major causes of death in the United States.

Hypertension Crataegus exerts a mild antihypertensive effect, which has been demonstrated in both experimental and clinical studies? Its action in lowering blood pressure is unique in that it produces a number of diverse pharmacological effects. Specifically, it dilates the coronary vessels, inhibits ACE, acts as an inotropic agent, and possesses mild diuretic activity. Its clinical effects in lowering blood pressure, however, are generally mild.*O Crataegus’s effects generally require prolonged administration, and in many instances it may take up to 2 weeks before adequate tissue concentrations are achieved. It should be kept in mind that as beta-blockers lower blood pressure by reducing cardiac output, crataegus administration to patients on these drugs may produce a mild hypertensive response.

Congestive Heart Failure Crataegus has a long history of use in the treatment of congestive heart failure, particularly in combination with

digitalis or other herbs containing cardiac glycosides such as Cereus grandiflorus, also known as Cactus grundifloris, and Convallaria mjalis. It potentiates the action of the cardiac glycosides,presumably via its ability to inhibit CAMP-PDEand to interact with calcium channels. Because of this enhancing effect, lower doses of cardiac glycosides can be used. In addition, magnesium has also been shown to augment digitalis action. For mild to moderate cases of CHF, crataegus extract used alone may be sufficient, but for moderate to severe CHF it should be used in combination with other cardiac glycosides. In early or mild stages of CHF, the effectiveness of crataegus has been repeatedly demonstrated in doubleblind ~ t u d i e s . 2 ” ~In~ ~a detailed metaanalysis, eight trials involving 632 patients with chronic heart failure (New York Heart Association [ M A ] classes I to 111) demonstrated that crataegus extract was more beneficial than placebo as shown by improvements in maximal workload, pressure-heart rate product, and symptoms such as dyspnea and fatigue. In an earlier double-blind study, 30 patients with congestive heart failure (NYHA stage 11) were assessed in a randomized, double-blind study.27Treatment consisted of a crataegus extract standardized to contain 15 mg procyanidin oligomers per 80 mg capsule. Treatment duration was 8 weeks, and the substance was administered at a dose of one capsule taken twice a day. The group receiving the crataegus extract showed a statistically significant advantage over placebo in terms of changes in heart function as determined by standard testing procedures. Systolic and diastolic blood pressures were also mildly reduced. Like all other studies with crataegus extracts, no adverse reactions occurred. In another study, 78 patients with CHF (NYHA stage 11) were given either 600 mg of extract standardized to contain 18.8%procyanidolic oligomers or placebo daily.28 The parameter used to measure effectiveness was the patient’s working capacity (W) on a bicycle ergometer. After 56 days of treatment, the crataegus p u p had a mean increase of 25 W compared with the placebo group’s increase of only 5 W. In addition, the crataegus group also experienced a mild, though sigruficant, reduction in systolic blood pressure (from 171 to 164 mmHg) and heart rate (from 115 to 110 beats/&). There was no change in blood pressure or heart rate in the placebo group. Crataegus provides a definite dose response. Individuals with more severe CHF require higher dosages in order to experience the most benefit. This comment is based on an important finding in a double-blind study of 209 patients with NYHA class III CHF. Although those receiving 900 mg of a crataegus extract standardized to contain 18.8%procyanidolic oligomers demonstrated improvement in all parameters tested, those receiving 1800 mg showed even better results.3o

Pharmacology of Natural Medicines

DOSAGE Clearly, the dosage depends on the type of preparation and source material. The amount of crataegus extract used in various clinical studies on CHF has been equivalent to 30 to 169 mg of epicatechin or 3.5 to 19.8 mg of flavonoids, usually administered in two or three doses. Standardized extracts are preferred, as flavonoid content in crude preparations can vary tremendously. The dosages listed for the various crataegus formulas are for use three times a day: Berries or flowers (dried): 3 to 5 g or as infusion Tincture (1:5): 4 to 5 ml (alcohol may elicit pressor response in some individuals) Fluid extract (1:l): 1to 2 ml Freeze-dried berries: 1 to 1.5 g Flower extract (standardized to contain 1.8%vitexin4'-rhamnoside or 18% procyanidolic oligomers): 200 to 600 mg

as unlikely. In another postmarketing surveillance study of 3664 patients who were treated with 900 mg of crataegus extract for 8 weeks, 48 patients (1.3%) reported adverse events including hot flushes, stomach complaints, palpitations, dizziness, dyspnea, headache, and epistaxis. In 19 patients, this resulted in discontinuationof the treatment.24 Hawthorn may potentiate or inhibit the actions of anticoagulants, antihypertensives, and cardiac glycosides. This concern is based primarily on theoretic grounds rather than clinical reports. Importantly, in a randomized, crossover trial with eight healthy volunteers, hawthorn did not signhcantly alter the pharmacokineticparameters for digoxin. This suggests that both hawthorn and digoxin may be coadministered safely?

TOXICOLOGY

Postmarketing surveillance studies report only mild and infrequent side effects with crataegus extract. In a study of 1011 patients, 14 adverse events (1.4%) occurred after the administration of 900 mg of hawthorn extract for 24 weeks. In two patients, a causal relation with crataegus was suspected but regarded by the treating doctors

Crataegus has been shown to have low t0xicity.3~In a human study in patients with CHF, dosages at levels 100 times the typical dosage did not produce any evidence of toxicity. Although some studies have shown that proanthocyanidins may be carcinogenic, more careful evaluation has indicated that the carcinogenicity was probably due to nitrosamines found in the extracts used.% Purified proanthocyanidins have been found to be nonmutagenic, according to the Salmonella mutagenicity assay system.

1. Grieve M. A modem herbal, vol 1. New York Dover Publications, 1971:385-386. 2. Chang Q,Zuo Z, Harrison F, Chow MS. Hawthorn. J Clin Pharmacol 2002;42:605-612 Sweet BV. Hawthorn: pharmacology and therapeutic 3. Rigelsky JM, uses. Am J Health Syst Pharm 2002;59:417-422. 4. Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000;52: 673-751. 5. Svedstrom U,Vuorela H, Kostiainen R, et al. Isolation and identification of oligomeric procyanidins h m Crataegus leaves and flowers. Phytochemistry 2002;60:821-825. 6. Ficarra P, Ficarra R, Tommasini A, et al. High-performance liquid chromatography of flavonoids in Cratnegrts oxyacanthn L. I. Reversedphase high-pressure liquid chromatography. Farmaco [Prat] 1983; 39:148-157. 7. Wagner H,Grevel J. [Cardiotonic drugs IV.Cardiotonic amines from Crataegus oxyacantha]. Planta Medica 1982;459&101. 8. Quettier-Deleu C, Voiselle G, Fruchart JC, et al. Hawthorn extracts inhibit LDL oxidation. Pharmazie 2003;58:577-581. 9. Bahorun T, Aumjaud E, Ramphul H, et al. Phenolic constituents and antioxidant capacities of Crntnegus rnonogyna (Hawthorn) callus extracts. Nahrung 2003;47191-198.

10. Nijveldt RJ, van Nood E, van Hoom DE, et al. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr 2001;74:418-425. 11. Blau LW. Cherry diet control for gout and arthritis. Tex Rep Biol Med 1950;8:309-311. 12.Schussler M, Hob1 J, Fricke U. Myocardial effects of flavonoids from Crataegus species. Arzneimittelforschung 1995;45:842-845. 13. Kim SH, Kang KW, Kim KW, Kim ND. Procyanidins in crataegus extract evoke endothelium-dependent vasorelaxation in rat aorta. Life Sci 2OOO;67121-131. 14. Mavers VWH, Hensel H. [Changes in local myocardial blood flow following oral administration of a Crataegus extract in non-narcotized dogs. Arzniemittelforschung 1974;24:783-785. 15. Roddewig C, Hensel H. Reaction of local myocardial blood flow in non-anesthetized dogs and anesthetized cats to oral and parented application of a Crataegus fraction (oligomere procyanidins). Arzneimittelforschung 1977;271407-1410. 16. Vierling W, Brand N, Gaedcke F, et al. Investigation of the pharmaceutical and pharmacological equivalence of different Hawthorn extracts. Phytomedicine 2003;10:8-16. 17. Schwinger RH, Pietsch M, Frank K, Brixius K. Crataegus special extract WS 1442 increases force of contraction in human myocardium CAMP-independently. J Cardiovasc Pharmacol 200035 700-707.

SIDE EFFECTS AND DRUG INTERACTIONS

Crataegus oxyacantha (Hawthorn 18. Muller A, Linke W, Klaus W. Crataegus extract blocks potassium currents in guinea pig ventricular cardiac myocytes. Planta Med 1999;65:335-339. 19. Schussler M, Holzl J, Fricke U. Myocardial effects of flavonoids from Crataegus species.Arzneimittelforschung 1995;45:842-845. 20. Walker AF, Marakis G, Morris AP,Robinson PA. Promising hypotensive effect of hawthorn extract: a randomized double-blind pilot study of mild, essential hypertension. Phytother Res 2002;1648-54. 21. Lacaille-Dubois, Franck U, Wagner H. Search for potential angiotensin converting enzyme (ACE)-inhibitors from plants. Phytomedicine 2001;8:47-52. 22.Petkov E, Nikolov N, Uzunov P. Inhibitory effect of some flavonoids and flavonoid mixtures on cyclic AMP phosphodiesterase activity of rat heart. Planta Medica 1981;43183-186. 23. Wegrowski J, Robert AM, Moczar M. The effect of prqanidolic oligomers on the composition of normal and hypercholesterolemic rabbit aortas. Biochem Pharm 19843334914497. 24.Pittler MH, Schmidt K, Emst E. Hawthorn extract for treating chronic heart failure: meta-analysis of randomized trials. Am J Med 2003;114665-674. 25.0Conolly VM, Jansen W, Bemhoft G, Bartsch G. [Treatment of decreasing cardiac performance. Therapy using standardized crataegus extract in advanced age]. Fortschr Med 1986;104:805-808. 26.0Conolly VM, Jansen W,Bemhoft G, Bartsch G. [Treatment of decreasing cardiac performance. Therapy using standardized crataegus extract in advanced age]. Fortschr Med 1986;104:805-808.

27.Leuchtgens H. [Crataegus Special Extract WS 1442 in NYHA 11 heart failure. A placebo controlled randomized double-blind study]. Fortschr Med 1993;111:352-354. 28.Schmidt U, Kuhn U, Ploch M, Hubner WD. Efficacy of the hawthorn (Crataegus) preparation LI 132 in 78 patients with chronic congestive heart failure defined as NYHA functional class II. Phytomedicine 1994;1:17-24. 29.Zapfe jun G. Clinical efficacy of crataegus extract WS 1442 in congestive heart failure NYHA class II. Phytomedicine 2001;8: 262-266. 30. Tauchert M. Efficacy and safety of crataegus extract WS 1442 in comparison with placebo in patients with chronic stable New York Heart Association class-III heart failure. Am Heart J 2002;143: 910-915. 31. Degenring FH, Suter A, Weber M, Saller R. A randomised double blind placebo controlled clinical trial of a standardised extract of fresh Crataegus bemes (Crataegisan) in the treatment of patients with congestive heart failure NYHA 11. Phytomedicine 2003;lO: 363-369. 32.Tankanow R, Tamer HR, Streetman DS, et al. Interaction study between digoxin and a preparation of hawthorn (Crataegus oxyacuiitha). J Clin Pharmacol2003;43437-642. 33. Schlegelmilch R, Heywood R. Toxicity of crataegus (hawthorn) extract (WS 1442).J Am Coll Toxicol 1994;13:103-111. 34. Yu CI, Swaminathan 8. Mutagenicity of proanthocyanidins. Food Chem Toxicol 1987;25135-139.

Croton lechleri (Dragon's Blood) Kathy Abascal, BS,JD, RH(AHG) Eric L. Ymell, ND, RH(AHG) CHAPTER CONTENTS General Description 887

Antiviral Effect 888 Cicatrizant Effect 889

Chemical Composition 887 History and Folk Use 887 Pharmacology 888 Analgesic Effect 888 Antidiarrheal Effect 888 Antimicrobial Effect 888 Antiproliferative or Cytotoxic Effect, or Both 888 Antiulcerogenic Effect 888

Croton spp. (family: Euphorbiaceae) Synonym: Many Crofon species are identified as dragon's blood, including Croton Zechleri, Croton sordidus, Croton urucurana, Croton draco. (Croton draconoides, Croton palantostigma), Croton xalapensis, and Croton eythrochikl-" Common names: dragon's blood, sangre de drago, sangre de grado, Lora sangre (sp.), sangre de perro (sp.)

GENERAL DESCRIPTION Dragon's blood comes from species of Euphorbiaceae trees that produce a red sap? The trees are native to Bolivia, Brazil, Columbia, Ecuador, and Peru and generally range in height from 3 to 25 meters, although they occasionally reach heights of 35 meters. The young trees have a sympodial branching pattern with three to five branches protruding off the trunk.The leaves are large, three veined, ellipsoid, and glandular at the base. The flowers are white and unisexual, and the fruit is three parted. The sap ranges in color from faint to deep red and occasionally a slight orange.

CHEMICAL COMPOSITION The sap, the part used medicinally, contains a single alkaloid, taspine.6The leaves contain additional alkaloids

Clinical Applications 889 Analgesic 889 Diarrhea 889 Herpes Simplex Viral Lesions 889 Dosage 889 Toxicology 889 Drug Interactions 889

(isoboldine, norisoboldine, manoflorine, thaliporphine, glaucine, and taspine). The sap consists primarily of proanthocyanidins (90%) but also contains crolechinol; crolechinic acid; korberin A and B; 3',4-0-dimethylcedrusin; simple phenols and diterpenes; phytosterols; and trace amounts of 1,3,5-trimethoxybenzene and 2,4,6-trimethoxyphenol?BThe air-dried, pulverized bark contains campesterol, beta-sitosterol, stigmasterol, acetyl aleuritolicacid, catechin, gallocatechin, and beta-sitosterol glucoside (Figure 86-1).9

HISTORY AND FOLK USE Dragon's blood is widely used by the indigenous peoples of the Amazon basin, and the Spaniards reported that it was widely used in the Amazon region in the 1600~.'~JThe sap is applied to the skin for abrasions, cuts, scratches, blisters, bites, and strings. It is taken internally in dilute form for gastrointestinal distress (e.g., gastritis, gastric ulcer, intestinal infections and inflammation, diarrhea). It is used as a gargle for sore throat; a vaginal antiseptic; a hemostatic after childbirth; a topical hemostatic for severe cuts and lacerations; and an analgesic applied directly to molar toothaches.12It is also taken internally for wound healing. The sap is used for various respiratory infections (tonsiltitis,pharyngitis, lung infections/pneumonia, influenza, and colds). 887

Antipro1iferative or Cytotoxic Effect, or Both Taspine, a dragon’s blood alkaloid, was cytotoxic in vitro against KB and V-79 cells in ~ i t r 0 . lDragon’s ~ blood induced apoptosis in human gastrointestinal cells in a dose-dependent manner, and cell proliferation decreased in all cells exposed to dragon’s blood for 48 hours.’* Overall, the effects were deemed similar to those observed with paclitaxel (Taxol).A sigruficant alteration of microtubular architecture was observed. Dragon’s blood significantly reduced cancer cell adhesion with more than 85% of cells remaining in suspension. When cells were transferred to another medium, they were unable to regain their ability to adhere.

Flgum 86-1 Taspine.

PHARMACOLOGY Analgesic Effect Dragon’s blood balm* had a sigruficant analgesic effect compared with a placebo balm in a series of animal e~periments.’~ Dragon’s blood completely prevented hyperalgesia induced by a protease and blocked hyperalgesia induced by prostaglandin. Dragon’s blood was analgesic even if the hyperalgesic stimuli were applied intradermally, suggesting that its active components can cross the skin. Dragon’s blood inhibited the responses of mesenteric arteries to calcitonin generelated peptide (a primary neurotransmitter of sensory afferent nerves) and attenuated the epithelial secretory response to capsaicin in guinea pigs, but not that of neurokinin-1 antagonist, suggesting a unique prejunctional and postjunctional effect on sensory afferent nerves. On the basis of pharmacologic results, researchers suggested that topical use of dragon’s blood may offer relief for conditions characterized by itching, pain, edema, redness, and discomfort.

Antidiarrheal Effect SP-303, a patented extractt from dragon’s blood sap, restored intestinal fluid accumulation to near-normal levels in mice administered cholera t0xin.14 Cholera toxin-induced diarrhea results from the irreversible activation of adenylate cyclase leading to elevated cyclic adenosine monophosphate (CAMP).SP-303 did not affect CAMPlevels, suggesting that it acts at a distal site.

Antimicrobial Effect Several phenolic compounds and diterpenes isolated from dragon’s blood demonstrated potent activity against Bacillus subtilis and Escherichia coli in ~ i t r 0 . IDragon’s ~ blood sap sigruficantlyinhibited growth of gram-positive and gram-negative organisms in vitro, including Proteus vulgaris, E. coli, and Staphylococcus aureus.16 ~

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‘1% Zangrado Bute Bite Balm. Rainforest Phytoceuticals,LLC, Delmar, NY. +SP-303 is available as a topical drug (Wend) and an internal drug (Pmvir),

Shaman Pharmaceuticals.South San Francisco, Calif.

Antiulcerogenic Effect Dragon’s blood administered at dilutions of 1:lOOO and 1:10,000in drinking water assisted the healing of ulcers in rats with acetic acid-induced gastric ulcers.19 These doses are equivalent to the doses used in traditional medicine for the treatment of gastric disorders. Dragon’s blood also reduced myeloperoxidase activity, the upregulation of proinflammatory genes tumor necrosis factoralpha, inducible nitric oxide synthase, interleukin-1-beta, and cyclooxygenase 2. Its healing of ulcers was comparable to that of a combination of penicillin and streptomycin and resulted in ulcers that were smaller, less inflamed, and possessing lower bacterial content. The authors note that the dragon’s blood in its natural, whole resin form is effective at lower doses than the patented extract of dragon’s blood (SP-303). They speculate that dragon’s blood’s polyphenolic fraction activates fibroblasts, resulting in improved wound healing, and note that the sap contains trace amounts of compounds that are 30 times more potent than penicillin.

Antiviral Effect Various compounds in dragon’s blood have shown antiviral activity against influenza, parainfluenza, herpes simplex viruses types I and II, and hepatitis A and B in vitro?O A patented extract of dragon’s blood sap (SP-303) showed antiviral activity against respiratory syncytial virus (RSV) and appeared to inhibit viral penetration of the host cell.2l SP-303 also showed antiviral activity against two strains of herpes simplex virus (HSV) type 1,as well as a strain of HSV type 2 at a dose comparable to that of acyclovir.” The compound significantly reduced HSV lesion formation in the mouse vaginal model (applied topically in a 5% to 10% preparation). At aerosol doses of 0.5 to 9.4 mg/kg/day, SP-303 significantly increased the survival of mice lethally infected with RSV? At aerosol doses of 1.3 to 9.8, it sigruficantly reduced lung titers of RSV in infected rats. SP-303 administered intraperitoneally also significantly reduced

Croton lechleri (Dragon’s Blood) pulmonary RSV titers in infected rats with a minimum efficacious dose of 3 mg/kg.” SP-303 administered once daily for 8 days beginning before or after influenza A infection in mice significantly reduced lung consolidationbut was lethally toxic at the dose of 30 mg/kg/day. The drug administered as an aerosol (2.5,5,10 mg/ml) for 1hour twice daily also reduced lung consolidation in animals. However, when administered before virus exposure, SP-303 treatment resulted in sigruficant increases in mean day to death but did not inhibit lung virus titer.%

Cicatrizant Effect Dragon’s blood forms a barrier by coprecipitating with proteinsand other matrix elements and, in the process, fosters accelerated wound healing with reduced pain, inflammation, and scarringF6 Taspine showed a dose-related cicatrizant effect when administered in vivo to mice.27

CLINICAL APPLICATIONS Analgesic Dragon’s blood sap offered rapid symptomaticrelief in a placebo-controlled study of its effect on insect Ten Terminex workers (who often suffer insect bites in their work) applied either dragon’s blood balm* or placebo balm to bites and recorded the results over a 3-month period. When workers suffered multiple simdtaneous bites, they used both balms on different bites and compared the results. Most of the treated bites were caused by fire ants that elicit initial pain, followed by intense itching that can persist for weeks.

Diarrhea SP-303, a patented compound extracted from dragon’s blood sap, shortened by 21%the duration of diarrhea in a double-blind, randomized, placebo-controlled study of 184 patients suffering diarrhea after traveling to Jamaica and Mexic0.2~Patients were treated four times a day for 2 days with 125 mg, 250 mg, or 500 mg doses or placebo. The drug was most effective at the 125- and 250-mg doses and was well tolerated. In another doubleblind, randomized, placebo-controlled study, SP-303 significantly reduced stool weight and abnormal stool frequency in HIV-positive patients with diarrhea.30Positive results were seen by day 4 in the 26 members of the active group treated with 500 mg orally of SP-303every 6 hours compared with the 25 patients in the placebo group.

Herpes Simplex Viral Lesions Virend (a topical formulation of SP-303) showed a trend toward decreased lesion pain in a double-blind,

‘1% Zangrado Bute Bite Balm, Rainforest Phytoceuticals,LLC. Delmar, NY.

placebo-controlledstudy of 45 patients positive for HIVantibody with active-phase, culture-positive genital or perineal herpes simplex viral lesions, or both.3I A statistical analysis showed Virend to be more active in patients with overall smaller lesion areas. Two patients experienced pain and burning after applying Virend, and one withdrew from the study for this reason. In another open-label study, nine AIDS patients with herpes simplex virus unresponsive to acyclovir were treated with SP-303.32The drug showed a transient positive effect but failed to completely heal or cause cessation of virus shedding. Several patients complained that SP-303 caused pain or burning on application.

DOSAGE In traditional medicine, the internal dose is 3 to 20 drops mixed in a beverage, 1 to 3 times daily for up to 3 ~ e e k s . ~The N pure sap is applied topically as needed. Doses of 125 and 250 mg of SP-303, administered every 6 hours, were more effective at reducing the duration of traveler’s diarrhea than the 500 mg dose.35

TOXlCOLOGY Dragon’s blood, used topically or at low internal doses, is considered nontoxicx Mice treated with dragon’s blood or taspine hydrochloride for 17 months evidenced a lack of carcinogenic or tumor-promoting effe~ts.3~ Taspine was nontoxic to human foreskin fibroblasts at concentrationsbelow 150 ng.= The alkaloid had no effect in vitro on cell proliferation and did not have a carcinogenic or tumor-promoting effect in vitro. The compound 3’,4-0-dimethycedrusin, isolated from dragon’s blood, did not stimulate cell proliferation but instead inhibited thymidine incorporation while protecting cells against degradation in a starvation medium.39 In another in vitro experiment, dragon’s blood had a negligible effect on proliferation of endothelial cells and was not cytotoxic.40SP-303, a patented dragon’s blood extract, was toxic to mice at 16 mg/kg/day, as evidenced by weight loss and a decrease in survival time compared with controls.41A similar weight loss occurred in rats at a dose of 18.7 mg/kg. SP-303 injected intraperitoneally caused sigruficant weight loss and death in rats at doses of 30 mg/kg/day. However, no toxicity was observed following oral administration of up to 270 mg SP-303 daily.“

LDesmarchelier C, Schaus FW. Sixty medicinal plants from the Peruvian Amazon, ecology, ethnomedicine and bioactivity. Lima, Peru: Grafica Bellido, 2000:12&129. 2. BorgesJR, King SR,Hughes K, et al. Conservationof b i d t u r a l diversity and benefit sharing mechanisms in the Amazon: C m t a leddm’,a traditional indigenous resource. presented at the INPI/EC meeting ‘‘Role of intellectd property protection in the field of biodiversity and traditional knowledge,” Manaus, Brazil, September 9-11,2001. 3. Miller MJ, Vergnolle N, McKnight W, et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest Dennatol2001;117:725-730. 4. Pieters L, de Bruyne T, Claeys M, et al. Isolation of a dihydrobenzofuran lignan from South American dragon’s blood (Croton spp.) as an inhibitor of cell proliferation. J Nat Prod 1993;56:899-906. 5.Desmarchelier C, Schaus FW. Sixty medicinal plants from the Peruvian Amazon, ecology, ethnomedicine and bioactivity. Lima, Peru: Grafica Bellido, 2000:126-129. 6.Milanowski DJ, Winter RE, Elvin-Lewis MP, Lewis WH. Geographic distribution of three alkaloid chemotypes of Croton lechleri. J Nat Prod 2002;65:814819. 7. Cai Y, Evans FJ,Roberts MF, et al. Polyphenolic compounds from Croton Zechlm’. Phytochemistry 1991;30:2033-2040. 8. Miller MJ, MacNaughton WK, Zhang XJ, et al. Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol 2000;279: G192G200. 9.Lopes Pereira Peres MT, Delle Monache F, Pizzolatti MG, et al. Analgesic compounds of Croton urucurunu Baillon. Pharmco-chemical criteria used in their isolation. Phytother Res 1998;12209-211. 10. Miller MJ, MacNaughton WK, Zhang XJ, et al. Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol2OOO;279:G192-G200. 11. Milanowski DJ, Winter RE, Elvin-Lewis MP, Lewis WH. Geographic distribution of three alkaloid chemotypes of Croton lechleri. J Nat Prod 2002;65:814819. 12. BorgesJR,King SR, Hughes K, et al. Conservation of b i d t u r a l diversity and benefit sharing mechanisms in the Amazon: Croton lechlm’,a traditional indigenous resource.Prepared for the INPI/EC meeting “Role of intellectual property protection in the field of biodiversity and traditional knowledge,” Manaus,Brazil, September 9-11,2001. 13.Miller MJ, Vergnolle N, McKnight W, et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest Dennatol2001;117725-730. 14.Orozco-Topete R, Sierra-Madero J, et al. Safety and efficacy of V i i n d for topical treatment of genital and anal herpes simplex lesions in patients with AIDS.Antiviral Res 199735:91-103. 15.Chen ZP,Cai Y, Phillipson JD.Studies on the anti-turnour, antibacterial, and wound-healing properties of dragon’s blood. Planta Med 1994;60:541-545. 16. Carpenter MR, Goodman-Snitkoff GW, et al. Antibacterial effects of sangre de grado on gram-positive and gram-negative bacteria. Abstr Gen Meet Am Soc Microbiol2001;101:38. 17.Itokawa H, Ichihara Y, Mochizuki M, et al. A cytotoxic substance from sangre de grado. Chem Pharm Bull (Tokyo) 199139:1041-1042. 18. Sandoval M,Okuhama NN, Clark M, et al. Sangre de grado Croton pulunostigma induces apoptosis in human gastrointestinal cancer cells. J Ethnopharmacol2002;80.121-129. 19. Miller MJ, MacNaughton WK, Zhang XJ, et al. Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol2000;279:G192-G200. 20. Williams JE. Review of antiviral and immunomodulating properties of plants of the Peruvian rainforest with a particular emphasis on una de gato and sangre de grado. Alt Med Rev 2001;6567-579.

21. Bamard DL, Huffman JH, Meyerson LR, Sidwell RW. Mode of inhibition of respiratory syncytial virus by a plant flavonoid, SP-303. Chemotherapy 1993;33212-217. 22. Bamard DL, Smee DF, Huffman JH, et aI. Antiherpesvirus activity and mode of action of SP-303, a novel plant flavonoid. Chemotherapy 1993;39:203-211. 23. Gilbert BE, Wyde PR, Wilson SZ, Meyerson LR. SP-303 small-particle aerosol treatment of influenza A virus infection in mice and respiratory syncytial virus in cotton rats. Antiviral Res 1993;21: 37-45. 24. Wyde PR, Ambrose MW,Meyerson LR, Gilbert BE. The antiviral activity of SP-303, a natural polyphenolic polymer, against respiratory syncytial and parainfluenza type 3 viruses in cotton rats. Antiviral Res 1993;20:145-154. 25. Sidwell RW, Huffman JH, Moscon BJ, Warren Rl? Influenza virusinhibitory effects of intrapentoneally and aerosol-administered SP-303, a plant flavonoid. Chemotherapy 1994;4042-50. 26. Miller MJ, Vergnolle N, McKnight W, et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest Dermatol2001;117725-730. 27. Vaisberg AJ, Milla M, Planas MC, et al. Taspine is the cicatrizant principle in sangre de grado extracted from Croton lechleri. Planta Med 198955140-143. 28. Miller MJ, Vergnolle N, McKnight W, et al. Inhibition of neurogenic inflammation by the Amazonian herbal medicine sangre de grado. J Invest Dermatol2001;117725-730. 29. DiCesare D, DuPont HL, Mathewson JJ, et al. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol2002;972585-2588. 30. Holodniy M, Koch J, Mistral M, et al.A double blind, randomized, placebo-controlled phase 11 study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS. Am J Gastroenterol 1999;94: 3267-3273. 31. Orozco-Topete R, Sierra-Madero J, Cano-Dominguez C, et al. Safety and efficacy of Virend for topical treatment of genital and anal herpes simplex lesions in patients with AIDS. Antiviral Res 1997;3591-103. 32. Safrin S, McKinley G, McKeough M, et al. Treatment of acyclovirunresponsive cutaneous herpes simplex virus infection with topically applied SP-303. Antiviral Res 1994;25185-192. 33. Miller MJ, MacNaughton WK, Zhang XJ, et al. Treatment of gastric ulcers and diarrhea with the Amazonian herbal medicine sangre de grado. Am J Physiol Gastrointest Liver Physiol 2000;279: G192G200. 34.Borges JR, King SR, Hughes K, et al. Conservation of biocultural diversity and benefit sharing mechanisms in the Amazon: Crotun lechlm‘, a traditional indigenous resource. Prepared for the INPI/EC meeting “Role of intellectual property protection in the field of biodiversity and traditional knowledge,” Manaus,Brazil, September 9-11,2001. 35. DiCesare D, W o n t HL, Mathewson JJ, et al. A double blind, randomized, placebo-controlled study of SP-303 (Provir) in the symptomatic treatment of acute diarrhea among travelers to Jamaica and Mexico. Am J Gastroenterol2002;97:2585-2588. 36. Duke JA. Handbook of medicinal herbs, ed 2. Boca Raton, Fla: CRC Press, 2002256. 37. Villegas LF, Frenandez ID, Maldonado H, et al. Evaluation of the wound-healing activity of selected traditional medicinal plants from Peru. J Ethnopharmacol1997;55193-200. 38.Vaisberg AJ, Milla M, Planas MC, et al. Taspine is the cicatrizant principle in sangre de grado extracted from Croton lechleri. Planta Med 1989;55:140-143.

Croton lechleri (Dragon’s Blood) 39. Sandoval M, Okuhama NN, Clark M, et al. S a n p de grado Croton palanosfigma induces apoptosis in human gastrointestinal cancer cells. J Ethnophamacol2002;80:121-129. 40.Chen ZP, Cai Y, Phillipson JD.Studies on the anti-hunour, antibacterial, and wound-healing properties of dragon’s blood. Planta Med 1994;60:541-545. 41.Gilbert BE, Wyde PR, Wilson SZ, Meyerson LR. SP-303 smallparticle aerosol treatment of influenza A virus infection in mice and

respiratory syncytid virus in cotton rats. Antiviral Res 1993;21: 37-45. 42. Wyde PR, Ambrose W ,Meyerson LR, Gilbert BE. The antiviral activity of SP-303, a natural polyphenolic polymer, against respiratory syncytial and parainfluenza type 3 viruses in cotton rats. Antiviral R ~ s199330145-154.

Curcuma longa (Turmeric) Michael T. Murray, ND Peter B. Bongiorno, ND, Dip1 Ac CHAPTER CONTENTS General Description 893

Neuroprotective Effects 896 Antimicrobial Effects 896

Chemical Composition 893 History and Folk Use 893 Pharmacology 893 Antioxidant Effects 894 Anticarcinogenic Effects 894 Antiinflammatory Effects 894 Cardiovascular Effects 895 Hepatic Effects 895 Gastrointestinal Effects 895

Curcuma longu (family: Zingiberaceae) Common names: turmeric, curcuma, Indian saffron

GENERAL DESCRIPTION Curcuma longu, a perennial herb of the ginger family, is cultivated extensively in India, China, Indonesia, and other tropical countries. It has a thick rhizome from which arise large, oblong, and long-petioled leaves. The rhizome is the part used; it is usually cured (boiled, cleaned, and sun dried) and polished.'

CHEMICAL COMPOSITION Turmeric contains the following*,2: 4% to 14% of an orange-yellow volatile oil that is composed mainly of turmerone, atlantone, and zingiberone 0.3% to 5.4% curcumin Sugars (28% glucose, 12% fructose, 1%arabinose) Resins Protein Vitamins Minerals

Figure 87-1 shows the chemical structure of turmeric.

Clinical Applications 896 Cancer Prevention and Treatment Adjunct Inflammation 896

896

Toxicology 897 Drug Interactions 897 Dosage 897

HISTORY AND FOLK USE Turmeric is the major ingredient of curry powder and is also used in prepared mustard. It is extensively used in foods for both its color and flavor. In addition, turmeric is used in both the Chinese and Indian (Ayurvedic) systems of medicine as an antiinflammatoryagent and in the treatment of numerous conditions including flatulence, jaundice, menstrual difficulties, bloody urine, hemorrhage, toothache, bruises, chest pain, and colic.' Turmeric poultices are often applied locally to relieve inflammation and pain.

PHARMACOLOGY Turmeric and its derivatives have a great deal of pharmacologic activity? Although a number of components have demonstrated activity, the volatile oil components and curcumin are believed to be the most active components. Turmeric has been described as follows: An effective antioxidant Anticarcinogenic Antiinflammatory A cardiovascular protectant Hepatoprotective 893

Pharmacology of Natural Medicines The protective effects of turmeric and its derivatives are only partially explained by its direct antioxidant and fwe radical-scavenging effects. It also inhibits nitrosamine formation, enhances the body’s natural antioxidant system, increases the levels of glutathione and other nonprotein sulfhydryls, and acts directly on several enzymes and gene loci. A gastrointestinal carminative and protectant Neuroprotective An antimicrobial agent

Antioxidant Effects Turmeric extracts exert significant antioxidant activity. Although both water- and fatsoluble extracts have been shown to be effective antioxidants in various in vitro and in vivo models, CurCulTLinis the most potent component.% The antioxidant activity of curcumin is comparable to standard antioxidants like vitamins C and E and butylated hydmxyanisole (BHA) and butylated hydroxytoluene (Bm.33 Because of its bright yellow color and antioxidant properties against lipid peroxidation, m u m i n is used in butter, margarine, cheese, and other food products. For active oxygen species, curcumin is slightly weaker than vitamin C but stronger than vitamin E and superoxide dismutase. Against hydroxyl radicals, curcumin offers greater effectiveness than these ita am ins.^,^,^ Not all of the antioxidant properties of turmeric are due to curcumin alone, as the aqueous extract of turmeric is more effective against superoxide than curcumin and is much stronger in inhibiting oxidative damage to DNA.5,6 The antioxidant activities of curcumin may in part explain the anticarcinogenic and cardioprotective capacity of this spice (see later). In vitro and in vivo studies have also shown this antioxidant action to be neuroprotective as well.8

Anticarcinogenic Effects The antineoplasticeffects of turmeric and curcumin have been demonstrated at all steps of carcinogenesis: initiation, promotion, and progression. In addition to inhibiting the development of cancer, several studies suggest that curcumin can also promote cancer regression. Turmeric and curcumin are nonmutagenic and have been shown to suppress the mutagenicity of several common mutagens (e.g., cigarette smoke condensates, benzopyrene, 7,12-dimethylbez[a]anthracene), as do chili and capsaicin?-” Turmeric and curcumin compounds have been found to induce apoptosis in lung and colon tumor cell l i n e ~ . ’ ~Turmeric J~ and curcumin have also demonstrated impressive anticancer effects against a number of chemical carcinogens on a wide range of cell types in both in vitro and in vivo Curcumin has demonstrated an impressive ability to reduce the levels of urinary mutagens.22D

Antiinflammatory Effects The volatile oil fraction of C. longu has been demonstrated to possess antiinflammatory activity in various experimental models (e.g., Freund’s adjuvant-induced arthritis,formaldehyde- and carrageenan-induced paw edema, and cotton pellet and granuloma pouch tests).”z Its effects in these studies were comparable to cortisone and phenylbutazone. Even more potent in acute inflammation is curcumin.2628Curcumin is as effective as cortisone or phenylbutazone in models of acute inflammation but only half as effective in chronic models. However, while phenylbutazone and cortisone are associated with significant toxicity, curcumin displays virtually no toxicity (see later discussion on toxicology). The rank in order of potency of curcumin analogs, cortisone, and phenylbutazone in carrageenan-induced paw edema is as follow^^^,^^: sodium curcuminate > tetrahydrocurcumin > curcumin > cortisone > phenylbutazone > triethylcurcumin Sodium curcuminate can be produced by mixing turmeric with slaked lime. This mixture, applied as a poultice, is an ancient household remedy for sprains, muscular pain, and inflamed Curcumin’s counterirritant effect may also be a major factor in its topical antiinflammatory acti0n.2~ Capsaicin, a similar pungent principle from Capsicum frutescens (cayenne pepper), has been shown to be quite effectiveas a topical pain reliever in cases of postherpetic neuralgia and arthritis. Both capsaicin and curcumin deplete nerve endings of the neurotransmitter of pain, substance P.29 Used orally, curcumin exhibits many direct antiinflammatory effects Inhibition of leukotiene formation Inhibition of platelet aggregation Promotion of fibrinolysis Inhibition of neutrophil response to various stimuli involved in the inflammatory process Stabilization of lysosomal membranes In addition to its direct antiinflammatory effects, curcumin also appears to exert some indirect effects. In models of chronic inflammation, curcumin is much less active in adrenalectomized animals.Possible mechanisms

of action include the following: with a curcuma extract (turmeric) on abnormally high plasma fibrinogen levels (values in mg/dl before and after a 15-day treatment)

Stimulation of the release of adrenal corticosteroids ”Sensitizing” or priming cortisol receptor sites, thereby potentiating cortisol action Increasing the half-life of endogenous cortisol through alteration of hepatic degradation Subiect number

Sex

Aae (vr) Before

After

Cardiovascular Effects

1

M

The effects of turmeric and curcumin on the cardiovascular system include the lowering of cholesterol level^^"^ and the inhibition of platelet aggregation.%J7 This is of great sigruficance in preventing atherosclerosis and its complications. In one small study, 10 healthy volunteers received 500 mg of curcumidday for 7 days.35A significant decrease in the level of serum lipid peroxides of 33%, increase in high-density lipoprotein cholesterol of 29%, and a decrease in total sem cholesterol of 11.63%was observed. Given the side-effect profile of standard cholesterol-lowering medications, more studies on this effect of curcumin are necessary. As an acute phase reactant, the protein fibrinogen circulates in the blood and provides the material from which insoluble fibrin clots can form during coagulation. It has been shown that high levels of plasma fibrinogen concentration can predict future coronary heart disease in men and women.%In a preliminary study of 30 apparently healthy volunteers, baseline levels of fibrinogen were recorded, and 8 subjects were found to have high plasma fibrinogen (above 350 11g/m1).3~These subjects were given a hydroalcoholic extract of C. longu containing 20 mg of curcumin for 15 days. Impressively, curcuma administration decreased the fibrinogen levels to values in the 240 to 290 mg/dl range (Table 87-1). In other studies, adding as little as 0.1% curcumin to a high-cholesterol rat diet decreases cholesterol levels to one half of those found in rats fed cholesterol but no c u r ~ u m i n .This ~ indicates that even at small doses, curcumin may be effective. Curcumin’s cholesterol-lowering actions include interfering with intestinal cholesterol uptake; increasing the conversion of cholesterol into bile acids by increasing the activity of hepatic cholesterol-7-alpha-hydroxylase, the rate-limiting enzyme of bile acid synthesis; and increasing the excretion of bile acids via its choleretic

2

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31

476

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Turmeric’s and curcumin’s action on inhibiting platelet aggregation appears mediated by inhibiting the formation of thromboxanes (a promoter of aggregation) while simultaneously increasing prostacyclin (aninhibitor of aggregati~n).~J’

Hepatic Effects Curcumin has exhibited hepatoprotection similar to that of glycyrrhizin and silymarin (see Chapters 99 and

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125 for further discussion) against carbon tetrachloride and galactosamine-induced liver injury.2~~~ This protection is largely a result of its potent antioxidant activity. Similar results are seen with Javanese turmeric (Curcurnu xunthorrhiziu). Mice given intraperitoneal injections of the hepatoxic drugs carbon tetrachloride (32 mg/kg) and acetaminophen (600 mg/kg) experienced significantly decreased liver damage, as measured by serum glutamate oxaloacetate (SGOT)and serum glutamate pyrur m (SGPT) when treated with 100 mg/kg vate t of turmeric.“ The antioxidant and hepatoprotective effects alone would support turmeric’s historical use in liver disorders; however, turmeric and curcumin also exert antiinflammatory and choleretic effects. The increases of SGOT and SGPT commonly seen in experimental models of inflammation have been prevented by curcumin.26 Curcumin is an active choleretic, increasing bile acid output by more than 100Y0.~ In addition to increasing biliary excretion of bile salts, cholesterol, and bilirubin, curcumin also increases the solubility of the bile.4O This suggests a benefit in the prevention and treatment of cholelithiasis.

Gastrointestinal Effects Turmeric and its components exert a number of beneficial effects on the gastrointestinal system. Turmeric’s long use as a carminative has significant research support.2 Specifically, curcumin has been shown to inhibit

Pharmacology of Natural Medicines gas formation by Clostridium petfringens and in rats given diets rich in flatulence-producing foods. In addition, sodium curcuminate has been shown to inhibit intestinal spasm, and another compound from turmeric, p-tolymethylcarbinol, has been shown to increase the secretion of secretin, gastrin, bicarbonate, and pancreatic enzymes? As a component of curries and spicy foods, there is some concern that turmeric may be irritating to the stomach. However, several studies have shown turmeric to be beneficial to gastric integrity. Turmeric and curcumin have been shown to increase the mucin content of the stomach and exert gastroprotective effects against ulcer formation induced by stress, alcohol, indomethacin, pyloric ligation, and re~erpine.2,~~ However, at high doses, curcumin or turmeric may be ulcerogenic (see later discussion on toxicology).

Neuroprotective Effects A number of animal studies have explored the effect of curcumin on nervous tissue pathology. For example, studies have suggested a neuroprotective role of curcumin in stroke models! Curcumin has been shown to reduce plaque burden in models of Alzheimer’s disease.44 Curcumin has also been shown to decrease naphthalene and 4hydroxy-2-nonenal-induced cataract formation on the lens by decreasing the rate of apoptosis and subsequent opacification resistance of the The authors postulate that induction of the glutathione Stransferase, which acts to decrease lipid peroxidation, was probably responsible for the cataractogenesisinhibiting effects.

Antimicrobial Effects Alcohol extracts and the essential oil of C. longu were shown in one study to inhibit the growth of most organi s m occurring in cholecystitis (i.e., Sarcinu, G u m u , Corynebuctm’um, and Clostridium)? Other microorganisms that are inhibited include Stuphylococcus, Streptococcus, Bacillus, Entumoebu histolyticu, and several pathogenic f ~ n g i .The ~,~ concentrations ~ used in these studies were relatively high 0.5 to 5 mg/ml of the alcohol extract and essential oil, and 5 to 100 mg/ml of curcumin.

CLINICAL APPLICATIONS Turmeric and curcumin have several clinical applications. Most notable are the following: Cancer prevention and treatment adjunct Inflammation Atherosclerosis Liver disorders Cholelithiasis Irritable bowel syndrome

Cancer Prevention and Treatment Adjunct As discussed earlier, turmeric and cucurninhave demonstrated sigruficant protective effects against cancer development in experimental studies in animals. Human research is showing similar results. In one human study, 16 chronic smokers were given 1.5 g of turmeric daily while a group of 6 nonsmokers served as a control g r o u ~At. ~the end of the 30-day trial, the smokers receiving the turmeric demonstrated significant reduction in the level of mutagens excreted in the urine. These results are quite significant, as the level of urinary mutagens is thought to correlate with the systemic load of carcinogens and the efficacy of detoxification mechanisms. Due to widespread exposure to smoke, aromatic hydrocarbons, and other environmental carcinogens, the frequent use of turmeric as a spice appears warranted. Turmeric extracts and curcumin have demonstrated direct antitumor results in a number of experimental models of skin, epithelial, stomach, lung, and liver cancers.12r18APJ This effect has also been substantiated in a human Sixty-twopatients with either ulcerating oral or cutaneous squamous cell carcinomas who had failed to respond to the standard treatments of surgery, radiation, and chemotherapy were given either an ethanol extract of turmeric (for oral cancers) or an ointin Vaseline. The ointment containing 0.5% curcment or extract was applied topically three times daily. At the end of the 18-month study, the treatment was found to have been effective in reducing the smell of the lesion (90%), itching, exudate (70%), pain (so%), and size of the lesion (10%).Although these are not spectacular results, it must be pointed out that this patient population had failed to respond to standard medical treatment. Although more human studies on the use of turmeric and curcumin in cancer are necessary, ample evidence supports their use in cancer prevention and as adjuncts in an overall cancer treatment plan.

Inflammation C. longu has been used in Ayurvedic medicine, both locally and internally, in the treatment of sprains and inflammation. This use seems to be substantiated not only by the experimental studies described earlier, but also by clinical inve~tigations.~~3 In one double-blind crossover clinical trial in patients with rheumatoid arthritis, curcumin (1200 mg /day) was compared with phenylbutazone (300 mg/day). The improvements in the duration of morning stiffness, walking time, and joint swelling were comparablein both groups.53However, although phenylbutazone is associated with sigruficant adverse effects, curcumin has not been shown to produce any side effects at the recommended dosage level.

Curcurna longa (Turmeric)

In another study, which used the postoperative inflammation model for evaluating nonsteroidal antiinflammatory drugs (NSAIDs), curcuinin was again shown to exert comparable antiinflammatory action to phenylbutazone.59Although c urhas an antiidlammatory effect similar to phenylbutazone and various NSAIDs, it does not possess dired analgesic action. Most likely due to its antiidammatory effects, topical application appears to be of benefit in wound The results of these studies indicate that turmeric or curcumin may provide benefit in the treatment of inflammation. Furthermore, the safety and excellent tolerability of curcumin compared with standard drug treatment is a major advantage.

DRUG INTERACTIONS No drug interactionshave been reported. Some theoretic concern has been raised that curcumin might increase the risk of bleeding of anticoagulant drugs due to its ability to decrease platelet aggregation.62

DOSAGE

Toxicity has not been reported at standard dosage levels. The oral LDNlevels for turmeric, its alcohol extracts, and curcumin have not been determined, as 2.5 g/kg fed to mice, rats, guinea pigs, and monkeys and 3 g/kg sodium curcuminate fed to rats resulted in neither mortality nor chromosomal aberrations in teratology tests?%% At high doses, curcumin or turmeric may damage the gastrointestinal system, as curcumin, with doses of 100 mg/kg body weight, is ulcerogenic in rats? Some studies have found sensitivity of mice to turmeric that resulted in hepatotoxi~ity.5~f" Curcumin toxicity has not been found in rats or other mammals, even at very high doses (5%to 10% by weight of diet).13Human studies suggest that curcumin is nontoxic to humans up to 8000 mg/day when taken by mouth for 3 months.61

On the basis of the evidence presented earlier, turmeric should be consumed liberally in the diet. When specific medicinal effects are desired, higher doses of turmeric can be given or extracts of C. Iongu or curcumin can be used. The recommended dosage for curcumin as an antiinflammatory is 200 to 400 mg three times a day. To achieve a similar amount of curcumin using turmeric would require a dosage of 4000 to 40,000 mg. Because the absorption of orally administered curcumin may be limited (pharmacokinetic studies in animals show that 40% to 85% of an oral dose of curcumin passes through the gastrointestinaltract u n ~ h a n g e d ~ 5 ~ ) , curcumin is often formulated in conjunction with bromelain to possibly enhance absorption. In addition, bromelain also has antiinflammatory effects (see Chapter 73). A curcumin-bromelaincombination is best taken on an empty stomach20 minutesbefore meals or between meals. Providing curcumin in a lipid base such as lecithin, fish oils, or essential fatty acids may also increase absorption. This combination is probably best absorbed when taken with meals.

1.h u n g A. Encyclopedia of common ~ t u r ai ln e e n t s used in food, drugs, and cosmetics. New York Wdey, 1980:313-314. 2. Ammon W, Wahl MA. Pharmacology of Curcum Zongu. Planta Med 1991571-7. 3. Toda S, Miyase T, Arichi H, et al. Natural antioxidants.Antioxidative compounds isolated from rhizome of Curcum Zonga L. Chem Pharmacol Bull (Tokyo)1985;33:1725-1728. 4. Zhao B, Li XJ, He RG, et al. Scavenging effect of extracts of green tea and natural antioxidants on active oxygen radicals. Cell Biophys 1989;14175-185. 5. Shalini VK, Srinivas L. Lipid peroxide induced DNA damage: pmtection by turmeric (Curcum Zongu). Mol Cell Biochem 1987;77:3-10. 6. SrinivasL, Shalini VK. DNA damage by smoke. Protection by turmeric and other inhibitors of ROS. Free Radical Biol Med 1991;11:277-283. 7. Sharma OP. Antioxidant properties of curcumin and related compounds. B i d e m Pharmacol1976;25:1811-1825. 8. Thiyagarajan M, Sharma SS. Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci 2004;74969-985. 9. Jensen NJ. Lack of mutagenic effect of turmeric oleoresin and curcumin in the salmonella/mammalian microsome test. Mutat Res 1982;105:393-396.

10. Nagabhushan M, Amonkar AJ, Bhide SV.In vitro antimutagenicity of curcuminagainst environmentalmutagens. Food Chem Toxic01 1987;25:545-547. 11. Nagabhushan M, Bhide SV.Nonmutagenicity of curcurnin and its antimutagenicaction versus chili and capsaicin. Nutr Cancer 1986; 8201-210. 12. Radhakrishna Pillai G, SrivastavaAs,Hassanein TI, et al. Induction of apoptosis in human lung cancer cells by curcumin. Cancer Letters 2004;208163-170. 13. Samaha H!3, Kelloff GJ, Steele V, et al. Modulation of apoptosis by sulindac, curcumin,phenylethyl-3-methylcaffeate,and 6-phenylhexyl isothiocyanate:apoptotic index as a biomarker in colon cancer chemopmention and promotion. Cancer Res 1997571301-1305. 14. Jiang TL, Salmon SE, Liu RM. Activity of camptothecin, harringtonin, catharidin and cucumae in the human tumor stem cell assay. Eur J Cancer Clin Oncol1983;19263-270. 15.Mehta RG, Moon RC. Characterization of effective chemopreventive agents in mammary gland in vitro using an initiationpromotion protocol. Anticancer Res 1991;11:593-596. 16.Kuttan R, Bhanumathy ,'F Nirmala K, et al. Potential anticancer activity of turmeric (Curcum Zongu). Cancer Lett 1985;29: 197-202.

TOXICOLOGY

17. Soudamini NK,Kuttan R Inhibition of chemical carcinogenesis by curcumin.J EthnophannaCOl1989;27227-233. 18. Azuine M, Bhide S. Chemopreventive effect of turmeric against stomach and skin tumors induced by chemical carcinogens in Swiss mice. Nutr Cancer 1992;1777-83. 19.Nagabhushan N, Bhide SV. Curcumin as an inhibitor of cancer. J Am Coll Nutr 1992;11:192-198. 20. Azuine MA, Kayal JJ,Bhide SV. Protective role of aqueous turmeric extract against mutagenicity of direct-acting carcinogens as well as benzo [alpha] pyrene-induced genotoxicity and carcinogenicity. J Cancer Res Clin Oncol1992;118:447-452. 21. Boone CW,Steele VE,Kelloff GJ. Screeningof chemopreventive (antiCarcinogenic)compounds in rodents. Mutat Res 1992;267251-255. 22. Polasa K, Raghuram TC, Krishna TP, et al. Effect of turmeric on urinary mutagens in smokers. Mutagenesis 1992;7107-109. 23. Polasa K, Sesikaran B, Krisha TP,et al. Turmeric (Curcumlongdinduced reduction in urinary mutagens. Food Chem Toxic 1991; 29699-706. 24. Chandra D, Gupta SS. Anti-inflammatory and anti-arthritic activity of volatile oil of curcuma longa (Haldi). Indian J Med Res 1972;~138-142. 25. Arora RB, Kapoor V, Basu N, et al. Anti-inflammatory studies on Curcum longu (turmeric).Ind J Med Res 197159:1289-1295. 26.Srimal R, Dhawan B. Pharmacology of diferuloyl methane (curcumin),a non-steroidal anti-inflammatory agent. J Pharm Pharmacol 1973;25:447-452. 27. Mukhopadhyay A, Basu N, Ghatak N, et al. Anti-inflammatory and irritant activities of CurCuIILin analogues in rats. Agents Actions 1982; 12508-515. 28. Ghatak N, Basu N. Sodium curcuminate as an effective anti-inflammatory agent. Indian J Exp Biol1972;10235-236. 29. Patacchini R,Mag@ CA, Meli A. Capsaicin-Like activity of some natural pungent substances on peripheral ending of visceral primary afferents. Arch Pharmacoll990;342:72-77. 30.Srivastava R, Srimal RC. Modification of certain inflammationinduced biochemical changes by cumurnin.Indian J Med Res 1985; 81:215-223. 31.Srivastava R. Inhibition of neutrophil response by curcumin. Agents Actions 1989;28:29&303. 32.Flynn DL, Rafferty MF, Boctor AM. Inhibition of 5-hydroxyeicosatetraenoicacid (5-HITE)formation in intact human neutrophils by naturdy-occurring dmyheptanoids. Inhibitory activities of curcuminoids and yakuchinones. Prostaglandins Leukot Med 1986; 2357-360. 33. Rao DS,Sekhara NC, SatyanarayanaMN, et al. Effect of Ncumin on serum and liver cholesterol levels in the rat. J Nutri 1970;loO: 1307-1315. 34.Srinivasan K, Samaiah K. The effect of spices on cholesterol 7 alphahydroxylase activity and on serum and hepatic cholesterol levels in the rat. Int J Vitam Nutr Res 1991;61:364-369. 35. Soni KB, Kuttan R. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Indian J Physiol Pharmacol1992;36:273-275. 36. Srivastava R, W h i t M, Srimal RC, et al. Anti-thrombotic effect of curcumin.Thmmb Res 1985;40:413-417. 37. Srivastava R, Puri V,Srimal RC, et al. Effect of curcuminon platelet aggregation and vascular prostacyclin synthesis. Arzneimittelforschung 1986;36:715-717. 38.Stone MC, Thorp JM. Plasma fibrinogen-a major coronary risk factor. J R Coll Gen Pract 198535565-569. 39. Ramirez Bosca A, Soler A, CarrionCutierrez MA, et al. An hydroalcoholic extract of Curcum h g u lowers the abnormally high values of human-plasma fibrinogen. Mech Ageing Dev 2OOO;114:207-210. 40.Ramprasad C, Sirsi M. Curcuma longu and bile secretion. Quantitative changes in the bile constituents induced by sodium curcuminate. I Sci Ind Res 1957:16C:108-110.

41. Kiso Y, Suzuki Y, Watanabe N, et al. Antihepatotoxic principles of Curcum Zongu rhizomes. Planta Med 1983;49185187. 42. Lm SC,Lin CC, Lin YH, et al. Protective and therapeutic effects of Curcum xanthom'hza on hepatotoxin-induced liver damage. Am J Chi Med 1995;23243-254. 43. Rafatullah S, Tariq M, Al-yahya MA, et al. Evaluation of turmeric c cur cum longa) for gastric and duodenal antiulcer activity in rats. J Ethnopharmacol1990;2925-34. 4.4.Lim GP, Chu T, Yang F, et al. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 2001;21:8370-8377. 45. Pandya U, !%h MK, i Jin GF, et al. Dietary curamin prevents ocular toxiaty of naphthalene in rats. Toxicol Lett 2000;115195-204. 46.Awasthi S, Srivastava SK, Piper JT, et al. Curcumin protects against 4-hydroxy-2-trans-nonenal-inducedcataract formation in rat lenses. Am J Clin Nutr 1996;64:761-766. 47. Lutomski J, Kedzia B, Debska W.[Effect of an alcohol extract and active ingredients from Curcum Zonga on bacteria and fungi]. Planta Med 1974;269-19. 48. Huang MT, Smart RC, Wong CQ, et al. Inhibitory effect of curcumin, chlorogenic aad, caffeic acid, and ferulic acid tumor promotion in mouse skin by 12-0-tetradecanoylphorbol-13-acetate. Cancer Res 1988;48:5941-5946. 49. Mukundan MA, Chacko MC, Annapurna W. Effect of turmeric and curcuminon BP-DNA adduds. Carcinogenesis 1993;14:493-496. 50. Singh SV, Hu X, Srivastava SK, et al. Mechanism of inhibition of benzo[a]pyrene-induced forestomach cancer in mice by dietary curcumin. Cardnogenesis 1998;19:1357-1360. 51. Banerji A, Chakrabarti J, Mitra A, et al. Effect of curcumin on gelatinase A (MMP-2) activity in B16F10 melanoma cells. Cancer Lett 2004;211:235-242. 52. Kuttan R, Sudheeran PC, Josph CD. Turmeric and curcumin as topical agents in cancer therapy. Tumori 1987;7329-31. 53.Deodhar SD, Sethi R, Srimal RC. Preliminary studies on antirheumatic activity of curcumin (diferuloylmethane).Ind J Med Res 1980;71:632-634. 54.Satoskar RR, Shah !3J, Shenoy SG.Evaluation of anti-infhnmatory property of CurCuIILin(diferuloyl methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol 1986;24.651-654. 55. Gopinath D, Ahmed MR, Gomathi K, et al. Dermal wound healing processes with curcumin incorporated collagen films.Biomaterials 2004;25:1911-1917. 56.Shankar TN, Shantha NV, Ramesh HP,et al. Toxicity studies on turmeric (CurcumZonga): acute toxicity studies in rats, guinea pigs & monkeys. Indian J Exp Biol1980;1873-75. 57. Wahlstrom B, Blennow G. A study on the fate of curamin in the rat. Ada Pharmacol Toxicol (Copenh) 1978;4386-92. 58. Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology 1980;16259-265. 59. Deshpande SS,Lalitha VS, Ingle AD, et al. Subchmnic oral toxicity of turmeric and ethanolic turmeric extract in female mice and rats. Toxicol Lett 1998;95183-193. 60.Kandarkar SV, Sawant SS, Ingle AD, et al. Subchronic oral hepatotoxicity of turmeric in mice-histopathological and ultrastructural studies. Indian J Exp Biol1998;36:675-679. 61. Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of Curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 2001;21:2895-2900. 62. Shah BH, Nawaz Z, Pertani SA. Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biochem Pharmacol 1999581167-1172.

Dehydroepiandrosterone Laurie I CHAPTER CONTENTS Introduction 899

Dehydmepiandrosterone-sulfate Biochemistry 899 Clinical Applications 900 Aging 900 Depression 901 Alzheimer's Disease 901 Osteoporosis 901 Sexual Function 902 Cardiovascular Disease 902 Myotonic Dystrophy 902

INTRODUCTION Dehydroepiandrosterone (DHEA) is a steroid hormone secreted by the adrenal glands and to a lesser extent by the testes and ovaries. Circulating levels of DHEA and its ester, DHEA-sulfate (DHEA-S) are 20 times higher than those of any other adrenal steroid. Until recently, this hormone was considered to function primarily as a reservoir on which the body drew as a precursor for the formation of other hormones. Only in recent years has a physiologic role for DHEA begun to be elucidated. Although first identified in 1934, DHEA did not gain popularity until 1993, when French scientists claimed it was a cure for aging' based on the observation that DHEA levels peak in the late 20s and steadily decline thereafter. Indeed, epidemiologic evidence suggests that higher DHEA levels are associated with increased life expectancy2and enhanced well-being?" It has therefore been postulated that some of the manifestations of aging may be caused by the decline in DHEA that occurs with age. DHEA-S production varies profoundly throughout life. Circulatinglevels are high at birth but quickly decline to the point of being almost undetectable within a few months. Levels begin to increase in children 8 to 10 years of age (adrenarche) and peak in the second decade. Beginning in the early 30s, levels decline by 10% per

Cancer 902 Immunology 903 Systemic Lupus Erythematosus 903 Rheumatoid Arthritis 903 Inflammatory Bowel Disease 903 Toxicity 904 Drug Interactions 904 Dosage 904 Summary 904

decade (adrenopause) and then plateau around the age of 80 years?~~ Adrenopause results in an 80%loss of total DHEA production compared with young-adult values. Interestingly, these age-associated fluctuations (including the eventual decline) do not occur with any other adrenal steroid (Figure 88-1).

DEHYDROEPIANDROSTERONE-SULFATE BIOCHEMISTRY DHEA and its ester, DHEA-S, are the most abundant hormones in the blood stream. DHEA and DHEA-S undergo continuous interconversion with DHEA-S, representing approximately 80%of the total pool and acting primarily as a storage form.5 Because DHEA-S is present in much greater quantity than DHEA, has a longer half-life, and lacks the circadian fluctuation seen with DHEA, it is more reliably used in clinical laboratory assessment.6 Despite DHEA-S's status as the major secretory product of the human adrenal, an understanding of its physiologic roles remains elusive. Assessing whether the effects of DHEA are a direct result of the hormone, its metabolites, or a combination of the two has been difficult? Although often chemically classified as a weak androgen, little evidence of direct androgenic activity exists. Any androgenic activity is most likely mediated through its conversion to other, more potent androgens. 899

The biosynthesis of all sex steroids in humans proceeds through DHEA.8 As a steroid precursor, DHEA is converted to both estrogens and androgens, depending on the requirements of the target tissue. The majority of DHEA conversion to metabolites occurs within peripheral cells via the enzymes aromatase and steroid Men

30

1

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25

CLINICAL APPLICATIONS Previous studies have demonstrated a wide variety of beneficial effects in conditions such as diabetes, obesity, decreased immune function, atherosclerosis,and many of the disorders associated with normal aging. The problem with many of these studies is that they have been conducted using rodent models. Rodents have little endogenous DHEA and do not have levels that decrease with age. DHEA in rodent studies is often administered at supraphysiologic doses, calling into question the relevance to humans at physiologic doses.This review intends to base recommendationson human studies to the extent possible.

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sulfatase (STS), which are present in the majority of human cells (Figure 88-2). Effects of DHEA in humans vary significantly depending on the individual's age, gender, menopausal status, and DHEA levels. On a cellular level, the target tissue and intracellular enzyme availability shape the fate of the molecule? Given the variability of DHEA's metabolism, one should exercise caution when considering supplementation at high dosages (>lo mg/day for women and 30 mg/day for men).

O 20 30 40 50 60 70 80

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Figum 861 Decline of dehydroepiandrosterone in men and women with age. (From Labrie F, Luu-TheV, Labrie C, Simard J. Frontiers Neuroendocrinology 2001;22:185-212.)

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Preliminary results suggest DHEA may retard the aging process. In a study of 75 healthy subjects age 90 to 106 years, men with the highest DHEA-S levels had the highest level of functioning.1oSeveral other studies in

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Dehydroepiandrosterone elderly humans have supported an inverse correlation between DHEA levels and the degree of dependence in activitiesof daily living and mobility. In one study, plasma DHEA level was low in 80% of the male nursing home residents who required total care compared with 40% low in other nursing home residents and 6%in independently living men of comparable age."" In men older than 90 years of age, higher DHEA-S levels were associated with a higher body mass index and waist-to-hip ratio, taken as indices of the body's energy (fat) reserves. In women older than 90 years of age, DHEA-S levels were positively correlated with serum-free triiodothyronine (FT3) and inversely with triglycerides.1° In an attempt to determine whether DHEA supplementation would counteract defects associated with aging, 280 healthy individuals between the ages of 60 and 79 years old were given 50 mg of DHEA daily or placebo for a year. In women older than 70 years of age, there was a reduction in the amount of bone loss and an increase in most libido parameters. Women also showed improvements of skin status including greater hydration, epidermal thickness, sebum production, and pigmentation.12 Although DHEA levels do not appear to correlate significantly with cognitive f u n ~ t i o n ? , ~low J ~ serum DHEA-S has been associated with decreased psychologic well-being and symptoms of depression?

Depression An extensive study of depression in adolescents showed

approximately 30%have abnormally low DHEA level^,'^ and mean levels of DHEA in the saliva of depressed adults are lower than those in normal control subjects.15 Improvements in cognition have been observed after oral administration of DHEA to middle-aged and elderly depressed patients,16 and the antidepressant actions of DHEA have been demonstrated in several randomized controlled trial^.'^,'^ The ability of DHEA to affect depressive symptomatology seems to be most substantial where DHEA levels are low or in those with an elevated cortisol-to-DHEA ratio. Cerebrospinal fluid DHEA-S levels are highly correlated with serum levels? DHEA easily crosses the blood-brain barrier, and evidence suggests the brain synthesizes DHEA from ch~lesterol.'~The ability of DHEA to enhance mood may be related to its role in the central nervous system. As a neurosteroid, research suggests the hormone may play a vital role in regulation of neuronal excitability. DHEA supplementation has been shown to increase levels of beta-endorphin, bind NMDA receptors, act as an antagonist at GABA receptors, and protect against the deleterious effects of glucocorti~ o i d s . ' ~ In J ~rats, , ~ ~ DHEA has been shown to increase hypothalamic serotonin levels.2l These pharmacologic properties may help explain the efficacy of DHEA in mood disorders.

Depression Associated with Aging Results from several studies suggest that DHEA treatment (30 to 150 mg/day) may decrease depressive symptomatology in age-advanced patients with major depression or d y ~ t h y m i a . ~ ~Replacement J~,~D of DHEA (50 mg/day) in 50-year-olds for 6 months resulted in a significant increase in the sense of well-being in both men and women. Another study demonstrated that supraphysiologic dosages of 90 and 450 mg/day of DHEA was associated with a substantial benefit in the treatment of midlife-onset dysthymia in both men and women."

Hypoadrenalism Individuals with reduced adrenal function, and thus low DHEA production, commonly report symptoms of depression and dysthymia. Studies in hypoadrenal patients have demonstrated that replacement with 50 mg/day DHEA results in an improvement in mood and overall sense of well-being3

Elevated Cortisol-toDehydroepiandrosterone Ratio Elevated cortisol levels are well documented in depression, occurring in approximately 50% of cases.15 Hypercortisolemia has been shown to impair learning and memory in humans, and prolonged exposure to excess glucocorticoids leads to neuronal a t r ~ p h y .The ~ ~ ,neu~ rocognitive deficits observed in depressive disorder, therefore, may be partially attributable to glucocorticoid hypersecretion. DHEA possesses significant antiglucocorticoid activityF6 and it may be via this mechanism that administration of DHEA reduces neurocognitive deficits in major d e p r e s s i ~ n . ~ ~ ~ ~ ~

Alzheimer's Disease Low DHEA-S plasma levels appear to be a risk factor A decreased for the development of Alzheimer's di~ease.2~ concentration of DHEA-S in patients with Alzheimer's disease has been reported, but the significance of DHEA in dementia remains u n ~ l e a r . Several ~ ~ , ~ small studies using DHEA in the treatment of Alzheimer's disease have produced unimpressive r e s ~ l t s . 3 ~ - ~ ~

Osteoporosis The possible relationship between DHEA deficiency and osteoporosis was suggested by a study of women with Addison disease. In these patients, the onset of menopause was followed by an unusually rapid rate of bone loss. This accelerated bone loss was associated with marked reductions in plasma concentrations of DHEA and testosterone (94% and 63%lower, respectively, than those of healthy postmenopausal women).MThese findings suggest that DHEA or testosterone, or both, are essential for the maintenance of bone mass in postmenopausal women.

When bone mineral density was measured at the lumbar spine, hip, and radius in women 45 to 69 years old, 55 of the 105 women in the study were found to have low bone density. The average serum DHEA-S level was 60% lower in the women with low bone density than in those with normal bones. Women with low DHEA-S values were 40 times more likely to have osteoporosis than were women with normal DHEA-S levels. In contrast, there was no relationship between estrogen levels and bone density.35Another study of 29 postmenopausal women demonstrated a significant positive correlation between bone mineral content of the distal radius and ulna and age-adjusted serum DHEA levels.% DHEA might prevent osteoporosis by several mechanisms. At the time of menopause, the amount of DHEA manufactured by the ovaries declines by more than 60Y0.~~ As an important precursor molecule, this reduction affects the formation of other sex steroids known to contribute to bone formation. A doubleblind, placebocontrolled study of 50 mg/day DHEA supplementation demonstrated improved bone turnover and decreased osteoclastic activity in women older than 70 years.'* Treatment using transdermal DHEA cream for 1 year in postmenopausal women demonstrated sigruficantly increased serum osteocalcin levels and bone mineral density of the femur, while the bone alkaline phosphatase levels decreased.%

Sexual Function Treatment with 50 mg DHEA each morning in 24 women with adrenal insufficiency significantly increased the frequency of sexual thoughts, sexual interest, and satisfaction for both the mental and physical aspects of sexuality in a double-blind study.39

Erectile Dysfunction The first study to describe an inverse correlation between DHEA-S levels and the incidence of erectile dysfunction (ED) was the Massachusetts Male Aging Study, a community-based,random-sample observational survey of men 40 to 70 years old conducted from 1987 to 1989. More than half (52%) of the men in the study had minimal, moderate, or complete impotence.40In these men the degree of impotence was directly correlated with low serum DHEA-S levels. Follow-up research suggests that this is especially true for men younger than the age of 60 years.4I Additional double-blind, placebo-controlled studies have demonstrated that 50 mg DHEA/day given orally for 6 months resulted in improvement in all five domains of the International Index of Erectile Function (IIEF), which quantitatively describes an individual's ability to achieve or maintain an erection sufficient for satisfactory sexual perf~rmance.",~~ Response was most

substantial in individuals with hypertension or lack of an organic etiology for their condition.42There was no impact of DHEA treatment on serum prostate specific antigen, prolactin, testosterone, mean prostate volume, or mean postvoid residual urine v0lume.4~

Cardiovascular Disease Mean plasma DHEA-S levels were significantly lower in men with a history of heart disease than in men without such a history. In men with no history of heart disease as a baseline, a low plasma DHEA-S level (440p,g/dl) was associated with a more than threefold increase in the age-adjusted risk of death from cardiovascular disease.44 Similar findings were reported by although another epidemiologic investigation found only a modest protective effect of DHEA.& In women, no inverse association was found between DI-EA-S and cardiovascular disease. In fact, cardiovascular death rates were highest in women in the highest tertile of DHEA-S levels and lowest in the middle tertile (a U-shaped di~tribution).~~ Since the highest serum DHEA-S levels are often present in women with PCOS, and PCOS is associated with insulin resistance and hypothyroidism, this could explain why very high DHEA-S levels are associated with heart disease.

Myotonic Dystrophy Myotonic dystrophy is an autosomal dominant multisystem disorder characterized by muscle weakness and myotonia. Myotonic dystrophy is associated with low DHEA levels, and DHEA has thus been proposed as a therapeutic option. DHEA receptors have been identified on skeletal muscle, and their presence may account for some of the benefit of DHEA seen in such conditions.@ The intravenous administration of DHEA-S (200 mg/ day for 8 weeks) in 11 patients with myotonic dystrophy induced an improvement in muscle strength and a decrease of myotonia. Improvement in the activities of daily living occurred, and in the four patients with cardiac involvement, the symptoms of conduction block and a premature heartbeat also impr0ved.4~

Cancer Premenopausal women with breast cancer had significantly lower plasma levels of DHEA than age-matched controls without breast cancer, whereas postmenopausal women had significantly higher DHEA levels than agematched controls.50 In another study, women with DHEA levels in the highest tertile were 60% less likely to develop breast cancer than were women in the lowest In a prospective case-control study, serum DHEA and DHEA-S levels were significantly lower in individuals who subsequently developed bladder cancer than in those who did

These findings suggest that DHEA has anticancer activity and that low DHEA levels may be a risk factor for cancer, except in postmenopausal women. However, further research is required before guidelines can be developed regarding DHEA therapy and cancer. The observation that some postmenopausal women with breast cancer have elevated DHEA levels, as well as the fact that DHEA is converted in part to estrogen and testosterone, should be cause for concern. It is unknown whether the anticancer effects of DHEA are stronger than the potential prostate cancer-promoting effects of additional testosterone or the breast cancer-promoting effects of additional estrogen. This is a complicated issue, since the metabolism of DHEA is usually ”crossgender” (i.e., women get an increase in testosterone, whereas estrogen levels often do not change, and vice versa for men). Until those questions can be answered, DHEA therapy should be approached with caution in patients who are at risk for developing hormonedependent cancers.

Immunology Serum levels of DHEA-S and interleukin-6 (IL-6) are inversely correlated. IL-6 is one of the pathogenic mediators in inflammatory and age-related diseases such as polymyalgia rheumatica, rheumatoid arthritis, inflammatory bowel disease, osteoporosis, atherosclerosis, and possibly Alzheimer’s disease, Parkinson’s disease, and beta-cell malignan~ies.~~ IL-6 is a cytokine that stimulates hepatocytes to produce acute-phase reactants and B-lymphocytes to produce immunoglobulin. Levels of IL-6 correlated strongly with the erythrocyte sedimentation rate and rheumatoid factor titers.% It has been theorized that the increase in IL-6 production during the process of aging might be due, in part, to diminished DHEA secretion.53This theory is based on research demonstrating serum DHEA correlates negatively with serum IL-6. Exogenously administered DHEA inhibits IL-secretion in a U-shaped fashion, with serum concentrations equaling that of healthy controls exerting the greatest effect.53 In a double-blind study, administration of 50 mg/day of DHEA to postmenopausal women produced a twofold increase in natural killer cell activity and a 6% decrease in the proportion of T helper ~ells.5~ Although the increase in natural killer cell activity might be expected to enhance immune surveillance against cancer and viral infections, the decline in T helper cells could have adverse consequences. On the other hand, since DHEA is known to mediate T-cell responses156 the decline in T helper cells could merely be a reflection of enhanced T-cell function. Activation of immune function by DHEA has also been demonstrated in ageadvanced men.57

Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a chronic inflammatory connective tissue disorder that occurs predominantly in women. Several studies have demonstrated efficacy in patients with SLE when treated with 50 to 200 mg D H E A / ~ ~ Y .A~ *double-blind, -~~ placebocontrolled trial of women with SLE demonstrated the group receiving DHEA had a significant reduction in the number of disease flares and serious lupus-related adverse events, as well as improvement in the person’s global assessment.61 The effects of DHEA in autoimmune conditions such as SLE are likely due to a decrease in inflammatory cytokines such as IL-6. DHEA appears to decrease IL,-6 production (which is responsible for stimulating antibody production). IL-6 inhibition may curb antibody production and thus clinical manifestations of antibody-mediated disease^.^^,^^

Rheumatoid Arthritis A decreased DHEA-S serum concentration is found in patients with rheumatoid arthritis (RA)64,65; however, low levels may be a consequence of RA rather than predisposing to the disease.65The decrease in DHEA-S is most probably due to increased aromatase activity in synovial tissue of RA patients. Thus an available steroid precursor, such as DHEA, may be rapidly converted to proinflammatory estrogens in the synovial tissue, which may in turn stimulate the inflammatory process in patients with RA.& Patients with RA have a high frequency of osteoporosis, which may be due, in part, to reduced levels of DHEA-S.@This is an key example of the intricacies of DHEA physiology: The use of DHEA offers protection against osteoporosis, which is common in RA, but the increase in synovial aromatase may excessively convert DHEA to estrogen, exacerbating the inflammatory process of arthritis. Despite these concerns, some practitioners have observed that patients with rheumatoid arthritis improve clinically after treatment with DHEA; however, those observations have not been investigated in controlled trials.

Inflammatory Bowel Disease DHEA-S concentrations are decreased in patients with both Crohn‘s disease and ulcerative colitis.67 In one study, 200 mg DHEA/day were given orally for 56 days to 7 patients with active Crohn’s disease and 13 patients with active ulcerative colitis (UC), all of whom were refractory to other drugs. Some patients went into remission: 6 of 7 Crohn’s patients and 6 of 13 UC patients. The treatment response rate was 85.7% for Crohn’s disease and 61.5%for UC. No patient withdrew from the study because of side effects.@

The mechanism of action may result from the ability of DHEA to decrease mediators of inflammation. It has been shown that DHEA inhibits the activation of nuclear factor-kappa-beta and the secretion of IL-6 and IL-12.53

Steroid sulphatase (STS) inhibitors are currently being developed for use in breast cancer therapy. STS controls the hydrolysis of DHEA-S.R DHEA may potentiate the action of thyroid hormones.n

DOSAGE

TOXICITY

Although DHEA appears to be safe, the long-term effects For a steroid hormone, DHEA appears to be relatively of moderate to high dosages are unknown. It is therefore safe. Cardiac arrhythmias have been exacerbated by important that this hormone is treated with respect and DHEA supplementation, according to several r e ~ o r t s . ~ ~ * ~ toOerr on the side of caution. In the elderly 50 mg/day Administration of 1600 mg/day for 28 days to healthy will increase DHEA levels into the reference range of volunteers resulted in some degree of insulin resistance, young adults? Although some practitioners are roubut no other sigruficant side effects. In the SLE studies, tinely prescribing 50 mg/day for healthy women and 200 mg/day given for a number of months was well tol100 mg/day for healthy men, such doses may be supraerated, with the exception of mild to moderate acne and physiologic. The safe dosage appears to be 5 to 15mg/day occasional mild hirsutism. Another study reported interfor women and 10 to 30 mg/day for men. Patients with mittent nausea, perioral dermatitis, subjective feelings of SLE or other autoimmune diseases sometimes need as aggressiveness, and intermittent hoarseness.@ Because much as 100 mg/day or more to obtain benefit. Large of DHEA’s role as a precursor to more potent sex doses should be split into twice-a-day dosing, usually hormones, it should be used with extreme caution in morning and evening. individuals with hormone-sensitive cancers. After oral administration, studies show that most DHEA is ab~orbed,’~ and that once in circulation, DHEA readily penetrates the blood-brain ~~

~

DRUG INTERACTIONS

Estrogen (oral contraception pills, hormone replacement therapykFree-testosterone and DHEA levels are reduced in women taking estrogen.71 Aromatase inhibitors-These drugs are used to interrupt the growth of hormone-dependent cancers. Aromatase is the enzyme responsible for many of the conversions in the steroid pathway.

In conclusion, DHEA appears to be one of the major therapeutic advances of the past two decades. However, we must treat this powerful hormone with caution and respect in order to maximize its benefits and minimize its risks.

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SUMMARY

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Echinacea Species (Narrow-Leafed Purple Conef lower ) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER C O N T E N T S General Description 907 Chemical Composition 907 Polysaccharides 908 Alkylamides 909 Caffeic Acid Derivatives 909 Flavonoids 909 Polyacetylenes 909 Miscellaneous 910 History and Folk Use 910 Pharmacology 910 Tissue Regeneration and Antiinflammatory Properties 910 lmmunostimulatory Properties 910 Antiviral Properties 911 Antibacterial Properties 911 Antineoplastic Activity 912

Echinuceu spp. (family: Asteraceae) Echinaceu ungustifoliu Common names: narrow-leafed purple coneflower, black sampson, snakeroot Echinuceu purpureu Common name: purple coneflower Echinucea pallidu Common name: pale purple coneflower

GENERAL DESCRIPTION Echinaceu spp. are perennial herbs native to Midwestern North America, from Saskatchewan to Texas. The genus derives its name from the Greek echinos, meaning sea urchin. This refers to the prickly scales of the dried seed head portion of the flower. Nine species of Echinuceu have been taxonomically classified by McGregor on the basis of comparative anatomy and morphology (Table 89-1)' Of the nine species, Echinuceu angustifolia, Echinacea purpureu, and Echinaceu pullidu are the most commonly

Clinical Applications 912 The Common Cold 913 Candidiasis 914 Snakebites 914 Wound Healing 914 Arthritis 914 Cancer 914 Commercial Preparations 914 Species 915 Part of the Plant to Use 915 Preparations 915 Solvents 915 Dosage 915 Toxicology 915 Drug Interactions 916

used clinically? E. angustifoh, with a typical height of up to 2 feet, is shorter than E. purpureu (1.5 to 5 feet) and E. pullidu (1to 3 feet). Another key to species identification is that E. angustifoh and E. purpureu have yellow pollen, while E. pullidu is noticeably paler and has white pollen. The portions of the plant used for medicinal purposes include the aerial portion, the whole plant including the root, and the root itself. The tap root of E. ungustifoliu can reach a length of 3 to 4 feet.3 E. ungustifoliu has thick, hairy, 1- to 3-inch-long leaves found at the base of a purple seed head shaped like a cone. The only exception to the family of "purple" coneflower is Echinaceu parudoxu, which has a yellow flower.

CHEMICAL COMPOSITION Analysis of Echinucea spp. has yielded a wide assortment of chemical constituents with pharmacologic activities. From a pharmacologic perspective, the important 907

SDecies

Svnonvms

~~

Echinacea angustifolia

Brauneria angustifolia

Echinacea atrorubens

Rudbeckia atrorubens

Echinacea laevigata

Brauneria laevigata

Echinacea pallida

Rudbeckia pallida

Brauneria pallida Echinacea paradoxa

Brauneria paradoxa

Echinacea purpurea

Rudbeckia purpurea

Rudbeckia hispida Rudbeckia serotina Echinacea speciosa Echinacea intermedia Echinacea simulata

Echinacea speciosa

Echinacea sanguinea Echinacea tennesseensis

Bra uneria tennesseensis

Modified from McGregor RL. Univ Kansas Sci Bull 1968;48:113-142.

constituents of Echinacea spp. can be divided into seven categories: Polysaccharides Alkylamides Caffeic acid derivatives Flavonoids Essential oils Polyacetylenes Miscellaneous chemicals

In the case of echinacea, it appears that while individual immune enhancing compounds produce significant effects when they are combined in meaningful amounts, there is an additive effect. The immune-enhancingcomponents of echinacea work together in a harmonious fashion to produce the phenomena of synergy. A key manner in which echinacea affects immune function is via enhancing the ability of macrophages to engulf and destroy particulate matter. The specific components of echinacea that possess this action are the polysaccharides, alkylamides, and cichoric acid. Although each component is effective alone, the greatest degree of enhancement was noted when the three active components were used in a specific ratio (0.25,2.5, and 25 mg/ml).4This phenomena of synergy was noted with a clear dose-dependent effect. In other words, the effects with the three actives were greater than any individual active and the higher the dosage, the greater the effect on enhancing macrophage function. A similar effect was noted in the ability of macrophages to detect the presence of foreign matter in the blood and

signal the other components of the immune system to mount an attack via interleukin-1 (IL-1) and granulocyte colony-stimulating factor (G-CSF). Because echinacea contains a wide assortment of chemical constituentswith confirmed immune-enhancing effects, it is important for manufacturers to recognize to ensure sufficient levels of all these active compounds. Unfortunately, most echinacea products on the market do not speclfy the levels of active compounds because they have not been analyzed for them. In addition, when manufacturers do state the level of a particular marker compound, most consumers fail to realize that concentrating only for one particular active compound of echinacea results in loss of other constituents and, as a result, all of the synergisticeffects. For example, some manufacturers standardize for "total phenolic content" or the compound echina~oside.~ Although these types of echinacea extracts were found to have some antioxidant properties, recent studies have found them to have no effect on enhancing immune function in experimental animal Growing understanding of the chemical composition of echinacea requires manufacturers to perform quality control tests not only on the finished product, but also on the plant to ensure that it is being grown properly and harvested at the exact time for maximal levels of all active compounds. It is imperative that echinacea be treated properly after harvesting. In addition, studies indicate that a significant amount of the active ingredients are destroyed in the drying process. If the fresh plant material is not processed immediately, the content of several key components-especially cichoric acid and alkylamides-will be low (as much as 80% will be lost).810 Chemical analysis of commercial echinacea preparations has demonstrated tremendous variation in the levels of key compounds. For example, one analysis of various commercial echinacea products found that there was not only tremendous variation in the level of cichoric acid, with most products containing either none or little, but even within the same product there was tremendous interbatch variation."

Polysaccharides A number of immunostimulatory and mild antiinflammatory polysaccharides have been isolated from Echinacea ~ p p . ~ , ~ JMost * - ' ~ notable are h u h , which is found in a high concentration (5.9%)in E . angustifoh root, and the high-molecular-weight (25,000 to 50,000) polysaccharides found in the aerial part of E. purpurea, as these components possess significant immuneenhancing properties. Typically the most potent immune-enhancing polysaccharidesare the water-soluble, acidic, branched-chain heteroglycans composed of many types of sugars rather than the polyfructose content of inulin.

Echinacea Species (Narrow-Leafed Purple Coneflower)

Alkylamides

0

Alkylamides typically exert a tingling sensation on the tongue, which is representative of their mild anesthetic effect. These compounds are found in highest concentrationsin the roots. The roots of E. angustifoh contain higher concentrations (0.004% to 0.039%) than E . purpurea (0.009% to 0.151%) and E. paZZida (0.001%).16~'7 Alkylamides are among the most active constituents of echinacea on macrophage function.18

Caffeic Acid Derivatives Caffeic acid serves as the backbone for a number of important medicinal plant compounds in other plants, as well as Echinacea spp. (Figure89-1). The first compound believed to be unique to Echinacea was echinacoside, a compound eventually shown to be composed of caffeic acid, a caffeic acid derivative (similar to catechol), glucose, and rhamnose, all attached to a central glucose molecule (Figures 89-2 and 89-3).19 Echinacoside accumulates in the roots but is also found in smaller concentrations in the flowers. The roots of E . angustifoh contain 0.3% to 1.3%,while the roots of E. pallida contain a similar concentration of 0.4% to 1.7Y0.l~It is assumed that E. purpurea has similar echinacoside levels as well. Other caffeic acid derivatives important in the pharmacology of Echinacea include cichoric acid, chlorogenic acid, and ~ y n a r i nCichoric .~ acid was originally isolated from E . purpureu and is found in much higher concentrations in this species compared with E. angustifolia and E . p ~ l l i d a . However, ~,~~ E. a n g u s t i f o h and E . pallida have

U

OH

R'

R"' R"

Compound

R

3-0-Caffeoyl- OH quinic acid (chlorogenic acid) lsochlorogenic OH acids OH OH Cynarine Caffeic acid

R'

R"

R"'

Caffeic acid

OH

OH

Caffeic acid Caffeic acid OH Caffeic acid OH Caffeic acid Caffeic acid Caffeic acid Caffeic acid Caffeic acid OH Caffeic acid

Figure 89-3 Other caffeic acid derivatives.

higher amounts of other types of caffeic acid derivatives. These differences are not thought to have much clinical sigruficance;rather, they may prove to be valuable in quick chemical differentiation of species.

Flavonoids The leaves and stems of E. angustifoh and E. purpurea have been shown to contain numerous flavonoids, with rutoside being the most a b ~ n d a n tThe . ~ total flavonoid content (calculated as quercetin) for E. angustifolia and E. purpureu was 0.48% and 0.38%, respectively3

Essential Oils The essential oil content varies among the three common speciesz1:

Figure 89-1 Caffeic acid.

E. angustifolia root and leaves contain less than 0.1%. E. purpurea root contains 0.2%,and flowers and leaves contain 0.6%. E. pullida root contains up to 2%, and the leaves contain less than 1%.

OR

Interestingly, in one study the essential oil content of E. pallida root was found to rise to 3.5% to 4% in April and May but fall to 1% to 1.5%for the rest of the year.u The major essential oil components are sesquiterpene derivatives, borneol, alpha-pinine, and related aromatic

compound^.^

Compound

R

R'

Echinacoside 6-0-Caffeoylechinacoside Verbascoside Desrhamnosylverbascoside

Glucose (1,6-) 6-0-Caffeoyl-glucose

Rharnnose (1,3-) Rharnnose (1,3-)

H H

Rharnnose (1,3-) H ~

Figure 89-2 Echinacoside and similar compounds.

Polyacetylenes A number of polyacetylenes have been identified from the roots of all three commercial ~pecies.2~ The difference in the type of polyacetylene and susceptibility to breakdown may help to differentiate which species is best for commercial use. Because the polyacetylenes of E. pallida

Pharmacology of Natural Medicines are quite susceptible to autoxidation, E. angitstifolia may be better for commercial products.” Research has shown that long-term storage greatly decreases the content of polyacetylenes to only trace levels at best. However, the polyacetylene derivatives of autoxidation of E. pallida are quite characteristic and useful in differentiating E. pallida from E . angustifolia.

Miscellaneous Undoubtedly, other constituents contribute to the pharmacology of echinacea. The occurrence of a “colorless alkaloid” was first reported by the great John Uri Lloyd in 1897 and substantiated recently by the isolation of the alkaloids tussilagine and isotussilagine.25Other compounds isolated from Echinacea spp. include the following? Resins Glycoproteins Sterols Minerals Fatty acids

HISTORY AND FOLK USE

among naturopathic physicians until around 1980 when it was rediscovered due to the increased consumer interest in immune system disorders such as candidiasis, chronic fatigue syndrome, AIDS, and cancer. Although interest in echinacea decreased in America between the 1930s and 1980s, European physicians continued research. Much of this research was initiated by a 1932 study by Gerhard Madaus, who demonstrated immune-enhancing effects of a preparation from the fresh juice of the aerial portion of E. purpurea. This was followed by development of a commercial product (Echinacin) and a great deal of scientific study. Thus E. purpurea began to be as respected as E. angitstifolia among herbal practitioners in E ~ r o p e . ~

PHARMACOLOGY The chemistry, pharmacology, and clinical applications of echinacea have been the subject of more than 300 scientific ~ t u d i e s . ~This , ~ , section ~~ summarizes some of the pharmacological information on Echinacea with attention to the species used, part of the plant used, solvent used for extraction, and other relevant features. When no species delineation is made, the activity described is similar in all species.

Echinacea was used extensively by the Native Americans Tissue Regeneration and living in areas where it grew. In fact, American Indians Antiinflammatory Properties used echinacea against more illnesses than any other Echinacin (a commercial product consisting of the plant. The root was used externally for the healing of wounds, burns, abscesses, and insect bites; internally for freshly pressed juice of E. purpurea stabilized in ethanol) infections, toothache and joint pains; and as an antidote as well as polysaccharide components of echinacea have for rattlesnake bites.26 been shown to promote tissue regeneration and reduce H.C.F. Meyer, a German lay healer, introduced a cominflammation in experimental studies.30This effect mercial product containing echinacea to Americans is apparently largely due to inhibition of the enzyme around 1870. He recommended ”Meyer’s blood ~ u r i f i e r ” ~ hyaluronidase via formation of a polysaccharide complex with hyaluronic acid, thereby maintaining the structure as a wonder cure for almost every conceivablemalady, and and integrity of the collagen matrix in connective tissue there were numerous case reports of successful treatments and ground substance. In addition to increased hyaluronic for snakebites, typhus, diphtheria, and other infections. acid stabilization, echinacea also stimulates fibroblast E. angustifoh became a favorite with eclectic physicians, growth and manufacture of glycosaminoglycans, a critias it was thought to be greater in activity than other cal goal in wound healing. species. Eclectics used it externally as a local antiseptic, Echinacea exerts a mild, direct cortisone-like effect stimulant, deodorant, and anesthetic and internally for and enhances the secretion of adrenal cortex hormones? “bad blood” (i.e., to correct ”fluid depravation with The polysaccharide portion appears to be responsible for tendency to sepsis and malignan~y”).~’,~ the direct antiinflammatory effects, although the alkyAlthough many physicians began to investigate and lamide fraction has also demonstrated some activity.3l use echinacea as a serious medicine, in 1909 the Council on Pharmacy and Chemistry of the American Medical lmmunostimulatory Properties Association refused to recognize echinacea as an active drug, stating: “Ln view of the lack of any scientific scrutiny Echinacea possesses a broad spectrum of effects on the of the claims made for it, Echiizacea is deemed unworthy immune system as a result of its content of a diverse range of active components affecting different aspects of of further consideration until more reliable evidence is immune f ~ n c t i o n .For ~ , ~example, inulin, the major compresented in its favor.” Despite this opposition, echiponent in the root of E. angustifoh, activates the alternanacea was included in the National Formulary of the United States and remained there until 1950.3 tive complement pathway and thus promotes chemotaxis of neutrophils, monocytes, and eosinophils; solubilizaWith the demise of the eclectic movement, the popution of immune complexes; neutralization of viruses; larity of echinacea in the United States waned except

Echinacea Species (Narrow-Leafed Purple Coneflower) and bacteriolysis. Echinacea also increases the levels of properdin, the normal serum globulin that stimulates the alternative complement pathway2JJ2Another nonspecific immune enhancement is echinacea's enhancement of serum leukocyte and granulocyte ~ o u n t s . " ~ , ~ ' ~ ~ The high-molecular-weight heteroglycan polysaccharide components of echinacea have profound immunostimulatory effects.The majority of these effects appear to be mediated by the binding of active echinacea polysaccharides to carbohydrate receptors on the cell surface of macrophages and T-lymphocytes. However, some of the T-cell activation in early studies is now thought to be due to a contaminantprotein. Later studies using a purer polysaccharide fraction have not shown si@cant results? Echinacea promotes nonspecific T-cell activation (i.e., transformation, production of interferon, and secretion of lymphokines). The resultant effect is enhanced T-cell mitogenesis, macrophage phagocytosis, antibody binding, natural killer cell activity; and increased numbers of circulating n e ~ t r o p h i l s . ~ , ~ ~ Echinacea polysaccharides have also been shown to enhance macrophage phagocytosis and stimulate macrophages to produce increased amounts of tumor necrosis factor (TNF), interferon, and IL-1; destroy tumor cells in tissue culture; and inhibit Candida albicans infection in rats infected intravenously with a lethal dose (3 x lo5 cells) of C. albicans?J3 The interactions with macrophages are most likely responsible for much of the immune system enhancement of echinacea polysaccharides. In addition to the polysaccharides, lipophilic alkylamides and caffeic acid derivatives like cichoric acid are thought to contribute to the immunostimulatory aspects of echinacea, especially alcoholic extract^.^"^^ Although most research has been devoted to the water-soluble components such as polysaccharides, the lipophilic fraction yields the most potent enhancement of macrophage phagocyt~sis.~,~ The carbon clearance test is often used to measure systemic macrophage activation. The method involves measuring the rate of disappearance of carbon granules from the blood at varying intervals following administration of the test substance. Root extracts of echinacea administered orally tend to yield greater effects on phagocytic activity than the aerial portion, with E . purpurea > E . angustifolia > E . p ~ l l i d a . ~ Many studies have used injectable preparations, but oral preparations are generally thought to yield similar or even better results, although direct comparisons are apparently not available. For example, intramuscular Echinacin administered to healthy males on 4 successive days was shown to increase granulocytic phagocytosis by nearly %YO, while the oral administration of an E. purpurea root extract at a dose of 30 drops three times daily to healthy males for 5 consecutive days resulted in an increase O.~ this difference may be due to the of ~ ~ O Y However,

differing constituents of the forms used. The expressed juice of the aerial portion E . purpurea, as found in Echinacin, has lower concentrations of several of the phagocytosis-stimulating compounds characteristic to echinacea including polysaccharides, alkylamides, and caffeic acid derivatives like cichoric acid compared with alcoholic extract? In general, echinacea appears to offer benefits for all infectious conditions. An exception to this statement may be acquired immunodeficiency syndrome (AIDS). It is unclear at this time if echinacea should be recommended for AIDS. Although this condition is associated with widespread depression of the immune system, presumably due to the human immunodeficiency virus (HIV),stimulation of T-cell replication may also stimulate replication of the virus as well. In addition, echinacea has been shown to lower T helper cells and decrease T helper cell-to-suppressor cell ratios.2JAlthough there are anecdotal reports of echinacea's efficacy in HIV-infected individuals, more research is necessary.

Antiviral Properties The juice of the aerial portion of E. purpurea, along with alcoholic and aqueous extracts of the roots, have been shown to possess antiviral activity. Some of the viruses inhibited in cell cultures include influenza, herpes, and vesicular stomatitis viruses?,34 Although certain Echinacea components (e.g., echinacoside, other caffeic acid derivatives, polysaccharides)may block virus receptors on the cell surface, the antiviral effects may also be due to inhibition of hyaluronidases. The viralinhibiting action of echinacea is significantly diminished when hyaluronidase is added to the cell culture^.^ Many organisms secrete hyaluronidase, which increases connective tissue permeability and allows the organism to become more i n ~ a s i v e . ~ ~ Clinically, the inhibition of hyaluronidase coupled with general immunostimulation of echinacea is probably more important than direct antiviral activity. The nonspecific antiviral action of echinacea enhances cytotoxic killing of virus-infected cells and the release of interferon. Interferons bind to cell surfaces, where they stimulate synthesis of intracellular proteins that block the transcription of viral ribonucleic acid (RNA).

Antibacterial Properties The direct antibacterial activity of echinacea is quite mild. This is somewhat surprising, as echinacea has a long history of effective use in both internal and external bacterial infections. Possibly, it possesses antiinfective properties that prevent bacterial adherence, though this has yet to be determined. Clearly, its clinical efficacy is due to its strong immune-potentiating actions. Echinacea possesses mild antibacterial action due largely to echinacoside, the complex caffeic acid derivative,

Pharmacology of Natural Medicines found in highest concentrations in the root of E. ungustifoliu. Echinacoside and caffeic acid have been shown to have antibacterialaction against Stuphylococcus uureus, Coynebucterium diphtheria, and Proteus vulgaris. Approximately 6.3 mg of echinacoside is equivalent to 10 Oxford units of ~enicillin.~,'~

Antineoplastic Activity Obviously, echinacea possesses indirect, antineoplastic activity via its general immuno-enhancing effects. Specifically important is its stimulation of macrophages to greater cytotoxic activity against tumor cells. (Z)-1,8pentadecadiene, a lipid-soluble component found in the root of E. angustifoh and E. pullufu, has been shown in vivo to possess signhcant direct antineoplastic activity.%

CLINICAL APPLICATIONS Echinacea has long been used clinically for conditions where its pharmacologic actions have proven efficacy, especially in infections. Clinical studies have demonstrated effectivenessin a number of infectious conditions using all three routes of administration: injectable, oral, and topical. However, not all of the clinical studies have been positive. Mixed results from clinical studies with echinacea are most likely due to lack of or insufficient quantity of active compounds. The axiom for effectiveness of any herbal product is its ability to deliver an effective dosage of active compounds. If the product, by chance, had sufficient levels of active compounds, it would be effective. If not, it would likely be no more effective than a placebo. For example, the most recent clinical trial using a well-defined echinacea extract containing alkamides, cichoric acid, and polysaccharides at concentrations of 0.25, 2.5, and 25 mg/ml, respectively, prepared from freshly harvested E. purpureu plants (commercially available as Echinilin), showed excellent results.37In this randomized, doubleblind, placebo-controlled trial, 282 subjects 18 to 65 years old with a history of two or more colds in the previous year, but otherwise in good health, were randomized to receive either echinacea extract or placebo. They were instructed to start the echinacea or placebo at the onset of the first symptom related to a cold, consuming 10 doses the first day and four doses per day on subsequent days for 7 days. Severity of symptoms (10-point scale: 0, minimum; 9, maximum) and dosing were recorded daily. A nurse examined the subjects on the mornings of days 3 and 8 of their cold. A total of 128 subjects contracted a common cold (59 echinacea, 69 placebo). The total daily symptom scores were found to be 23.1%lower in the echinacea group than in the placebo group. Throughout the treatment period, the response rate to treatments was greater in the echinacea group. This study indicated that early intervention with a

standardized formulation of echinacea resulted in reduced symptom severity in subjects with naturally acquired upper respiratory tract infection. In contrast to this positive result, several studies with less welldefined echinacea products showed little benefit, especially in experimentally induced rhinovirus infections. For example, in one double-blind study 160 subjects were given either echinacea or placebo and then exposed to a common cold virus. Infection occurred in 44 and 57%and illness occurred in 36 and 43% of the echinaceaand placebo-treated subjects, respectively. However, the preparation contained no echinacosides or alkamides and contained only 0.16%cichoric acid. In another double-blind study illustrating the problems with clinical research on echinacea, 302 volunteers from four military institutions and one industrial plant in Germany were given either a placebo or alcohol-based tinctures from either E. purpureu or E. angustifilia for 12 weeks.38The main outcome measure was time until the first upper respiratory tract infection. The secondary outcome measures were the number of participants with at least one infection, global assessment, and adverse effects. The time until occurrence of the first upper respiratory tract infection was 66 days in the E . angustifoh group, 69 days in the E. purpureu group, and 65 days in the placebo group. In the placebo group 36.7% had an infection, while in the E . ungustifoliu group it was 32% and in the E. purpureu group it was 29.3%.These results indicate that there was no significant benefit with either form of echinacea, although there was an approximately 20% reduced risk of infection in the echinacea groups. In addition, 70% of the E. purpureu and 78% of the E. angustifoh group felt they had benefited from treatment compared with 56% in the placebo group. The E. ungustifolia had a slightly higher percentage of subjects experiencing side effects (18%)compared with the E. purpureu (10%) and placebo (11Y0)groups. On the surface, these results do not seem to support the effectiveness of echinacea preparations in the prevention of upper respiratory infections. However, both echinacea preparations used were weak ethanol-based tinctures. The herb-to-solvent ratio was 1:11, meaning that for every gram of herbal material there were 11 ml of the water and alcoholic (30% ethanol) solution. The dosage that was administered was 50 drops twice daily, supplying a daily dosage of approximately 2 ml (or, using the herb-to-solvent ratio, about 200 mg of echinacea, hardly a therapeutic dose). Furthermore, the starting material of both forms of echinacea was dried root and neither preparation was analyzed for active compounds. If they had been, it is likely that neither would have contained sufficient levels to produce an effect. At present, although the results from clinical research are mixed, given the long history, safety, and confirmed

Echinacea Species (Narrow-Leafed Purple Coneflower) immune-enhancing effects in experimental modes, as well as the numerous clinical studies that have shown positive results, the clinical applications of echinacea include the following: Treatment of the common cold and other viral respiratory tract infections Possible prevention of the common cold and viral respiratory tract infections Treatment of temporary immune deficiency and increased susceptibility to infections Children in daycare or nurseries Adults experiencing undue stress Sport-induced immunodeficiency Supportive therapy to enhance the effectiveness of antibiotics in bacterial infections Chemotherapy and radiation-induced immune suppression Herpes simplex infections

The Common Cold One of the most popular uses of echinacea is in the treatment of the common cold. This application has been extremely difficult to venfy in clinical studies for several reasons beyond the issue of quality control and dosage given earlier. Nonetheless, reasonably large and welldesigned, double-blind, placebo-controlled studies have found echinacea effective for aborting, as well as reducing the symptoms and duration of ~ o l d s . * ~ ”These 3~ studies have used all various species and extracts of the herb. In one study, 180 patients with influenza were given either an extract of E. purpureu root at a daily dose of 450 mg or 900 mg or a placebo. The 450-mg dose was found to be no more effectivethan a placebo; however, the group taking the 900-mg dose had a sigruficant reduction in cold symptoms.40 In the other study, 108 patients with colds received either an extract of the fresh-pressed juice of E. purpureu (4 ml twice daily) or placebo for 8 weeks.4l The number of patients remaining healthy was as follows: echinacea, 35.2%; placebo, 25.9%. The length of time between infections was: echinacea, 40 days; placebo, 25 days. When infections did occur in patients receiving echinacea, they were less severe and resolved quicker. Patients showing evidence of a weakened immune system (CD4CD8 ratio < 1.5) benefited the most from echinacea. The results from one trial were especially encouraging, as they suggested that echinacea can not only make colds shorter and less severe, it can sometimes stop a cold that is just starting.42In this study, 120 people were given E. purpureu or a placebo as soon as they started showing signs of getting a cold. Participants took either echinacea or placebo at a dosage of 20 drops every 2 hours for 1 day, then 20 drops 3 times a day for 9 more days.

Fewer people in the echinacea group felt that their initial symptoms actually developed into “real” colds (40% of those taking echinacea vs. 60% taking the placebo actually became ill).Also, among those who did come down with ”real” colds, improvement in the symptoms started sooner in the echinacea group (4 days instead of 8 days). Both results were statistically sigruficant. However, echinacea’s ability to shorten the duration of colds was more dramatic. On the other end of the spectrum, a trial of the freshpressed juice of €. purpureu in reducing the duration or severity, or both, of upper respiratory infections in children 2 to 11 years old was quite disappointing. The results from the trial indicated that E. purpureu, as dosed in this study, was not only ineffective, but its use was associated with an increased risk of r a ~ h . 4 ~ In another double-blind trial, 128 patients received either 100 mg of E. purpureu (freeze-dried pressed juice from the aerial portion of the plant) or a placebo three times daily until cold symptoms were relieved or until the end of 14 days, whichever came first.41Symptoms (sneezing, nasal discharge, nasal congestion, headache, sore or scratchy throat, hoarseness, muscle aches, and cough) were scored subjectively by the patient and recorded daily in a diary. No statistically sigruficant difference was observed between treatment groups for either total symptom scores or mean individual symptom scores. The time to resolution of symptoms was also not statistically different. Clearly, more research using well-characterized echinacea preparations at appropriate dosages are necessary in well-designed trials. Currently, the “gold standard” for evaluating cold remedies involves inoculating healthy individuals with rhinovirus. Though the concentration of viral assault is much greater than what one might encounter in the real world, any substance showing efficacy in this model is regarded as being highly efficacious. In one study, 48 healthy adults received echinacea or placebo, 2.5 m13 times per day, for 7 days before and 7 days after intranasal inoculation with rhinovirus (RV-39)j5A total of 92% of echinacea recipients and 95% of placebo recipients were infected. However, colds developed in 58% of echinacea recipients compared with 82% of placebo recipients. Although administration of echinacea before and after exposure to rhinovirus did not decrease the rate of infection, it did appear to reduce the clinical development of a cold. However, because of the small sample size, statistical hypothesis testing had relatively poor power to detect statistically significant differences in the frequency and severity of illness. The only other experimental rhinovirus infection and echinacea study was seriously marred. In this trial, 160 subjects were given either echinacea or placebo and then exposed to rhinovirus. Infection occurred in 44%

Pharmacology of Natural Medicines and 57% and illness occurred in 36% and 43% of the echinacea- and placebo-treated subjects, respectively.& These results indicate that eclunacea was not very effective; however, the preparation used contained no echinacosides or alkamides and contained only 0.16%cichoric acid.

Candidiasis Echinacea’s effect against C. ulbicuiis noted in animal studies has been confirmed in several human clinical ~ t u d i e sA . ~ study featured in Table 89-2 demonstrated that Echinacin greatly accentuated the efficacy of a topical antimycotic agent (econazole nitrate), decreasing reoccurrence from 60.5% to 5% to 16.7%.The researchers used standardized skin tests to show that this enhancement was due to echinacea’s boosting of cell-mediated imm~nitY.4~ Also of interest is the similarity in the efficacies of the oral and injectable forms.

Arthritis Echinacea’s antiinflammatory activity has been shown in uncontrolled studies to be useful in rheumatoid arthritis. In one study, 15 drops of Echinacin three times daily resulted in a 21.8% decrease in inflammation. Although this improvement was less than cortisone (42%) and prednisone (49.2%),no side effects are associated with Echinacin while the drugs have well-known side effects.50

Cancer

Several studies have noted a stimulatory effect of echinacea on leukocyte counts in patients receiving radiation for cancer therapyM5’A study using the commercial preparation Esberitox demonstrated that 85% of 55 patients showed a stabilization of leukocyte counts compared with the control group, which showed a steady decline in levels (starting at 6000 and decreasing to 2500 after Snakebites 45 days).ls This strongly supports the recommendation of echinacea to patients undergoing orthodox cancer Echinacea has quite a reputation among naturopathic treatments. physicians and native American healers for the treatment of snakebites. No studies of this use have been carried In an open prospective study with matched historical out, but echinacea’s inhibition of hyaluronidase might controls, an injection of polysaccharide fraction isolated account for much of its reputed efficacy, since most snake from the herb E. purpureu was shown to counteract the venoms permeate the system as a result of hyaluronidase undesired effects of chemotherapy? Fifteen patients in the venom breaking down connective tissue of the with advanced gastric cancer undergoing palliative ground substance. chemotherapy with etoposide, leucovorin, and 5-fluorouracil (ELF) received for 10 days (beginning 3 days Wound Healing before chemotherapy) daily intravenous injections of 2 mg of a polysaccharide fraction isolated from E . purpureu herb Several uncontrolled clinical studies have been reported to substantiateechinacea’s wound-healing a~tivities?J6,~*~~ cell cultures. The median number of leukocytes 14 to The largest (4598 patients) demonstrated that a salve of 16 days after chemotherapy was 3630/pl in the patients the juice of the aerial portion of E. piirpureu had an 85% receiving echinacea polysaccharide compared with 2370/p1(870 to 3950) in the patients of the historical conoverall success rate in the treatment of inflammatory skin conditions such as abscesses, folliculitis, wounds trol group. These results suggest that echinacea might be of all kinds, eczema, burns, herpes, and varicose ulcers effective in reducing chemotherapy-induced leukopenia. of the leg3

COMMERCIAL PREPARATIONS

Therapeutic scheme

No. of patients

Recurrence rate (%)

Topical antimycotic alone

43

60.5

Topical antimycotic + subcutaneous Echinacin

20

15

Topical antimycotic + intramuscular Echinacin

60

5

Topical antimycotic + intravenous Echinacin

20

15

Topical antimycotic + oral Echinacin

60

16.7

Modified from Coeugniet EG. Kuhnast R. Therapiewoche 1986:36:3352-3358.

As evident from the above information, determining which Echinacea preparation is best is difficult to determine. It is not only difficult to determine which species is most effective, the portion of the plant used and how it is prepared are also seriousissues. Dosage recommendations for all currently available forms follow, along with a few observations regarding the ”preparations controversy.” Another problem that needs to be addressed is quality control. Since as early as 1904, many commercial sources of echinacea have contained adulterants and no echinacea. For example, it has been estimated that due to supplier errors in collection, more than 50% (and possibly as high as 90% at times) of the echinacea sold in the United States from 1908 to 1991 has actually been Purthenium integrifolium, or Missouri ~ n a k e r o o tSome .~~ suggest that this adulteration is due to confusion of the common names. Others point out that although the

Echinacea Species (Narrow-Leafed Purple Coneflower)

Parthenium integrifolium plant looks quite different ". . . once the root is cut and sifted it has an uncanny resemblance to E. angustifoh or E. PaZZida roots, though it possesses its own characteristic flavor and fragrance."53 From practical and clinical viewpoints, physicians should require from suppliers adequate documentation that they are, in fact, supplying echinacea, as well as its species.

Species Although studies have shown various echinacea species, or components found in higher concentrations in one species, to be more effective than others, each commercial species has its advantages and disadvantages. No "best" species can be recommended at this time, as differing experimental models have yielded inconsistent results. Rather, the clinician must recognize the unique value of each species. Although E. angustifoliu has long been considered the best species and to possess the greatest activity, some studies dispute this.For example, several studies have shown E. purpurea to demonstrate greater enhancement of phagocytosis. In fact, in one study, an aqueous extract of E. angustifoh did not demonstrate any impact on phagocytic function in rats, whether it was administered orally, intraperitoneally, or intravenously? As E. purpurea is the easiest to grow commercially, it may become the most used in the United States, as it is in Europe.

Part of the Plant to Use The portion of the plant that possesses the greatest immune-enhancing properties depends on the experimental model. The key points, as described earlier, are that various echinacea components have exerted immuneenhancing effects and there is clearly a synergistic effect among these constituents.

Preparations Echinacea products are available in many different forms: Crude plant in either ground or powdered form Freeze-dried Alcohol-based tinctures and liquid extracts Aqueous tinctures and liquid extracts Dry, powdered alcoholic or aqueous It is popular to standardize hydro/alcoholic extracts for echinacoside (for E . angustifolia) or cichoric acid (for E. purpurea). Although these extracts are thought by their proponents to be the most potent, it must be noted that even 4-10 X homeopathic preparations have been shown to produce activity.31

Solvents Which solvent is best to use? Again, this question is extremely difficult to answer, as both hydrophilic

and lipophilic components have been shown to possess immune-enhancing activities. Even a small amount of ethanol results in precipitation or breakdown of the immuno-active polysaccharides, suggesting that aqueous extracts may be best. However, an aqueous extract would leave behind valuable lipophilic immuneenhancing alkylamides and caffeic acid derivatives. To optimize an extract's immune-enhancing effects, many manufacturers use low ethanol (10% to 20%) hydro/ alcoholic mixtures or combine a low ethanol extract with a high ethanol extract. Both products typically contain both polar and lipophilic compounds.

DOSAGE Box 89-1 lists dosages of echinacea as a general immune stimulant during infection. The question of whether echinacea should be used on a long-term or continual basis really depends on the need. In a healthy individual with no apparent depression of the immune system, continual administration is certainly not indicated. However, as recent studies have shown, patients with impaired immune function experience longterm benefit.4O The usual recommendationwith long-term use is 8 weeks on, followed by 1week off.

TOXIC0LOGY When used at the recommended doses, there is no danger of toxicity, as no studies have reported acute or chronic toxicity reactions due to Echimcea extracts. Echinacin, given intravenously, has resulted in the production of fever (0.5" C to 1" C elevation in body temperature) on occasion. This is presumably a result of secretion of interferon-alpha and IL-1 by activated macrophages.3 The median lethal dose (LDm)of intravenous Echinacin has been determined to be 50 d / k g body weight in mice and rats. The polysaccharides in E. purpurea (aerial portion) were shown to have an LDm of 1000 to 2500 mg/kg when given peritoneally to mice. Chronic administration of Echinacin to rats at doses many times the human therapeutic doses gave no evidence of any toxic effects." Mutagenic tests with Echinacin demonstrated no mutagenic activity?

Dried root (or as tea): 0.5-1 g Freeze-dried plant: 325-650 mg Juice of aerial portion of Echinacea purpurea stabilized in 22% ethanol: 2-3 ml (0.5-0.75 tsp) Tincture (15): 2-4 ml (1-2 tsp) Fluid extract (1:l):1-2 ml ('12-1 tsp) Solid (dry-powdered) extract (6.51 or 3.5% echinacoside): 150-300 mg

Pharmacology of Natural Medicines

Modem reviews of the safety and efficacy of Echirzacea are theoretic, as there is no evidence that echinacea use spp. have found no toxicity in both adults and children in has actually harmed anyone with these diseases. cases of both acute and long-term a d m i n i ~ t r a t i o n . ~ - ~ ~ * ~ 5~ Echinacea appears to be safe even for pregnant or lactatReported side effects are also uncommon and usually ing women based on both animal studies and evaluation limited to minor gastrointestinal symptoms, increased studies in women using echinacea during pregnancy urination, and mild allergic reactions. However, severe showing no harmful effects.59 allergic reactions have occurred occasionally, some of them life threatening. Allergic reactions have most often DRUG INTERACTIONS been reported in people who are also allergic to other members of plants in the daisy (Compositae) family Theoretically, echinacea may interfere with drugs that (e.g., daisy, ragweed, marigolds).% are purposely used to suppress the immune system. The German Commission E warns against using echiThese include cyclophosporin, which is used in patients nacea in cases of autoimmune disorders such as multiple who have had organ transplants to prevent the immune sclerosis, lupus, and rheumatoid arthritis. These warnings system from rejecting the transplanted organ.

1. McGregor RL. The taxonomy of the genus Echinncen (Compositae). UNv Kansas Sci Bull 1968;48:113-142. 2. Barrett 8. Medicinal properties of Echinacea: a critical review. Phytomedicine 2003;10:66-86. 3. Bauer R, Wagner H. Echinacea species as potential immunostimulatory drugs. In Wagner H, Famsworth NR,eds. Economic and medicinal plant research, vol5. New York: Academic Press, 1991:253-321. 4. Gwl V, Chang C, Slama J, et al. Echinacea stimulates macrophage function in the lung and spleen of normal rats. J Nutr Biochem 2002; 13487. 5. Perry NB,Burgess EJ, Glennie VL. Echinacea standardization: analyhcal methods for phenolic compounds and typical levels in medicinal species. J Agric Food Chem 2001;49:1702-1706. 6. Pellati F, Benvenuti S, Magro L, et al. Analysis of phenolic compounds and radical scavenging activity of Echiiiacea spp. J Pharm Biomed Anal 2004;35:289-301. 7. Rininger JA,Kickier S, Chigurupati P, et al. Immunopharmacological activity of Echinacea preparations following simulated digestion on murine macrophages and human peripheral blood mononuclear cells. J Leukoc Biol2000;68:503-510. 8.Perry NB, van Klink JW, Burgess EJ, et al. Alkamide levels in Echinucea purpurea: effects of processing, dqmg and storage. Planta Med 2000;66:54-56. 9. Kim HO,Durance TD, Scaman CH, et al. Retention of caffeic acid derivatives in dried Echinacea purpurea. J Agric Food Chem 2000; 4tk41824186. 10. Stuart DL, Wills RB. Effect of drying temperature on alkylamide and cichoric acid concentrations of Echinacea purpurea. J Agric Food Chem 2003;51:1608-1610. 11. Bauer R. Standardization of Echinacea purpurea expressed juice with reference to cichoric acid and alkamides. J Herbs Spices Medicinal Plants 1999;651-61. 12. Wagner H,Proksch A, Riess-Maurer I, et al. [Immunostimulating action of polysaccharides (heteroglycans) from higher plants. Arneimittelforschung 1985;35:1069-1075. 13. Stimpel M. Proksch A, Wagner H, et al. Macrophage activation and induction of macrophage cytotoxicity by purified polysaccharide fractions from the plant Echinacea purpurea. Infect Immun 1984; 46: 845-849. 14. Luettig B, Steinmuller C, Gifford GE, et al. Macrophage activation by the polysaccharide arabinogalactan isolated from plant cell cultures of Echinacea purpurea. J Natl Cancer Inst 1989;81:669-675.

15. Tubaro A,Tragni E, Del Negro P, et al. Anti-inflammatory activity of a polysaccharide fraction of Echinacea angustifolia. J Pharm Pharmacol 1987;39:567-569. 16. Clifford LJ, Nair MG, Rana J, et al. Bioactivity of alkamides isolated from Echinucea piirpurea (L.) Moench. Phytomedicine 2002;9:249-253. 17. Bauer R, Remiger P. TLC and HPLC analysis of alkylamindes in echinacea drugs. Planta Med 1989;55367-371. 18. Goel V, Chang C, Slama JV, et al. Alkylamides of Echinacea purpurea stimulate alveolar macrophage function in normal rats. Int Immunopharmacol2002;2:381-387. 19. Stoll A, Renz J, Brack A. Antibacterial substances 11. Isolation and constitution of echinacoside, a glycoside from the roots of Echinacea angustifoh. Helv Chim Acta 1950;33:1877-1893. 20. Bauer R, Reminger P, Alstat E. Alkamides and caffeic acid derivatives from the roots of Echinacea tennesseensis. Planta Med 1990;56:533-534. 21. Neugebauer H. The constituents of Echinacea. Pharmazie 1949;4: 137-140. 22. Heinzer F, Meusy JP, Chavanne M. Echinacea pallida and Echinacea purpurm. Follow-up of weight development and chemical composition for the first two culture years. Proceedings of the 36th Annual Congress of the Society of Medicinal Plant Research. Freiburg, Germany, September 12-16,1988. 23. Schulte KE, Rucker G, Perlick J. [The presence of polyacetylene compounds in Echinacea purpura Mnch and Echinacea angustifolia DC.]Arzneimittelforschung 1967;17825-829. 24. Bauer R, Khan IA,Wagner H. TLC and HPLC analysis of Echinacea pallida and E. angustifoh roots. Planta Med 1988;54:426-430. 25. Roder E, Wiedenfeld H, Hille T, et al. Pyrrolizidine in Echinucea angustifoh DC,und Echinacea purpurea MOENCH-Isolierung und Analytik. Dtsch Apoth Ztg 1984;1242316-2318. 26. Vogel VJ. American Indian medicine. Norman, OK University of Oklahoma Press, 1970:356-357. 27. Felter H.The eclectic materia medica, pharmacology and therapeutics. Portland, OR Eclectic Medical Publications, 1983547-351. 28. KutsCheraux AW. Naturae medicina and naturopathic dispensatory. Yellow Springs, OH: Antioch Press, 1953. 29. Percival SS. Use of echinacea in medicine. Biochem Pharmacol 2000;60:155-158. 30. Tragni E, Tubaro A, Melis S, et al. Evidence from two classic irritation tests for an anti-inflammatory action of a natural extract, Echinacina B. Food Chem Toxic01 1985;23:317-319.

Echinacea Species (Narrow-Leafed Purple Coneflower) 31. Wagner H,Breau W, Wder F, et al. In v i h inhibition of arachidonate metabolism by some alkamides and phenylated phenols. Planta Med 198935566-567. 32. Mose JR. [Effect of echinacin on phagocytosis and natural killer cells.] Med Welt 1983;34:1463-1467. 33. Roesler J, SteinmullerC, Kiderlen A, et al.Application of purified polysaccharides from cell cultures of the plant Echinacea purpum to mice mediates protection against systemic infections with Listerin monocytogenes and Candida albicuns. Int J Immunopharmacol1991;1327-37. 34. Wacker A, Hilbig W. [Virus-inhibitionby Echinucea purpurea.] Planta Med 1978;33:89-102. 35. Hopp ES, Bum HF. Ground substance in the nose in health and infection. Ann Otol Rhino1 Laryngol1958;67480-490. 36. Voaden D, Jacobson M. Tumor inhibitors. 3. Identification and synthesis of an oncolytic hydrocarbon from American coneflower roots. J Med Chem 1972;15:619-623. 37. Goel V, Lovlin R, Barton R, et al. Efficacy of a standardized echinacea preparation (Echinilin) for the treatment of the common cold: a randomized, double-blind, placebc-controlled trial. J Clin Pharm Ther 2004;2975-83. 38.Melchart D, Linde K, Worku F, et al. Immunomodulation with Echinacea-a systematic review of controlled clinical trials. Phytomedicine 1994;1:245-254. 39. Melchart D, Linde K, Fischer P, et al. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2000;Z: CDO00530. 40.Braunig B, Dom M, Limburg E, et al. Echinacea purpurea radix for strengthening the immune response in flu-like infections. Z Phytother 1992;13:7-13. 41. Schoneberger D.The influence of immune-stimulating effects of pressed juice from Echinucea purpureu on the course and severity of colds. Results of a double-blind study. Forum Immunologie 1992; 8: 2-12. 42. Hoheisel 0,Sandberg M, Bertram S, et al. Echinagard treatment shortens the course of the common cold: a double-blind, placebocontrolled clinical trial. Eur J Clin Res 1997;9:261-268. 43. Taylor JA, Weber W, Standish L, et al. Efficacy and safety of echinacea in treating upper respiratory tract infections in children: a randomized controlled trial. JAMA 2003;290:28242830. 44.Yale SH,Liu K. Echinacea purpurea therapy for the treatment of the common cold: a randomized, double-blind, placebo-controlled clinical trial. Arch Intem Med 2004;162:1237-1241.

45. Sperber SJ,Shah LP, Gilbert RD, et al. Echinaceu purpureu for prevention of experimental rhinovirus colds. Clin Infect Dis 2004; 38:1367-1371. 46. Turner RB, Riker DK, Gangemi JD. Ineffectiveness of eclunacea for prevention of experimental rhinovirus colds. Antimicrob Agents Chemother 2000;441708-1709. 47. Coeugniet EG, Kuhnast R. Recurrent candidiasis: adjuvant immunotherapy with different formulations of Echinacin. Therapiewoche 1986363352-3358. 48. Pohl P. [On the therapy of irradiation-induced leukopenia with Esberitox.] Med Klin 1969;62:1546-1547. 49. Kinkel HJ, Plate M, Tullner HU. [Effect of Echinacin ointment in healing of skin lesions.] Med Klin 1984;79:580-583. 50.Seidel K, Knobloch H. [Determination & comparison of the antiphlogistic effects of antirheumatic drugs.] Z Rheumaforsch 1957;16:231-238. 51. Chone B, Manidakis G. [Echinacintest for the provocation of leukocytes in effective radiotherapy.] Dtsch Med Wochenschr 1969;94: 1406-1410. 52. Melchart D, Clemm C, Weber B, et al.Polysaccharides isolated from Echinacea purpum herba cell cultures to counteract undesired effects of chemotherapy-a pilot study. Phytother Res 2002;16:138142. 53. Foster S. Echinacea. Nature's immune enhancer. Rochester, VT: Healing Arts Press, 1991. 54. SchumacherA, Friedberg KD. [The effect of Echinaceu ungrrstifoliu on non-specific cellular immunity in the mouse.] Arzneimittelforschung 1991;41:141-147. 55. Mengs U,Clare CB, Poiley JA. Toxicity of Echinuceu purpurea. Acute, subacute and genotoxicity studies. Arzneimittelforschung 1991; 41:1076-1081. 56. Pamham MJ. Benefit-risk assessment of squeezed sap of the purple coneflower (Echinaea purpurea) for long-term oral immunostimulation. Phytomedicine 19963:95-102. 57. Giles JT,Palat CT ID,Chien SH, et al. Evaluation of echinacea for treatment of the common cold. Pharmacotherapy 2000;20:690-697. 58. Mullins RJ, Heddle R. Adverse reactions associated with echinacea: the Australian experience. Ann Allergy Asthma Immunol 2002; 88:42-51. 59. Gallo M, KO= G. Can herbal produds be used safely during pregnancy? Focus on echinacea.Can Fam Physiaan 2001;471727-1728.

Eleuthermoccws senticosws (Siberian Ginseng) Michael T. Murray, ND Joseph E.Pizzorno Jr, ND CHAPTER C O N T E N T S General Description 919 Chemical Composition 919

Clinical Applications 922 Adaptogenic Activity in Healthy Individuals 922 Adaptogenic Activity in Disease States 922

History and Folk Use

Dosage 923

919

Pharmacology 921 Adaptogenic Activity 921 Stress Control 922 Radiation Protection 922 Carcinogenesis Inhibition 922

Eleutherococcus or Acanthopanax senticosus (family: Araliaceae) Common names: Siberian ginseng, touch-me-not, devil's shrub, eleuthero ginseng

GENERAL DESCRIPTION Eleutherococcus senticosus, or Siberian ginseng, is a shrub that grows 5 to 8.5 feet high. Its erect, spiny shoots, 1.5 to 2.5 inches in diameter, are covered with a light gray or brownish bark. The leaves are long petioled in a compound, palmate configuration. The five leaflets are elliptic and finely serrated at the margins on both sides, with scattered, minute spinules along the veins.' Eleuthero grows abundantly in parts of the Soviet Far East, Korea, China, and Japan, north of latitude 38. Its distribution is much greater than that of Panax ginseng (see Chapter l l l ) . I The root is the most widely used component, with the highest concentration of biologically active substances occurring in the fall, just before defoliation. The leaves are also used medicinally, with their highest concentration of biologically active substances occurring in July, just before flowering.

CHEMICAL COMPOSITION The initial phytochemical report on eleuthero was published in 1965 by members of the Institute of

Toxicology 923 Drug Interactions 923

Biologically Active Substances in Vladivostok, Russia.' Seven compounds, termed eleutherosides A-G, were isolated from a physiologically active fraction of the methanol extract of eleuthero. The total eleutheroside content of the root ranges from 0.6% to 0.9%, and of the stems it ranges from 0.6% to 1.5%. The ratio of the eleutherosides A-G obtained is approximately 8:30:10:12:4:2:1,respectively. Figure 90-1 illustrates structure of a key type of constituent. Table 90-1, modified from reviews of eleuthero, summarizes what is currently known about the components of E. senticosus.' It is important to recognize that thin-layer chromatographic analysis has shown that the ginsenosides characteristic of Panax sp. (American, Chinese, Korean, Japanese ginsengs) are not present in the roots of

E. senticosus.

HISTORY AND FOLK USE Ginseng plants, members of the family Araliaceae including Eleutherococcus senticosus, are among the most ancient and esteemed of all medicinal herbs. Their use in Chinese herbal medicine dates back more than 4000 years.lr2 References in ancient documents to members of the Araliaceae family were imprecise, giving rise to some confusion in modem interpretation. However, the value of eleuthero as a medicinal agent was certainly known to the Chinese, as evidenced by the following ode [Ode to Wujia ( E . senticosus) by 919

Pharmacology of Natural Medicines

p - D - Glucoside

Ye Zhishen (Qmg Dynasty)12:

V '

From earth and heavens the quintessence originates, Five folioles clustering your leaves, And pretty little thorns wrapped whole your shoots; Oh what a jackal's gaunt leg looks much alike. How wonderful is Winzhang-grass, the Eleutheroginseng Dispensing in liquor for drinking, And decocting with burnet for daily using, It will keep your virgin face younger And prolong your life for ever and ever; Even i f a cartload of gold and jewels, That cannot estimate your price of nature.

CH,OH

OCH,

Flgure 90-1 Eleuthemside 6.

Compoundsfound in €leuthemcoccus senticosus Compound

Type

Location

Eleutheroside A (daucosterol)

Sterol

Roots, stems

Eleutheroside B(syringin)

Phenylpropanoid

Roots, stems

Eleutheroside B, (isofraxidin-7-0-alpha-L-glumside;also known as beta-calycanthoside)

Coumarin

Roots

Eleutheroside 82

Unknown

Roots

Eleutheroside 83

Unknown

Roots

Eleutheroside B4 [(-)-sesamin]

Lignan

Eleutheroside C (methyl-alpha-D-galactoside) Eleutheroside D [(-)-Syringarsinoldi-0-beta-D-glucoside]

Sugar Lignan

Roots Roots, stems

Eleutheroside E (different crystalline form of D; also known as acanthoside D)

Lignan

Roots, stems

Eleutheroside F

Unknown

Roots

Eleutheroside G Eleutheroside I (=mussenin B)

Unknown

Roots

Triterpene

Leaves

Triterpene Triterpene

Leaves Leaves

Triterpene

Leaves

Triterpene

Vitamin E

Benzofuran

Leaves Roots

Beta-carotene

Carotenoid

Roots

lsofraxidin

Coumarin

Roots

Coumarin X

Coumarin

Roots

Complex mixture

Essential oil

Roots

Copper (-)-Syringaresinol

Mineral

Roots

Lignan

Caffeic acid Caffeic acid ethyl ester

Phenylpropanoid

Roots Roots

Eleutheroside K Eleutheroside L Eleutheroside M (= hederasaponin B) Senticosides A-D (may be identical to eleutherosid

nd M)

Roots, stems

Phenylpropanoid Phenylpropanoid Phenylpropanoid

Roots Roots

Sterol

Roots

Polysaccharides

Sugar

Galactose Glucose (alpha and beta)

Sugar

Roots, fruit Roots

Sugar

Roots

Maltose (alpha and beta) Sucrose

Sugar Sugar Triterpene

Roots Roots

Coniferyl aldehyde Synapyl alcohol Beta-sitosterol

Oleanolic acid Modified from Davydov M, Krikorian AD. J Ethnopharmacol2OOO;72:345-393.

Roots

Roots

Eleutherococcus senticosus (Siberian Ginseng)

The Chinese have long believed that the regular use of eleuthero would increase longevity, improve general health and appetite, and restore memory. The Russians have a separate history of eleuthero and even claimed, despite a long history of use by Chinese herbalists (references date back to 2000 BC), that "Eleutherococcus was not known in Oriental folk medicine." The Russian history of eleuthero begins in 1855 when a pair of Russian scientists, C. I. Maximovich and L.I. Shrenk, traveled from St. Petersburg to the Ussuri region of Russia on the Amur River. It was in this area that Maximovich observed a vast thicket of unusual plants, with leaves resembling horse chestnut and young shoots resembling ginseng. Unable to idenhfy the plant, the two scientists brought back samples to St. Petersburg for classification. The plant was given the genus name of EZeuthero, or "free-berried shrub," and the species name of senticosus, which means "thorny" in Latin. Not until the middle of the twentieth century was eleuthero again "discovered," when Russian scientists began investigating substances that produce a "state of nonspecific resistance" in the body. Substances with this effect were termed adapfogens.In 1958Brekhman described an adaptogen as It must be innocuous and cause minimal disorders in the physiologic functions of an organism. It must have a nonspecific action (i.e., it should increase the resistance to adverse influences by a wide range of physical, chemical, and biochemical factors). It usually has a normalizing action irrespective of the direction of the pathologic state (alterative action). Brekhman's research with adaptogens began with P. ginseng, since this was the best-known natural adaptogen. After confirming the adaptogenic action of panax in human studies, Brekhman began searching for an alternative to this plant because of the difficulty and expense in obtaining panax. Initially, all six species of Araliaceae native to Russia were investigated and eleuthero was found to be the most promising. Numerous studies (in vivo, in vitro, and human studies) have been conducted since the late 1950s, nearly all in the Soviet Union. They are not referenced here as they are not translated and not widely available. Instead, review articles and original articles in English are ~ i t e d . l - ~

Adaptogenic Activity An important characteristic of an adaptogen is its ability

to "normalize," irrespective of the direction of pathology. E. senticosus has been found to do the following in experimental models: Impede the adrenal hypertrophy induced by adrenocorticotropic hormone and the adrenal atrophy induced by cortisone Impede the thyroid hypertrophy induced by thyroidin and thyroid gland atrophy induced by 6-methylthiouracil Reduce blood glucose levels in alimentary and adrenal hyperglycemia and increase glucose levels in insulininduced hypoglycemia Reduce leukocytosis induced by the parenteral administration of milk, as well as leukopenia induced by endotoxins Reduce erythrocytosis induced by cobaltous nitrate and erythropenia induced by phenylhydrazine These are summarized in Table 90-2. Similar results have been obtained with I? ginseng (see Chapter 111).

Function

Normalization action of Eleutherococcus senticosus

Adrenal

Impedes hypertrophy induced by ACTH Impedes atrophy induced by cortisone

Thyroid

Impedes hypertrophy induced by thyroidin Impedes atrophy induced by 6-methylthiouracil

Kidney

Increases renal capacity in pyelonephritis

Blood pressure

Decreases high blood pressure through improvement of atherosclerosis Increases pressure in hypotension

Blood glucose

Reduces alimentary and adrenal hyperglycemia Increases blood sugar in insulin-induced hypoglycemia

Leukocyte

Reduces leukocytosis induced by the administration of milk Reduces leukopenia induced by endotoxins

Erythrocyte

Reduces erythrocytosis induced by cobaltous nitrate Reduces erythropenia induced by phenylhydrazine

Stress

Reduces activation of the adrenal cortex in response to stress Prevents stress-induced thymic and lymphatic involution

Radiation

Protects against radiation exposure

Cancer Cholesterol

Inhibits carcinogenesis from urethane, 6-methylthiouracil indole Reduces hepatic biosynthesis

DNA

Stimulates synthesis

PHARMACOLOGY As mentioned earlier, a number of experimental and clinical studies have demonstrated that eleuthero possesses adaptogenic properties (i.e., the ability to increase nonspecific body resistance to stress, fatigue, and disease). Additional experimental and clinical research supports other therapeutic applications of E. senticosus.

ACTH, Adrenocorticotropic hormone; DNA, deoxyribonucleic acid.

Pharmacology of Natural Medicines

Stress Control Another important action of adaptogens is the inhibition of the alarm phase of the stress reaction. Eleuthero has shown similar action to P. ginseng in experiments designed to demonstrate an antialarm action. Specifically, eleuthero has been shown to increase the swimming time of rats, reduce activation of the adrenal cortex in response to stress (alarm phase reaction), and prevent stress-induced thymic and lymphatic involution.'"

Radiation Protection In addition to its confirmed adaptogenic activity, eleuthero has also demonstrated both protective and therapeutic actions in animals exposed to both single and prolonged x-ray radiation. In one study, both E. senticosus and P. ginseng were found to double the life span of rats exposed to prolonged radiation (total doses of 1620 to 7000 rads). When eleuthero was combined with antibiotics, the lifetime of irradiated rats (total dose of 3000 rads over 60 days) increased threefold.' These results suggest that eleuthero may be of benefit in protecting against harmful radiation and as an adjunctive aid in radiation therapy in oncology. The latter suggestion is further supported by studies of eleuthero that have demonstrated an inhibition of carcinogenesis.

Carcinogenesis Inhibition Eleuthero preparations have been shown in experimental studies in animals to inhibit'? Urethane-induced lung adenomas 6-methylthiouracil-induced tumors of the thyroid Myeloid leukemia induced by indole The formation of spontaneous mammary gland tumors and leukemia Transplantation of various tumors As is evident from the discussion of eleuthero's adaptogenic activities, it shares many features with P. ginseng. In addition to adaptogenic activities, eleuthero, like panax, has been shown to do the following': Increase resistance to infection in animals Reduce hepatic cholesterol biosynthesis Increase reproductive capacity and sperm counts in bulls Possess sigruficant antioxidant activity Stimulate DNA synthesis and cellular repair enzymes Part of eleuthero's anticancer effects may be due to its immune-stimulating effects. In vitro, it increases phagocytosis of Candida albicans by granulocytes and monocytes from healthy donors by 30% to 459'0.*,~In vitro studies have shown that whole ethanolic fluid extract of E. senticosus can induce and enhance interleukin-1 and interleukin-6 but not interleukin-2 production.'0

CLINICAL APPLICATIONS Adaptogenic Activity in Healthy Individuals A fluid extract (33% ethanol) of E. senticosus root has been administered to more than 2200 human subjects in clinical trials conducted in Russia designed to evaluate the "adaptogenic" effects of eleuthero. The data indicated that eleuthero had the following effects: Increased the ability of humans to withstand many adverse physical conditions (e.g., heat, noise, motion, work load increase, exercise, decompression) Increased mental alertness and work output Improved the quality of work under stressful conditions and improved athletic performance The male and female subjects ranged in age from 19 to 72 years. Dosages of the fluid extract (33%ethanol) ranged from 2 to 16 ml, one to three times a day, for periods of up to 60 consecutive days. Results from research outside of Russia have been mixed, with little evidence to support that eleuthero improves physical performance in athletes."-13

Adaptogenic Activity in Disease States A fluid extract (33% ethanol) of E. senticosus root has been administered to more than 2200 human subjects with various illnesses including angina, hypertension, hypotension, acute pyelonephritis, various types of neuroses, acute craniocerebral trauma, rheumatic heart disease, chronic bronchitis, and cancer.] Eleuthero appears to be effective in atherosclerotic conditions, as evidenced by its ability to lower elevated serum cholesterol and prothrombin levels, reduce blood pressure, and eliminate anginal symptoms in human subjects. Its action on blood pressure is truly adaptogenic, as eleuthero has also been shown to increase blood pressure in subjects with hypotension? Its effect in regulatingblood pressure may be indicative of improved renal function; it has been demonstrated that patients with acute pyelonephritis given eleuthero extract demonstrate increased renal capacity, as measured by an increased secretion of phenol red.' Eleuthero appears to have some psychotropic action, as it has been proven effective in the treatment of various psychologic disturbances. Eleuthero has consistently demonstrated an ability to increase one's sense of wellbeing, regardless of the psychologic complaint (e.g., insomnia, hypochondriasis, various neuroses). A possible explanation of this effect is improved balance of the biogenic amines including serotonin, dopamine, norepinephrine, and epinephrine, as eleuthero extract administered to rats has been shown to increase biogenic amine content in the brain, adrenals, and urine.'

Eleutherococcus senticosus (Siberian Ginseng)

Data are insufficient enough to fully evaluate eleuthero's action in other disease states. However, it must be kept in mind that an adaptogen is nonspecific in its action and possesses a normalizing action irrespective of the direction of the changes from physiologic norms.

DOSAGE The standard dosage of the fluid extract (33%ethanol) of E . senticosus roots used in the majority of studies ranged from 2 to 4 ml (up to 16 ml), one to three times a day, for periods of up to 60 consecutive days. In multiple dosing regimens, there is usually a 2- to 3-week interval between course^.^,^

Dosages are as follows: Dried root: 2 to 4 g Tincture (1:5):10 to 20 ml Fluid extract (1:l):2 to 4 ml Solid (dry-powdered) extract (20:l): 100 to 200 mg

TOXIC0LOGY Toxicity studies in animals have demonstrated that eleuthero extracts are virtually nontoxic. The median lethal dose of the 33% ethanol extract of eleuthero is 14.5 ml/kg in mice and greater than 20 ml/kg in rats. No long-term toxicity was observed when a daily dose of 5 ml/kg of the fluid extract was administered to rats.

1. Davydov M, Krikorian AD. Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Araliaceae) as an adaptogen: a closer look. J

Ethnopharmacol2000;72:345-393. 2. Duke JA. CRC handbook of medicinal herbs. Boca Raton, n. CRC Press, 1985:337-338. 3.Baranov AI. Medicinal uses of ginseng and related plants in the Soviet Union. Recent trends in the Soviet literature. J Ethnopharmacol 1982;6:339-353. 4. Brekhman 11, Dardymov Iv.New substances of plant origin which increase nonspecific resistance. Ann Rev Pharmacol 1969;9: 419-430. 5. Brekhman 11, Dardymov Iv.Pharmacological investigation of glycosides from ginseng and Eleutherococcus. Lloydia 1969;32:46-51. 6. Brekhman 11, Kirillov 01.Effect of eleutherococcus on alarm-phase of stress. Life Sci 1969;8:113-121. 7. Ben-Hur E, Fulder S. Effect of Panax ginseng saponins and Eleutherococcus senticosus on survival of cultured mammalian cells after ionizing radiation. Am J Chin Med 1981;948-56. 8. Windfeuer A, Mayerhofer D. [The effects of plant preparations on cellular functionsin body defense]. Arzneimittelforschung Mar 1994; M361-366.

Teratogenicity has been studied in three species (rats, rabbits, and minks), with no adverse effects observed.' In human clinical studies, it was demonstrated that eleuthero extracts (33% ethanol) in the recommended dosage range are well tolerated and side effects are infrequent. A few studies found mild side effects at higher dosages (4.5 to 6 ml three times daily) when used for long periods (60 days). The symptoms included insomnia, irritability, melancholy, and anxiety. In individuals with rheumatic heart disease, pericardial pain, headaches, palpitations, and elevations in blood pressure have been reported.' These symptoms are probably due to the mild stimulating effects of eleuthero and, although not serious, indicate the need to decrease the dosage or allow a washout period, or both.

DRUG INTERACTIONS A clinical study in healthy humans indicated that extracts of eleuthero at generally recommended doses are unlikely to alter the levels of drugs primarily dependent on the CYP2D6 or CYP3A4 pathways for eliminati~n.'~However, in one case report, although a clear relationship could not be established, a person taking eleuthero with digoxin (Lanoxin) developed dangerously high serum digoxin levels.15 Therefore simultaneous use with digoxin requires close medical supervision and regular monitoring of blood digoxin levels.

9. Wagner H, Proksch A, Riess-Maurer I, et al. [Immunostimulating action of polysaccahrides (heteroglycans) from higher plants]. Arzneimittelforschung 198535:1069-1075. 10. Steinmann GG, Esperester A, Joller P. Immunopharmacological in vitro effects of Eleutherococcus senticosus extracts. Arzneimittelforschung 2001;51:76-83. 11. Gafhey BT, Hugel HM, Rich PA. The effects of Eleutherococcus senticosus and Panax ginseng on steroidal hormone indices of stress and lymphocyte subset numbers in endurance athletes. Life Sci 2001;70431-442. 12. Szolomicki J, Samochowiec L, Wojcicki J, et al. The influence of active components of Eleutherococcus senticosus on cellular defence and physical fitness in man. Phytother Res 2000;1430-35. 13.Eschbach LF, Webster MJ, Boyd JC, et al. The effect of Siberian ginseng (Eleutherococcus senticosus) on substrate utilization and performance. Int J Sport N u b Exerc Metab 2000;10444-451. 14.Donovan JL, DeVane CL, Chavin KD, et al. Siberian ginseng (Eleutherococcus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers. Drug Metab Dispos 2003;31:519-522. 15.McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. CMAJ 1996;155293-295.

Ephedra Species* Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 925

Dosage 927

Chemical Composition 925

Toxicology

History and Folk Use

Drug Interactions 928

926

927

Pharmacology 926 Ephedrine 926 Pseudoephedrine 926 Clinical Applications 926 Asthma and Hay Fever 926 Common Cold 927 Weight-Loss Aid 927

Ephedru sinicu (family: Ephedraceae) Common names: Chinese ephedra, Ma Huang, Chinese joint fir Related species: Ephedru distucha (European ephedra) Ephedra trifurcu or Ephedra viridis (desert tea) Ephedru nevudensis (Mormon tea, cay note, canutillo, whorehouse tea, tapopote, teamster's tea) Ephedru umericunu (American ephedra) Ephedru gerurdiuna (Pakistani ephedra)

GENERAL DESCRIPTION Ephedru spp. are erect, branching shrubs found in desert or arid regions throughout the world. The 1.5-to 4-foot shrubs typically grow on dry, rocky, or sandy slopes.

'On February 6,2004, the U.S. Food and Drug Administration (FDA) issued a ban on the sale of dietary supplements containing ephedra. This ban was finalized on April 6, 2004.The FDA made this decision on the basis of clinical studies and adverse event. Dietary supplements containing ephedrine alkaloids, like other sympathomimetics. raise blood pressure and increase heart rate. The FDA thought ephedrine-based products exposed users to several risks including the consequences of a sustained increase in blood pressure (e.g., serious illnesses or injuries including stroke and heart attack that can result in death). There was also a risk of increased morbidity and mortality from worsened heart failure and proarrhythmic effects in susceptible individuals.

The many slender, yellow-green branches of ephedra have two small leaf scales at each node. The mature, double-seeded cones are visible in the fall.

CHEMICAL COMPOSITION The chemical analysis of the stems and branches of Ephedru spp. has focused on their alkaloid content. In Ephedreu sinicu, the total alkaloid content can be up to 3.3%, with 40% to 90% of this being ephedrine. The remaining alkaloids are primarily pseudoephedrine and norpseudoephedrine.'J2In Ephedru gerurdiunu, the alkaloid content usually varies from 0.8%to 1.4%,about half ephedrine and half other alkaloids (e.g., pseudoephedrine, N-methylephedrine, norephedrine) Ephedru nevudensis contains little or no ephedrine. Depending on species, parts used (aerial, stem, leaf or a combination of stem and leaf), harvesting, and extraction techniques, the alkaloid content of the commercially available ephedra products varies considerably. In a series of studies, the alkaloid content in ephedra-based products varied by as much as fivefold with different brands exhibiting lot-to-lot differences ranging from 44% to 260%. Although some products listed the ephedrine content on the label, many did not. In addition to the variations in alkaloid content, commercial ephedra products .*j3

925

Pharmacology of Natural Medicines

usually contained other highly active botanicals including kola nut, guarana, and St. John's wort, as well as many contaminants (e.g., heavy metals).3A

CH3

I

HOCHCH,NHCH,

I

HISTORY AND FOLK USE E. sinicu has been used for medicinal purposes in China since approximately 2800 BC. Ma Huang (the stem and branch) was used primarily in the treatment of the common cold, asthma, hay fever, bronchitis, edema, arthritis,fever, hypotension, and urticaria.' The Chinese believed the effect of the root and rhizome (Ma Huanggen) to be the opposite of the stem and branches and limited its use to the treatment of profuse night sweating.' Two hypotensive principles (ephedradine A and B) have since been isolated from ephedra root, along with a hypertensive compound (1-tyrosine betaine or maokine).I Western medicine's interest in ephedra began in 1923 with the demonstration that the isolated alkaloid ephedrine possessed a number of pharmacologic effects. Ephedrine was synthesized in 1927 and has since been used extensively for clinical conditions in which sympathomimetic effects are d e ~ i r e d . ~

PHARMACOLOGY The pharmacology of ephedra centers around its ephedrine content. Ephedrine and pseudoephedrine have been extensively investigated and are widely used in both prescription and over-the-counter (OTC)medications for asthma, hay fever, and rhinitis. In 1973 more than 20 million prescriptions contained one of these alkaloids. In 2000 ephedra was found in at least 200 over-thecounter products, and it was estimated that as many as two to three billion doses were consumed that year in the United States.

Ephedrine Ephedrine's basic pharmacologic action is that of a sympathomimetic. Ephedrine stimulates both alphaand beta-adrenergic receptors, as well as the release of norepinephrine. Ephedrine shares many pharmacologic actions with epinephrine, although ephedrine is much less active. Ephedrine also differs from epinephrine in its ability to be absorbed orally, its longer duration of action, and its more pronounced effect upon the central nervous system (CNS). The CNS effects of ephedrine are similar to those of amphetamines but, again, are much less potent.14 Figure 91-1 illustrates its chemical structure. The cardiovascular effects of ephedrine are also similar to those of epinephrine. It increases both diastolic and systolic blood pressure, cardiac output, and heart rate, but for a longer (about 10 times) period. Like epinephrine, ephedrine increases coronary, cerebral, and

Figure 91-1 Ephedrine.

muscle blood flow at the expense of renal and splanchnic blood flow.'-5 The bronchial muscle relaxation induced by ephedrine is much less than epinephrine, but, again, the duration of action is much longer. Other smooth muscles, with the exception of the human uterus, are generally affected by ephedrine in the same manner (mild relaxation) as epinephrine. Ephedrine relaxes the human uterus, where the effects of epinephrine are more complex.14 Extracts of ephedra have been shown to inhibit complement in vitro, and a Chinese herbal medicinal prescription, Makyo-kanseki-to, has been found to inhibit cyclic adenosine monophosphate activity?r7 The principle adverse effects of ephedrine are CNS stimulation, nausea, tremors, tachycardia, and urinary retention.'r2 The major route of elimination of ephedrine is as the unchanged drug in the urine. The average half-life is 6 hours, although acidifymg the urine decreases the halflife considerably. Alkalinization increases the ha1f-life.*p9

Pseudoephedrine Pseudoephedrine exhibits bronchodilating activity similar to ephedrine but has weaker pressor, cardiac, and CNS effects. Pseudoephedrine is often recommended over ephedrine in the treatment of chronic asthma, as it has fewer side effects. Pseudoephedrine has also demonstrated sigruficant antiinflammatory effects in various experimental models.g'O Other ephedra alkaloids, including ephedrine, also exhibited antiinflammatory activity, although at much lower potency. As the antiinflammatory effect of pseudoephedrine is essentially identical in normal and adrenalectomized mice, the antiinflammatory activity is not exerted via the adrenal glands. Instead, it appears that the antiinflammatory activity of pseudoephedrine and other ephedra alkaloids is due to inhibition of prostaglandin E2 synthesis.

CLINICAL APPLICATIONS Asthma and Hay Fever Ephedra and its alkaloids have proven effective as bronchodilators for the treatment of mild to moderate asthma and hay fever. The peak bronchodilation effect occurs in 1 hour and lasts about 5 hours after administration.

Ephedra Species The therapeutic effect of ephedra diminishes if used over a long period of time due to the weakening of the adrenal gland caused by ephedrine. Therefore it is often necessary to use ephedra in combination with herbs such as GZycyrrhizu glubru and Pumx ginseng and nutrients such as vitamin C, magnesium, zinc, vitamin B6, and pantothenic acid, which all support the adrenal glands. The folklore herbal treatment of asthma involved the use of ephedra in combination with herbal expectorants. (Expectorants are herbs that modify the quality and quantity of secretions of the respiratory tract, resulting in the expulsion of the secretions and an improvement in respiratory tract function.) Commonly used expectorants include the following:

Glycyrrhizu glubru (licorice) Grindeliu camparum (grindelia) Euphorbiu hirtu (euphorbia) Droseru rotundifolia (sundew) Polygulu senegu (senega)

Common Cold Ephedrine and pseudoephedrine are components of many OTC products for the self-treatmentof the common cold. In China ephedra, in combination with various other herbs, has been found to be clinically effective in the treatment of cold symptoms, as well as those of influenza, pneumonia, whooping cough, and bronchitis.'

Weight-Loss Aid In both human and animal studies, ephedrine has been shown to promote weight ~oss?,'~-'~ Although ephedrine has demonstrated an anorectic effect," its main mechanism for promoting weight loss appears to be increasing the metabolic rate of adipose tissue."-16 Therefore ephedra's weight-reducing effects are most significant in those individuals with a low basal metabolic rate.13 These effects can be greatly enhanced when used in combination with methylxanthines, caffeine, and theophylline, as well as aspirin,1~'8~20 which potentiates the action of ephedrine and other ephedra compounds. In one animal study, when ephedrine was used alone, it resulted in a 14%decrease in body weight and a 42% decrease in body fat. However, when used in combination with caffeine or theophylline, the decreases were 25% and 75%, re~pective1y.l~ However, when either caffeine or theophylline was used alone, there was no significant loss in body weight. The reason for the greater decrease in body weight is the increased metabolic rate and fat cell breakdown promoted by ephedrine and enhanced by caffeine and theophylline. It is recommended that, for methylxanthines, Camellia sinensis (green tea) or extracts of Cola sp. be used rather than coffee or black tea.

One of the better-designed studies on the use of an ephedrine/caffeine combination determined the safety and efficacy of an herbal supplement containing Ma Huang (90 mg/day ephedrine) and kola nut (192 mg/day caffeine)given to subjects for 6 months for weight loss. A total of 167 subjects were randomized to receive either a placebo or ephedrine/caffeine combination. The subjects were monitored primarily for changes in blood pressure, heart function, and body weight. In addition to these parameters, body composition and metabolic changes were studied. The results of this study demonstrated significant beneficial effects on body weight, body fat, and blood lipids of the herbal supplement in overweight men and women who were otherwise healthy. Herbal versus placebo treatment decreased body weight (-5.3 vs. -2.6 kg), body fat ( 4 . 3 vs. -2.7 kg) and low-density lipoprotein cholesterol (-8 vs. 0 mg/dl), and increased high-density lipoprotein cholesterol (+2.7 vs. -0.3 mg/dl, p = 0.004). The ephedrine/caffeine mixture produced small changes in blood pressure variables (+3 to -5 mm Hg) and increased heart rate ( 4 f 9 beats/min), but cardiac arrhythmias were not increased. Compared with placebo treatment, the herbal supplement produced no adverse events and only minimal side effects consistent with the known stimulant action of ephedrine and caffeine (e.g., dry mouth,

DOSAGE The optimum dosage of ephedra depends on the alkaloid content in the form used. The average total alkaloid content of E. sinicu is 1%to 3%.When used in the treatment of asthma or as a weight-loss aid, the ephedra dose should have an ephedrine content of 12.5 to 25 mg and be taken two to three times daily. For the crude herb, an equal dose would be approximately 500 to 1000 mg three times/day. Standardized preparations are often preferred, as they have more dependable therapeutic activity.

TOXICOLOGY Ephedra can obviously produce the same side effects as ephedrine (e.g., increased blood pressure and heart rate, insomnia, anxiety). The FDA advisory review panel on nonprescription drugs recommended that ephedrine not be taken by patients with heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland. Nor should ephedrine be used in patients on antihypertensive or antidepressant drugs. Pregnant women should also avoid the use of ephedra and ephedrine. Ephedrine administered to chick embryos has resulted in cardiovascular teratogenicity and

Pharmacology of Natural Medicines embryotoxicity at doses as low as 1 pmol/egg.21The teratogenic effect of ephedrine is potentiated by caffeine.u Presumably, this activity of ephedrine is the result of the production of nitrosamines.23Simultaneousvitamin C administration might reduce the formation of nitrosamines from ephedra A key reason that the FDA issued the ban on ephedra products was the tremendous amount (more than 2000) of adverse event reports filed with the FDA related to the use of supplements containing ephedra alkaloid^.*^,^^ However, when the Council of Responsible Nutrition studied the adverse event reports (AERs) filed with the FDA, it found that 98% of the AERs did not contain complete information and in 81% of the reports, information on total daily intake of ephedra was not provided.28Of the 1173reports, 121 were selected for further evaluation. Of the 121 selected cases, 47 were considered to contain serious adverse events including 15 cases of stroke and strokelike symptoms, 13 cases of seizures, 15 cases of cardiac arrest, and 2 cases of individuals who collapsed. From the selected 121 cases, there were 8 reports of death: 6 were cardiovascular, 1 occurred in an automobile accident, and 1was a spontaneous abortion. Among the six cardiovascular-related deaths, five were males

and one was female. All five males who died from cardiovascular problems were using dietary supplements containing ephedra as an athletic performance enhancer. Additionally, four of the five were simultaneously using other performance-enhancing products such as caffeine; therefore their deaths cannot be directly attributed to the use of ephedra. The report concluded that after extensive examination of these adverse event reports, it was not possible to conclusively determine if there were any unexpected toxicologic effects due to the ephedra contained in the dietary supplements solely on the basis of the information presented in the adverse event reports.

1.Chang Hh4, But PP. Pharmacology and applications of Chinese Materia Medica. Philadelphia: World Scientific, 1986:1119-1124. 2. Abourashed EA, El-AIfy AT, Khan IA,et al. Ephedra in perspective a current review. Phytother Res 2003;17703-712. 3. Gurley BJ, Gardner SF, Hubbard MA. Content versus label claims in ephedra-containing dietary supplements. Am J Health Syst P h m 200057963-969. 4. Haller CA, Duan M, Benowitz NL, et al. Concentrations of ephedra alkaloids and caffeine in commercial dietary supplements. J Anal Toxicol 2004;28:145-151. 5. White LM, Gardner SF,Gurley BJ, et al. Pharmacokinetics and cardiovascular effects of ma-huang (Ephrdm sinicn) in normotensive adults. J Clin Pharmacol1997;37116-122. 6. Ling M, Piddlesden SJ, Morgan BP. A component of the medicinal herb ephedra blocks activation in the classical and alternative pathways of complement. Clin Exp Inmuno1 1995;102:582-588. 7.Nikaido T,Iizuka S, Okada N, et al. [The study of Chinese herbal medicinal prescription with enzyme inhibitory activity. VI. The study of makyo-kanseki-to with adenosine 3’,5’-cyclic monophosphate phosphodiesterase.] Yakugaka Zasshe 1992;112:124-128. 8. W h o n GR, Beckett AH. Absorption metabolism and excretion of the ephedrines in man. I. The influence of urinary pH and urine volume output. J Pharmacol Exp Ther 1968;162139-147. 9. Pickup ME, May CS, Sendagire R, et al. The pharmacokinetics of ephedrine after oral dosage in asthmatics receiving acute and chronic treatment. Br J Clin Pharmacol 1976;3:123-134. 10. Hikino H, KOMO C, Takata H, et al.Anti-inflammatory principle of ephedra herbs. Chem Pharm Bull 1980;28:2900-2904. 11. Kasahara Y, Hikino H, Tsuru S, et al. Anti-inflammatory actions of ephedrines in acute inflammations. Planta Med 1985;54: 325-331.

12. Zarrindast MR, Hosseini-Nia, Farnoodi F. Anorectic effect of ephedrine. Gen Pharmacol1987;18:559-561. 13. Ashup A, Madsen J, Holst JJ, et al. The effect of chronic ephedrine treatment on substrate utilization, the sympathoadrenal activity, and expenditure during glucose-induced thermogenesis in man. Metabolism 1986;35:260-265. 14. Bailey CJ, Thombum CC, Flatt PR. Effects of ephedrine and atenol on the development of obesity and diabetes in ob/ob mice. Gen Pharmacol 1986;17:243-246. 15. M o o AG, Miller DS.The thermogenic properties of ephedrine/ methylxanthine mixtures: animal studies. Am J Clin Nutr 1986; 43:388-394. 16. Pasquali R, Cesari MP, Melchionda N, et al. Does ephedrine promote weight loss in low-energy-adapted obese women? Int J Obesity 1987;11:163-168. 17. Miller DS.A controlled trial using ephedrine in the treatment of obesity. Int J Obesity 1986;10:159-160. 18. Dulloo AG, Mdler DS.Aspirin as a promoter of ephedrine-induced thermogenesis: potential use in the treatment of obesity. Am J Clin Nutr 1987;45:564-569. 19. Boozer CN, Daly PA, Home1 P, et al. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J Obes Relat Metab Disord 2002;26:593-604. 20. Daly PA, Krieger DR, Dulloo AG, et al. Ephedrine, caffeine and aspirin. Safety and efficacy for the treatment of human obesity. Int J Obes Relat Metab Disord 1993;17 Suppl 1:S73-S78. 21. Kalix P. The pharmacology of psychoactive alkaloids from ephedra and catha. J Ethnopharmacol1991;32:201-208. 22. Nishikawa T, Bruyere HJ Jr, Takagi Y, et al. Cardiovascular teratogenicity of ephedrine in chick embryos. Toxicol Lett 1985;29: 59-63.

DRUG INTERACTIONS As mentioned earlier, ephedrine should not be taken by patients with heart disease, high blood pressure, thyroid disease, diabetes, or difficulty in urination due to enlargement of the prostate gland. Nor should ephedrine be used in patients on antihypertensive or antidepressant drugs. Ephedrine will potentiate other stimulant/ sympathomimetic drugs and will likely counteract antihypertensives.

Ephedra Species 23. Nishikawa T, Bruyere HJ Jr, Gilbert EF, et al. Potentiating the effects of caffeine on the cardiovascular teratogenicity of ephedrine in chick embryos. Toxicol Lett 1985;2965-68. 24. Alwan SM, Al-Hindawi MK, Abdul-Rahman SK, et al. Production of nitrosamines fiom ephedrine, pseudoephedrine and extracts of ephedra foliata under physiological conditions. Cancer Lett 1986; 31:221-226. 25. Sever PS,Dring LG, Williams RT. The metabolism of (-)-Ephedrine in man. Eur J Clin Pharmacol1975;9193-198.

26. SON MG, Carabin IG, Griffiths JC, et al. Safety of ephedra: lessons learned. Toxicol Lett 2004;15097-110. 27. Schulman S. Addressing the potential risks associated with ephedra use: a review of recent efforts. Public Health Rep 2003;118:487-492. 28. Council for Responsible Nutrition. Safety Assessment and Determination of a Tolerable Upper Limit for Ephedra. Cantox Health Sciences International, 20009-169.

Epilobium Species (Fireweed) Kathy Abascal, BS, JD, RH(AHG) Eric L. Yarnell, ND, RH(AHG) CHAPTER CONTENTS General Description 931

Effect on Prostate and Prostatic Enzymes 932

Chemical Composition 931 Clinical Applications 933 History and Folk Use 931 Dosage 933 Pharmacology 932 Analgesic Effect 932 Antiinflammatory Effect 932 Antimicrobial Effect 932 Antitumor Effect 932

Epilobium spp. (family: Onograceae) Synonym: Chamaenerion spp. Common names: fireweed, willow herb, great willow herb (Epilobiumangustifoliurn),rose-bay (Epilobiumangustfoliurn),wickup (Epilobiurn angustfolium);small-flowered willow herb (Epilobium parvijlorum), marsh epilobium (Epilobium palustre), wickop (Epilobium palustre), swamp willow herb (E. palustre)

GENERAL DESCRIPTION Epilobium is a genus of some 200 species that typically grow at relatively high latitudes or high altitudes.’ This plant is found in all parts of the world. Fireweed is a perennial that grows in colonies connected by underground roots. It has tall, erect, and somewhat woody stems, from 2 to 7 feet tall, crowded with long, narrow, alternate leaves that are from 2 to 6 inches long. The leaves are dark green on the upper surface and silverydowny on the underside. Its flowers range from lavender to pink to carmine-purple, and its pods are long, narrow, and filled with feathery seeds? The Latin name Epilobium derives from Greek words that describe how the flower sits on long, thin, podlike seed cases. Most species have small flowers (e.g., Epilobium parviflorum, known as small-flowered willow herb). A few have large flowers (e.g., Epilobium angustifoliurn,known as great willow herb). Despite the use of the term “willow,” there is no relationship between Epilobium spp. and Salix spp. (willow).

Toxicology 933 Drug Interactions 933

CHEMICAL COMPOSITION The aerial parts are rich in flavonoids (quercitrin, isoquercitrin, myricitrin, isomyrcitrin, myricetin 3-O-betaD-glucoronide),3 and the various species contain at most seven flavonol glycosides based on kaempferol, quercetin, and myricetin skeletons: The plants contain complex tannins such as ellagitannins (oenothein A and B) and gallotannins5;beta-sitosterol; triterpenes (taraxasterol, oleanolic acid)6;fatty acids (linolenic acid, palmitic acid, linoleic acid); and gallic, chlorogenic, and ellagic acids.’ The small-flowered species contain myricitrin, quercitrin, and isomyricitrin, with myricitrin present in the largest amount. The large-flowered species have a completely different flavonoid pattern, with isoquercitrin being predominant. The plant contains the highest content of the flavonoid myricetin 3-O-beta-~-glucoronide shortly after flowering (Figure 92-1).

HISTORY AND FOLK USE Fireweed has been widely used as a medicine and as a food in many parts of the world. Native Americans used it for burning urination, male urination problems, coughs and sore throats, stomachaches and intestinal discomfort, bowel hemorrhages, gastritis, tuberculosis, and as a panacea for pain? It was used as a poultice for boils; abscesses; carbuncles; bruises; infected sores, cuts, and wounds; and other skin ailments. Various Eskimo 931

OH

OH

0

Figure 92-1 Quercitrin.

and Siberian tribes also used the plant to treat sores? Young shoots were widely consumed as food and fodder, as were the roots and leaves. The seed fluff was used for weaving cloth, making thread, and starting fires. Fireweed is named mjoelke in Scandinavia, a derivation of the word milk, because of centuries of observation that cows grazing on the plant produce more milk. Eclectic physicians considered fireweed unequaled as a treatment for summer bowel troubles and also used it in other types of diarrhea including cholera infantum and typhoid dysentery.'O The Eclectics often administered fireweed as an infusion, using frequent small doses (up to every 10 minutes). Epilobium hirsutism was used in Egyptian and European folk medicine to treat inflammation, adenoma, and prostate tumors." Europeans also used the plant to treat eczema, seborrhea, other skin conditions, and menstrual disorders.I2

20% of the effect on prostaglandin release. Experiments show that flavonoids and sitosterol derivatives are not responsible for these actions. Myricetin-3-0- beta-^ glucuronide, isolated from fireweed, was 10 times more effective than indomethacin at inhibiting carrageenaninduced edema in rats, was equally effective at inhibiting prostaglandin biosynthesis, and had a dose-related antiarthritic effect.15J6 The compound inhibited both cyclooxygenase-1 and -2 nearly equivalently. It inhibits 5-lipooxygenase comparably to the reference compound nordihydroguaiaretic acid. It significantly and dosedependently inhibited platelet aggregation equivalently to indomethacin but, in contrast to indomethacin, induced no gastric ulcers in rats. We speculatethat the compound may have greater safety than nonsteroidal antiinflammatory drugs because it prevents the arachidonic shunting that results in the formation of leukotrienes.

Antimicrobial Effect Dilute ethanolic extracts of fireweed ( E . angustifolium, Epilobium hirsutum, Epilobium palustre, Epilobium tetragonum, and Epilobium rosmarinifolium) are antimicrobial in ~ i t r 0 . IE.~ angustifolium and E . rosmarinifolium have the broadest spectrum of action, inhibiting bacteria, yeast, and h g i . E. angustifolium and E. hirsutum inhibited Microspontm canis at concentrations as low as 10 pg/ml. In another study, a methanolic extract of E. angustfohn failed to inhibit mold (Aspergillus niger) but somewhat inhibited Candida albicans while strongly inhibiting Staphylococcus aureus and Escherichia coli.18

PHARMACOLOGY

Antitumor Effect

Analysis of studies on fireweed may be complex given subtle differences among species and differences in the actions of aqueous and alcoholic extracts. Overall, though, most species in this genus appear to have analgesic, antiinflammatory, antimicrobial, antineoplastic, and prostate-related activities.

Oenothein B, isolated from fireweed, showed some antitumor activity against sarcoma 180 in mice and some selectivity in vitro against lung cancer cells and two colon cancer lines but did not have a noticeable effect on the prostate cancer lines tested.I9 In another series of experiments, the alcoholic extract of E . angustifolium had a specific and signhcant antiproliferative effect on human prostate epithelial cells.2O In addition, several of its flavonoids were potent growth inhibitors when tested on various hormone-sensitive and hormone-nonsensitive cell lines.

Analgesic Effect Ethanolic extracts of E. angustifolium injected subcutaneously had a weak analgesic effect on mice in the hot plate test, while its analgesic effect on mice injected intraperitoneally with acetic acid was greater than that of a~etylsalicylate.'~ The latter test is more sensitive for nonsteroidal analgesics.

Antiinflammatory Effect Aqueous extracts of E. angustifolium strongly reduce the release of prostaglandins and strongly depress carrageenan-induced edema when administered orally (40mg/kg) in animal models.I4The effect on edema formation was equivalent to that of indomethacin (2 mg/kg). E. parviflorum did not suppress edema and had about

Effect on Prostate and Prostatic Enzymes The aqueous-methanolic extracts of various fireweed species inhibit aromatase in vitro.2l This action is primarily attributed to the ellagitannins oenothein A and 8, but other fireweed flavonoids (kaempferol, quercetin, myricetin) also inhibit aromatase. Both oenothein A and B had a considerably greater inhibitory action on 5 alphareductase in vitro than the reference drug hestride. The aqueous extract and ultrafiltrate of E. angustifolium had an antiandrogenic effect in intact rats, and the aqueous extract had a proandrogenic effect in castrated rats.22

The hexane extract did not have similar effects. In another study, alcoholic extracts of fireweed failed to inhibit 5-alpha-reductase, while the aqueous extract showed sigruficant inhibition.23This action was attributed to the compound oenothein B.

CLINICAL APPLICATIONS No clinical studies were found on any of the fireweed species. This is unfortunate, as preliminary studies indicate that fireweed may be more effective than drugs such as finestride and indomethacin, as discussed earlier. The existing pharmacologic research supports fireweed’s well-established use in traditional medicine as a treatment for prostate disorders and as a topical medicine in various skin conditions.

DOSAGE

as needed.” The suggested dose for an aqueous/alcoholic tincture is 2 to 6 ml three times a day. Aqueous/alcoholic tinctures appear more effective than tinctures with a high alcohol concentrat i ~ n 26 . ~No ~, widely accepted standardization exists to ensure quality fireweed extracts, although flavonoid profiles can be used to distinguish the various specie^.*^^^^ Species grown in Africa appear to have a significantly higher content of oenothein B than the same species grown in Europe.29

TOXICOLOGY Fireweed has no known toxic effects, and its lack of toxicity is underscored by a worldwide use as both food and fodder. The median lethal dose for injected ethanol extract in mice is 1.4 g/kgW

DRUG INTERACTIONS

Dosages for fireweed are not well established. Fireweed is traditionally administered as a standard infusion using 2 to 3 teaspoons of herb to 1 cup of boiling water, taken

There are no documented drug interactions with fireweed.

1. Averett JE, Kerr BJ, Raven PH. The flavonoids of Onagraceae, tribe Epilobieae: Epilobium sect. Epilobium. Am J Bot 1978;65:567-570. 2. Moore M. Medicinal plants of the Pacific West. Santa Fe, NM: Red Crane Books, 1995136-138. 3. Ducrey 8, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species. Planta Med 1997;63:111-114. 4. Averett JE, Kerr BJ, Raven PH. The flavonoids of onagraceae, tribe Epilobieae: Epilobiurn sect. Epilobium. Am J Bot 1978;65:567-570. 5. Ducrey B, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species. Planta Med 1997;63:111-114. 6.Glowniak K, Zareba S, Kozyra M, Turewicz K. P23 sterols and triterpenoids from Epilobium sp. and some other medicinal plants. [poster] Eur J Pharm Sci 1994;2124. 7. Lesuisse D, Berjonneau J, Ciot C, et al. Determination of oenothein B as the active 5-alpha-reductase-inhibitingprinciple of the folk medicine Epilobium paruiflorum. J Nat Prod 1996;59:490-492. 8. Moerman DE. Native American ethnobotany. Portland, OR T i b e r Press, 1998212-213. 9. Kallman S. [Wild Plants as Food & Medicine.] Vasteras, Sweden: ICA Bokforlag, 1997152-155 [in Swedish]. 10. Felter HW,Lloyd JU. King’s American Dispensatory,vol 1. Sandy OR Eclectic Medical Publications, 1993:711-712. 11. Barakat HH, Hussein S A M , Marzouk MS, et al. Polyphenolic metabolites of Epilobium hirsutum. Phytochem 1997;&935-941. 12. Battinelli L, Tita B, Evandri MG, Mazzanti G. Antimicrobial activity of Epilobium spp. extracts. Farmaco 200156345-348. 13.Tita B, Abdel-Haq H, Vitalone A, et al. Analgesic properties of Epilobium angustifolium, evaluated by the hot plate test and the writhing test. Farmaco 2001;56:341-343.

14. Hiermann A, Juan H, Sametz W. Influence of Epilobium extracts on prostaglandin biosynthesis and carrageenin induced oedema of the rat paw. J Ethnopharmacol1986;17161-169. 15. Hiermann A, !khramm HW,Laufer S. Anti-inflammatoryactivity of myricetin-3-0-beta-D-glucuronide and related compounds. Inflamm Res 1998;47421-427. 16. Hiermann A, Reidlinger M, Juan H, Sametz W. [Isolation of the antiphlogistic principle from Epilobium angustifolium.] Planta Med 199157357-360, 17. Battinelli L, Eta B, Evandri MG, Mazzanti G. Antimicrobial activity of Epilobium spp. extracts. Farmaco 2001;56:345-348. 18. Rauha JP, Remes S, Heinonen M, et al. Antimicrobial effects of Finnish plant extracts containing flavonoids and other phenolic compounds. Int J Food Microbiol2000;563-12. 19. Ducrey 8, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species. Planta Med 1997;63111-114. 20. Vitalone A, Bordi F, Baldazzi C, et al. Anti-proliferative effect on a prostatic epithelial cell line (PZ-HPV-7) by Epilobium angustifolium L. Farmaco 200136483-489. 21. Ducrey 8, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobium species. Planta Med 1997;63:111-114. 22. Hiermann A, Bucar F. Studies of Epilobium angustifolium extracts on the growth of accessory sexual organs in rats. J Ethnopharmacol 1997;55179-183. 23. Lesuisse D, Berjonneau J, Ciot C, et al. Determination of oenothein B as the active 5-alpha-reductase inhibiting principle of the folk medicine Epilobiurn parviflorum. J Nat Prod 1996;59:490-492. 24. Moore M. Medicinal plants of the Pacific West. Santa Fe, N M Red Crane Books, 1995:136-138.

Pharmacology of Natural Medicines 25. Hiermann A, Bucar F. Studies of Epilobiuni aiigustifoliurn extracts on the growth of accessory sexual organs in rats. J Ethnopharmacol 199755179-183. 26. Lesuisse D, Berjonneau J, Ciot C, et al. Determination of oenothein B as the active 5-alpha-reductase inhibiting principle of the folk medicine Epilobium pawiflorum. J Nat Prod 1996;59:490-492. 27. Slacanin I, Marston A, Hostettmann K, et al. Isolation and deterrnination of flavonol glycosides from Epilobiurn species. J Chromatol 1991557391-398.

28.Averett JE, Kerr BJ, Raven PH. The flavonoids of onagraceae, tribe Epilobieae: Epilobiurn sect. Epilobium. Am J Bot 1978;65: 567-570. 29. Ducrey B, Marston A, Gohring S, et al. Inhibition of 5 alpha-reductase and aromatase by the ellagitannins oenothein A and oenothein B from Epilobiirrn species. Planta Med 1997;63111-114. 30.Tita 8, Abdel-Haq H, Vitalone A, et al. Analgesic properties of Epilobiitrn nngustifolium, evaluated by the hot plate test and the writhing test. Farmaco 2001;56:341-343.

Fatty Acid Metabolism Richard S. Lord, PhD J. Alexander Bralley, PhD CHAPTER CONTENTS Introduction 935 Fatty Acid Structure and Metabolism 935 Saturated Fatty Acids 936 Unsaturated Fatty Acids 936 Trans Fatty Acids 938 Polyunsaturated Fatty Acids 939

Fatty Acids and Human Diseases 941 Developmental Disorders 942 Heart Disease 942 Cancer 943 Neurologic Disorders 943 Summary

943

Control of Fatty Acid Supply and Distribution 940 Digestion and Assimilation 940 Synthesis and Distribution 941 Effect of Low-Fat Diets 941

INTRODUCTION Fatty acids are common denominators for all life forms. The same oleic acid that is found in the cell membranes of olive trees is also critical for the cellular structure and functions of bacteria, fungi, and humans. Thin layers of fatty acids provide the separation of the inside from the outside of living cells. Plants fill their seeds with fatty acids because they are the most efficient storage form of energy. Although a growing body of research is now documenting the critical importance of fatty acids for maintaining health, common food choices in modern society do not lead to appropriate levels or balances of these nutrients. Years of negative associations of dietary fat with calories, cholesterol, and cancer have resulted in a general public attitude that foods containing fats should simply be avoided. Many food manufacturers have taken advantage of this attitude by modifying fat content and labeling, wherever possible, to tout "low-fat" foods. Advertisements for such foods further instill the notion that dietary fat is bad. Amid the clamor over the largely mistaken problems associated with dietary fats, many problems have been created by the large-scale use of modified fats by food suppliers. Individuals do not feel the effects of abusing dietary fats on the short term because of the presence of many protective mechanisms that make health threats from fat abuse an insidious process.

Modem diets of fast foods and packaged dinners tend to be rich in saturated fats and hydrogenated oils and lacking in essential fatty acids (EFAs). We now know that the amount and type of dietary fat play major roles in maintaining health. Some saturated fatty acids stimulate cholesterol formation, but most do not. The old concept of three EFAs has been replaced by recognition of critical roles for multiple polyunsaturated fatty acids (PUFAs).Dietary fats simultaneously provide the major cellular energy source, control the passage of compounds into and out of cells, determine the integrity of nerve tissue, and serve to form powerful hormones. The essential hormone function is mediated by some special fatty acids that affect energy flow, cell division, immune responses, and many other body controls. These critical fatty acids are used to make powerful tissuespecific compounds called eicosanoids. Figure 93-1 illustrates the various roles of fatty acids. This chapter discusses more about these functions after some basic fatty acid relationships are explained.

FATTY ACID STRUCTURE AND METABOLISM About 30 structural isomers and homologs of fatty acids occur in human tissues. They are named in various ways, including those with Latin prefixes such as pentaand hexa- for the number of carbon atoms. These are the 935

Pharmacology of Natural Medicines

chemical names approved by the International Union of Pure and Applied Chemists. Many also have common names. Because common names are in widest use among clinicians, they are used here. Table 93-1 provides a lexicon of fatty acid terms.

Saturated Fatty Acids Fatty acids containing the maximum number of carbonhydrogen bonds are called saturated. They have a higher energy or caloric yield than corresponding unsaturated fatty acids. They are present as major components of most foods and are high in manufactured foods such as candy bars. The most abundant members in human tissues are those that are 14 (myristic),16 (palmitic),or 18 (stearic)carbons long. The elongation process can be repeated to yield members that are 20, 22, and 24 carbons long. Although such longchain fatty acids are minor components of the lipid membranes of the body they undoubtedly perform valuable functions, apparently helping to stabilize membranes, especially those in peripheral nerve cells.

Unsaturated Fatty Acids

Blood Lipoproteins

Three major families of unsaturated fatty acids (UFAs)

A

Diet

Figure 93-1

Hepatic Synthesis Elongation, Desaturation

Metabolic roles of fatly acids.

are found in human tissues: the omega-9, omega-6, and omega-3 UFAs (or n-9, n-6, and n-3). The omega-6 and omega-3 PUFAs are defined by the position of the double bond closest to the terminal methyl group of the fatty acid molecule. In the omega-6 family, the first double bond occurs between the sixth and seventh carbons from the methyl group end of the molecule, whereas in the omega-3 family, the first double bond occurs between the third and fourth carbons (Figure 93-2 provides naming conventions).

Lexicon of fatty acid terms Term or abbreviation

Definition or explanation

AA

Arachidonic acid

A M

Alpha-linolenic acid

Alpha-linolenic acid

Delta 9,12,15 octadecatrienoic acid; 18:3 omega-3

Arachidonic acid

Delta 5,8,11,14 eicosatetraenoic acid; 20:4 omega-6

Beta-oxidation

The mitochondrial metabolic pathway whereby fatty acids are converted into acetyl coenzyme A (acetyl CoA) which enters the citric acid cycle to ultimately yield adenosine triphosphate. The carbon atoms of the fatty acid are oxidized to C02.

Carnitine

The molecule to which fatty acids are attached in the process of their enzyme-mediated entry into the mitochondrial matrix. This enzyme is inhibited by malonyl coenzyme A (malonyl CoA) formed during fatty acid synthesis from carbohydrates.

Cerebronic acid

The 2-hydroxy derivative of lignoceric acid (24:O); found in glycosphingolipids in the brain

Cervonic acid

Another name for docosahexaenoic acid

cis

Geometrical isomer in which two groups are on the same side of a double bond

Clupanodonic acid

Another name for delta 7.10.1 3,16,19-docosapentaenoicacid (DPAS), an omega-3 series, long-chain, highly unsaturated fatty acid; found in fish oils and phospholipids in the brain

Delta

Used to describe the position of double bonds relative to the carboxyl end of a fatty acid

Desaturase

Tightly bound to the endoplasmic reticulum membrane, this enzyme, in association with cytochrome b5 and cytochrome b5 reductase, uses reduced nicotinamide adenine dinucleotide and O2to introduce

Fatty Acid Metabolism . a

-

*

Lexicon of fatty acid terms-cont'd

Term or abbreviation

Definition or explanation double bonds into fatty acids. There are at least four separate desaturases, named according to the position of inserted double bonds. Delta-9-desaturase, delta-6-desaturase,and delta-5(4) desaturase act on fatty acetyl CoA thioesters, always inserting double bonds between the thioester bond (carboxylate group) and the double bond closest to it, leaving a three-carbon gap. Activities of these enzymes fluctuate according to dietary fat intake to maintain optimal fluidity state of the membrane lipids. Their concentrations decrease in starvation and increase greatly on refeeding carbohydrates. They are suppressed when dietary unsaturatedfatly acid intake (including trans isomers) is high.

DGLA

Dihomogammalinolenic acid

Dihomogammalinolenic acid

Delta 8,11,4 eicosatrienoicacid; 20:3 omega-6

DHA

Delta 4,7,10,13,16,19 docosahexaenoic acid; 22:6; an omega-3 series long-chain, highly unsaturated fatty acid; found in fish oils and the phospholipidsin the brain (also known as cervonic acid)

Dienoic

Contains two double bonds

EFA

Essential fatty acid

Eicosanoid

A product of the specific, enzyme-directedoxidation of polyunsaturatedfatty acids containing 20 (eicosa) carbons. This term encompasses the prostaglandins, thromboxanes, and leukotrienes.

Eicosapentaenoic acid

Delta 5,8,11,14,17 eicosapentaenoic acid; 20:5 omega-3; one of the most abundant fatty acids in fish oils

Elongase

An enzyme that adds 2-carbon units (acetate) to the carboxyl end of an existing saturated or unsaturated fatty acid. Mitochondria1form uses acetyl CoA, while endoplasmic form has malonyl CoA as substrate.

EPA

Eicosapentaenoic acid

Gamma linolenic acid

Delta 6,9,12 octadecatrienoic acid; 18:3 omega-6

GLA

Gamma-linolenic acid

HUFA

Highly unsaturatedfatty acid; generally having five or six double bonds

LA

Linoleic acid

Lauric acid

Tetradecanoic acid; C12:O; first isolated and identified from the laurel plant

LCP

Long-chain polyunsaturated fatty acid

Linoleic acid

Delta 9,12 octadecadienoic acid; 18:2 omega-6

Meads acid

Delta 5,8,11 eicosatrienoicacid; 20:3 omega-9. This compound is not normally produced in appreciable amounts due to the preferential loading of the desaturase enzymes with the more strongly binding essential fatty acids and their metabolic products. It accumulates, however, in essential fatty acid deficiency, making it a marker for this condition.

Monoenoic

Containing one double bond

MUFA

Monounsaturated fatty acid

Omega

Used to describe the position of double bonds relative to the methyl end of a fatty acid

P + MIS ratio

Polyunsaturated + monounsaturated to saturated fatty acid ratio

PIS ratio

Polyunsaturated-to-saturatedfatty acid ratio

Phospholipase A2

An enzyme that catalyzes the hydrolysis of the fatty acid ester from position 2 of phosphoglycerides. Dependent on calcium, this enzyme is responsive to intracellular calcium, calmodulin, etc. It releases primarily polyenoic fatty acids (arachidonicacid, etc.) from membranes for eicosanoid synthesis.

PUFA

Polyunsaturated fatty acid

Phosphatide

Diacylglycerolphosphate, to which various groups may be attached through phosphoester linkage; the principal components of cell membranes

Polyenoic

Containing two or more double bonds

Saturated fatty acid

A fatty acid in which all of the carbon atoms except for the carboxyl carbon are fully hydrogenated as -CHr (and 4 H 3 )

Stearidonic acid

Delta 6,9,12,15 octadecatetraenoic acid; 18:4 omega-3; a product of elongation of ALA and a precursor to EPA. A good source is black currant seed oil.

Timnodonic acid

Another name for eicosapentaenoic acid (EPA) or 20:4 omega-6

Trans

Geometrical isomer in which two groups are on opposite sides of a double bond

Unsaturatedfatty acid

A fatty acid in which two or more adjacent pairs of carbon atoms are lacking hydrogen atoms, having instead an additional carbon-carbon bond or double bond

A

The Greek letter delta

0

The Greek letter omega

Dihomogammalinolenicacid

or 8,11,14-eicosatrienoicacid or 20:3A8,11,14 or 20:306 Figure 93-2 Naming conventions for unsaturated fatty acids.

Saturated

Monounsaturated Myristoleic (n-5)

Myristic Palmitic Stearic Figure 93-3

L?E!E%E.

Palmitoleic (n-7) Oleic (n-9)

Formation of monounsaturatedfatty acids.

The older delta (A) naming scheme gives the positions of all double bonds, counting from the carboxyl or number 1carbon. The omega (a)scheme takes advantage of the fact that the double bonds are always separated by three carbons and simply gives the total length and number of double bonds separated by a colon. The number following the o symbol gives the position of the first double bond counting from the omega-1 carbon. Fatty acids can be synthesized from acetyl coenzyme A derived from carbohydrate, protein, and other nonlipid sources. This pathway produces saturated fatty acids, predominantly palmitic acid (16:O). Palmitic acid can be desaturated, forming palmitoleic acid of the omega-7 class of unsaturated fatty acids. Palmitic acid can also be lengthened to stearic acid (180) and desaturated to form oleic of the omega-9 class. Under ordinary metabolic conditions, these two classes are not further lengthened or desaturated to any appreciable extent. The omega-6 and omega-3 classes of unsaturated fatty acids are derived from dietary polyunsaturated fats. These classes can be further lengthened and desaturated. None of the four

omega classes of unsaturated fatty acids, however, is interconvertible. These reactions can be repeated in various combinations, giving an array of saturated and unsaturated fatty acids for use in the essential functions of tissue maintenance. The desaturase enzymes function to place double bonds at positions up to nine carbons from the carboxyl end of the molecules. When you count from the other end, the position varies, depending on the length of the fatty acid. Thus for stearic acid with 18 carbons, a desaturase can form a double-bond nine carbons from the carboxyl end, which is also nine carbons from the methyl end (18 - 9 = 9). These differences become important because the type of eicosanoid hormones that can be formed later depend on the position of the first double bond from the methyl end. The geometry of the desaturase will not allow insertion farther than nine carbons (A9) from the carboxyl group. This is the reason that linoleic acid (LA, A9, 12) cannot be synthesized in humans. Fatty acids of various chain lengths can act as desaturase substrates, as well as those that already possess double bonds at other positions. Figure 93-3 shows the products of the A9 desaturase acting on three saturated fatty acids. The activity of the desaturase enzymes is critical for maintaining the ratio of saturated and unsaturated components in cell membranes. Tumor tissue and virustransformed cells have a higher content of unsaturated fatty acids, especially oleic acid, which increases relative to the amount of stearic acid. Such shifts increase the metabolic rates of many lipid-dependent enzymes and are associated with a higher capacity for cell division.’ Individuals with recurrent tumors may already have too much oleic acid relative to stearic acid, and encouraging a diet high in olive oil or other highly unsaturated fatty acids may be contraindicated.

Trans Fatty Acids In the tissues of plants and higher animals, the insertion of double bonds always results in the cis geometry. The phrase “partiallyhydrogenated vegetable oil” on food labels indicates that a natural oil has been chemically modified in a process that converts some of the cis unsaturated fatty acids to the trans form. Oleic acid is changed into its trans isomer, elaidic acid, which is the most abundant trans fatty acid in most hydrogenated oils. In human metabolism, trans unsaturated fat behaves similar to saturated fat, meaning more risk of heart disease, etc. Adverse effects of trans fatty acids on high-density lipoprotein or low-density lipoprotein cholesterol are well documented in the medical research literature.24 Interference with eicosanoid production is also suspected, and research in the area of health risks of trans fatty acids is accelerating. Trans fatty acid levels in cell membranes are determined by dietary intake of

Fatty Acid Metabolism

hydrogenated A person eating a doughnut for breakfast (3.19 g of trans fatty acids), a small order of French fries with lunch (3.43 g), two teaspoons of margarine on bread with dinner (1.24 g), and two cookies for a snack (1.72 g) would ingest a total of 9.58 g of trans fatty acids, enough to negate the serum cholesterollowering effects of a decrease in saturated fat of 10% of total energy intake.6 Elaidic acid is generally the most abundant of the trans fatty acids because it is produced by the hydrogenation of the most common oils used in the food industry including corn, soybean, and safflower.These oils contain relatively high amounts of oleic and linoleic acids, both of which may convert to elaidic acid during the hydrogenation process. Hard margarine may contain as much as 60% of the total unsaturated fatty acids as elaidic acid. Palmitelaidic acid is a trans fat that can be formed from hydrogenation of natural fatty acids containing palmitoleic acid or partial saturation of PUFAs with isomerization. The plasma level reflects body burden of trans fatty acids and is useful in monitoring intake of hydrogenated oils.

Family

Configuration

Omega-6

Name

18:2 18:3 20:3

Linoleic acid (LA) Gamma linolenic acid (GLA) Dihornogarnmalinolenic acid (DGW Arachidonic acid (AA)

20:4 Omega-3

18:3 205

Alpha-linolenic acid ( A M ) Eicosapentaenoic acid (EPA) Docosapentaenoic acid (DPA-3) Docosahexaenoic acid (DHA)

225 22:6

Polyunsaturated Fatty Acids Dietary PUFAs are largely composed of two classes of fatty acids, the omega-6 family (e.g., LA), which is abundant in vegetable seed oils, and the omega-3 family (e.g., alpha-linolenic acid [ALA]), which is high in vegetable leaves and modest in soybean oil.' Table 93-2 lists other members of these classes. When the diet supplies adequate LAs and ALAS, they may be used to form the other members in their classes by repeated desaturation and elongation reactions. The delta-6 desaturase enzyme acts as a gateway for the flow of fatty acids through the desaturation and elongation pathway. Although it can act on any longchain fatty acid, the substrate binding affinity increases greatly with the number of double bonds already present (Figure 93-4). Thus 18:3 binds stronger than 18:2, which binds stronger than 18:l. The result is that ALA is quickly converted to EPA, while oleic acid is slowly converted into 20:309 in the presence of appreciable amounts of either LA or ALA. When the two EFAs are absent, however, 20:309 accumulates because the desaturase is free to act on oleic acid. Elevated 20:309 (Mead or eicosatrienoicacid) is a marker that can be used to detect EFA deficiency in addition to the actual concentrationsof the EFAs in plasma and erythrocyte membranes. The delta-6 desaturase enzyme requires the zinc ion for activity. For this reason, supplementing a patient with sources of LA and ALA does little good if zinc deficiency is present. The changes in body growth, organ weights, and lipid concentrations of plasma and liver produced by zinc deficiency are reversed by the addition of GLA-rich primrose oil, but not LA-rich safflower oil,

Delta-6-desaturase

I

I

I

I

I

Elongase

1

1

I

Delta-Sdesaturase

1

I

f pi-lpi Figure 93-4 Formation of longer and more saturated fatty acids. The line thicknesses for the arrows that run from top to bottom indicate the relative binding strengths to the desaturase enzymes.

showing the role of zinc in the delta-6 desaturase enzyme.8The enzyme is also inhibited by high concentrations of saturated fatty acids, monounsaturated acids, and trans fatty acids, all of which compete for the enzyme binding site and yield products that are of less sigruficance to the cell.

Pharmacology of Natural Medicines The primary function of the pathway described earlier is to supply the parent compounds for the 1-, 2-, and 3-series prostanoid and leukotriene pathways (see later). The PUFAs have great impact on health due to their conversion to these compounds, collectively called eicosanoids. They possess extremely potent biologic activities, and their homeostatic functions in regulating blood vessel leaking, lipid accumulation, inflammation, and immune cell behavior are relevant to the initiation and progress of heart and blood vessel disease? These compounds, in turn, are used to amplify and balance signals to the organs, the blood clotting system, and the immune system. Production of eicosanoid hormones is shown in Figure 93-5. The parent compounds are the PUFAs, DGLA, AA, and EPA, and the pathway uses the same enzyme for all three series of products. The concentrations of the three fatty acids present in the phospholipid of the cell membranes where the hormones are produced determine which product will predominate. There is direct substrate competition for the active site on the enzyme, as depicted in Figure 93-5. In a similar manner, the lipoxygenase enzyme initiates the sequence of reactions leading to leukotriene formation. The 2-series that is derived from AA is by far the most proinflammatory. The effects of GLA and DGLA on rheumatoid arthritis and many other inflammatory diseases are mediated via this mechanism. Since dietary intake is a primary determinant of the fatty acids that go into this pathway, there is a direct link between the balance of specific fats in the diet and inflammatory responses and other local control processes. Long-term health maintenance is highly dependent on proper balance of dietary fatty acids. Many people do not eat the fresh nuts, seeds, whole grain breads, and seafood products that are the rich sources of EFAs. The same individuals are likely to have high intakes of saturated and trans fatty acids. The recognition of vast health effects has led to the recent surge of interest in fatty acids. It is no longer adequate (or even correct) simply to recommend the replacement of fats high in saturated fatty acids with those that are high in unsaturated fatty acids. Balanced intake of the unsaturated fatty acids, not just a high PUFA-to-saturated ratio, is required for optimal control of every tissue in the body.1° Although the actions needed to correct fatty acid abnormalities are quite straightforward, the subject of clinical applications of fatty acid profiling is complex. Those who seek to understand the underlying biochemical and physiologic concepts are generally in need of good reference sources. Some that we have found helpful are listed later in “Further Reading.” In addition, Chapter 17 discusses the interpretation of fatty acid testing and clinical interventions.

Figure 93-5

Fatty acid relationships to eicosanoid formation.

Dietary sources of even-numbered medium- and long-chain saturated fatty acids No. of carbons

Common name

Source

10

Capric (C1O:O)

Most plants and butter

12

Lauric (C12:O)

Palm kernel, coconut, laurels

14

Myristic (C14:O)

Nutmeg, palm kernel, coconut, myrtle

16

Palmitic (C16:O)

Common in all animal and plant fats

18

Stearic (C18:O)

Common in all animal and plant fats

20

Arachidic (C20:O)

Peanut (arachis) oil

22

Behenic (C22:O)

Seeds

24

Lignoceric (C24:O)

Cerebrosides, peanut oil

CONTROL OF FAlTY ACID SUPPLY AND DISTRIBUTION Fatty acids are present in the diet in the form of triglycerides in solid fats or liquid oils and as phosphatides in cell membranes of whole foods. They are rarely present in nature as free fatty acids. Table 93-3 lists food sources of the more abundant fatty acids. Foods always contain complex mixtures of fatty acids with enrichment of any single fatty acid rarely exceeding 70%.

Digestion and Assimilation Fats are first digested by the action of bile acids and then pass into intestinal epithelial cells along with cholesterol, where they are associated with proteins, becoming particles called chylomicrons. These are passed into the lymphatic system to flow directly through the heart into systemic circulation. Enzymes in capillary cell walls cause the transfer of fatty acids from the chylomicrons, which become greatly reduced in size and return for

Fatty Acid Metabolism uptake by the liver as chylomicron remnants. By this process, the fatty acids in foods become directly incorporated into the membranes of all tissues.

carbohydrate fat, or protein

Synthesis and Distribution Because of the critical life-supporting functions in forming cell membranes and supplying energy sources and hormone controls, several mechanisms assure that the supply of fatty acids will be continuous, even during short intervals between meals (Figure 93-6). In the fasting state, fatty acids are either produced from carbohydrates or protein or mobilized from adipose stores. The liver handles the role of supply depot by forming another class of lipid-protein particles called very low density lipoproteins (VLDLs). These particles deliver fatty acids and cholesterol to the tissues by mechanisms similar to those for chylomicrons, except that the remnant LDL particles are taken up in total by binding to receptor sites on cell surfaces. By ensuring a constant supply of fatty acids, the body controls one of the most critical materials for carrying out the various life-sustaining functions of growth and repair.

+ 1 Malonyl CoA

Fatty acylcarnitine

i

Fatty acid

Citrate

fatty acid synthesis cycle

a

IStearic (18carbons long) I Figure 93-7

Carbohydrate conversion to fat; inhibition of fatty acid oxidation.

Effect of Low-Fat Diets An individual on a low-fat, high-carbohydrate diet uses the fatty acid synthetic pathway extensively. As shown in Figure 93-7, this pathway requires citrate to leave the mitochondria to generate malonyl coenzyme A (malonyl CoA). The resultant high concentrations of malonyl CoA inhibit the activity of the enzyme that is

I

FOOD

I-Gut Lymphatics

Chylomicrons

the gateway to fatty acid oxidation. For this reason, very low-fat diets do not result in weight loss nearly as fast as one might expect. The burning of excess fat is actually inhibited by the high carbohydrate intake. In individuals with low body fat and good lean mass, high carbohydrate intake spares the use of fatty acids. In more sedentary individuals with lower rates of fatty acid oxidation, the medium-chain fatty acids that are otherwise so quickly used for energy may accumulate above normal levels in membranes. Many other factors influence the rate of oxidation of fatty acids. Dramatically increased fatty acid oxidation occurs in starvation and diabetes mellitus with production of large amounts of ketone bodies that accumulate to give the ketoacidotic condition. Carnitine deficiency results in impairment of fatty acid oxidation and failure of gluconeogenesis, leading to hypoglycemia.

FArrY ACIDS AND HUMAN DISEASES distribution fatty acids (FASTING)

Liver Figure 93-6

Mechanisms for continuous supply of fatty acids to all tissues.

Quantification of the approximately 30 fatty acids present in human tissues is now routinely available. Both deficiencies and excesses of individual fatty acids lead to metabolic problems. A brief discussion of a few highly relevant conditions affected by fatty acid intake is presented here (see Chapter 17 for additional discussion of specific fatty acid imbalances). Table 93-4 lists typical signs and symptoms of fatty acid abnormalities, while Table 93-5 lists some well-documented clinical applications of supplemental fatty acids.

Pharmacology of Natural Medicines Signs and symptoms associated with fatty acid abnormalities Sians and symptoms

Fatty acid association

Action

Emaciation, weakness, disorientation

Caloric deprivation

Add sources of balanced omega-3 and omega-6 fatty acids

Reduced growth, renal dysplasia, reproductive deficiency, scaly skin

Classic essential fatty acid deficiency

Add good quality fats and oils

Eczema-like skin eruptions, loss of hair, liver degeneration, behavioral disturbances, kidney degeneration, increased thirst, frequent infections, poor wound healing, sterility (male) or miscarriage (female), arthralgia, cardiovascular disease, growth retardation

Linoleic acid insufficiency

Add corn or safflower oils

Growth retardation, weakness, impairment of vision, learning disability, poor coordination, tingling in armdegs, behavioral changes, mental disturbances, low metabolic rate, high blood pressure, immune dysfunction

Alpha- or gamma-linolenic acid insufficiency

Add flax, primrose, borage, or black currant oils

Depression, anxiety, learning and behavioral disorders, age-related eye disorders

Longchain PUFA-dependent neuromembrane function

Add fish oils, avoid hydrogenated oils

Cardiovascular disease risk

Prostanoid balance

Add omega-3 PUFAs

Cancer

Low stearic to oleic ratio

Use omega-6 PUFAs with caution

Rheumatoid arthritis

Low GLA and DGLA

Add primrose oil

Deficiency of vitamin B12or carnitine, or both

Increased odd-numbered FAs

Add B12or carnitine, or both

Myelinated nerve degeneration

Increased long-chain FAs

Add high-erucate canola or mustard oils

Fatty liver

Saturated and omega-9 accumulation in liver

Restrict alcohol, add lecithin, increase methionine

Accelerated aging

High PUFA intake without increased antioxidants

Add vitamins E and C, Se, Mn, and Zn

DGLA, Dihomogamma-linolenic acid; FAs, fatty acids; GLA, gamma-linolenic acid; PUFA, polyunsaturated fatty acid.

Developmental Disorders The very-long-chain PUFA docosahexaenoic acid (DHA) has a special role in the formation of the developing nervous system."J2 Children with attention-deficit hyperactivity disorder have lower concentrations of key fatty acids in plasma and in red blood cells.I3 Preterm infants deprived of EFAs during late pregnancy are likely to have failures of normal development, especially the visual system, unless omega-3 fatty acids are ~upp1emented.l~

Heart Disease As mentioned earlier, the general association of dietary fat rather than the specific association of the type of dietary fat with heart disease is a misguided notion that has affected public health for several decades. The notion apparently stems from biochemical studies showing the potential conversion of fatty acids into cholesterol and from blood lipid abnormalities involving familial

hypertriglyceridemias, in which heart disease is a frequent clinical outcome. In the general population the cardiovascular disease association is not with total dietary fat but with fatty acid composition of the diet. We are now seeing the emergence of firm conclusions about the decades-long encouragement of intake of hydrogenated oils in the form of hard margarines and bakery products. By the late 1960s, processed vegetable fats had displaced animal fats in the diets of most people in industrialized countries due to lower costs and purported health benefits. Increased tissue levels of the trans fatty acids from hydrogenated oils is clearly a factor in the etiology of heart di~ease.'~,'~ Higher palmitic and lower omega-3 fatty acids in serum are correlated with higher incidence of coronary heart disease in middle-aged men at high risk for cardiovascular disease." Improvements in plasma fatty acids and vitamins E and C were the only factors found to be related to improvements in life expectancy and 70% lowering of heart disease in a study population.l8

Fatty Acid Metabolism Clinical use of gamma-linolenic acid and alpha-linolenic acid Application

Gamma-linolenic acid

Alpha-linolenic acid

X

xx

Lower blood pressure, lower blood cholesterol, and lower risk of stroke and heart attack Normalize fat metabolism in diabetes and decrease the amount of insulin required by diabetics

X

Prevent liver damage due to alcoholism and decrease withdrawal symptoms after discontinuing the habitual use of alcohol

X

Cancer Because of the pivotal role in tumorigenesis of cellcell recognition factors and the membrane-associated functions controlling that process, changes in the fatty acid composition of cell membranes signal tumor activity. Tumor tissue and virus-transformed cells have a higher content of unsaturated fatty acids, especially oleic acid, which increases relative to-the amount of stearic acid. Such shifts increase the metabolic rates of many lipid-dependent enzymes and are associated with a higher capacity for cell division.19 Changes in dietary fatty acid intake cause alterations in immune response, including antitumor activity?O

Neurologic Disorders

Provide adjunctive treatment for schizophrenics

X

xx

Cause weight loss by increasing metabolic rate and fat burn-off

X

xx

Relieve premenstrualbreast pain (mastalgia) and premenstrual syndrome of bloating, irritability, depression, and aggressive behavior

xx

Prevent drying and atrophy of tear and salivary glands (Sjogren's syndrome)

X

Prevent arthritis in animals

X

X

Improve the condition of hair, nails, and skin

X

xx

Improve certain kinds of eczema

X

X

Slow down or stop deterioration in multiple sclerosis

X

X

Help treat diabetic neuropathy in type II diabetes

X

X

Kill cancer cells in tissue culture without harming normal cells

X

xx

X

Adrenal leukodystrophy and related conditions are associated with the accumulation in nerve sheath membranes of fatty acids more than 20 carbons longz1This situation may be made worse by the lack of sufficient long-chain PUFAs. The indicator for this situation is the sum of the 22-26 carbon length even-numbered fatty acids. Fatty acids have long been known to be important in brain function. The brain has a high content of lipid, and the fatty acid composition is unique in the high content of very-long-chain PUFAs, especially DHA. Strong evidence suggests a relationship between depleted DHA levels in postpartum depression and other forms of depression.22 These results have led to acceleration of studies of the proper clinical application of essential fatty acid therapies in depressed

~

Many health problems are related to inappropriate fat intake and suboptimal fatty acid composition of the body. The therapeutic value of oils rich in specific fatty acids is being reported in the research literature with increasing frequency for a wide range of diseases. The availability of laboratory methodologies for accurate evaluation of fatty acid status now allows for sophisticated clinical manipulation of these important nutrients . ~~

x, Moderate; xx, strong clinical response.

1. Wood CB, Habib NA, Apostolov K, et al. Reduction in the stearic to oleic acid ratio in human malignant liver neoplasms. Eur J Surg On~011985;11:347-348. 2. Mensink RP, zodc PL, Katan MB, Hornstra G. Effect of dietary cis and trans fatty acids on serum lipoprotein[a] levels in humans. J Lipid Res 1992;331493-1501. 3. Longnecker M. Do trans fatty acids in margarine and other foods increase the risk of coronary heart disease? Epidemiology 1993;4 492-495.

4. Lichenstein A. Trans fatty acids, blood lipids, and cardiovascular risk. Where do we stand? Nutr Rev 1993;51:340-343. 5. Pettersen J, Opstvedt J. Fatty acid composition of lipids of the brain and other organs in suckling piglets. Lipids 1992;27761-769. 6. Litin L, Sacks F. Trans fatty acid content of common foods. N Engl J Med 1993;329:1969-1970. 7. Kinsella JE. Requirements and sources of n-3 polyunsaturated fatty acids in the human diet. In Karel M, Lees R, eds. Proceedingsof the MIT conferenceon fish oils. New York Marcel Dekker, 1989.

Pharmacology of Natural Medicines ~

~~

8. Huang YS, Cunnane SC,Horrobin DF, Davignon 1. Most biological effects of zinc deficiency corrected by g-linolenic acid, (18:3 omega 6) but not by linoleic acid (18:2 omega 6). Atherosclerosis 1982;41: 193-207. 9. Stamler J. Nutrition related risk factors for the atherosclerotic diseases-present status. Prog Biochem Pharmacol1983;19:245-308. 10. Horrobin DF, ed. Clinical uses of essential fatty acids. Montreal: Eden Press, 1981. 11. Green P, Glozman S, Kamensky B, Yavin E. Developmental changes in rat brain membrane lipids and fatty acids. The preferential prenatal accumulation of docosahexaenoic acid. J Lipid Res 1999;40:960-966. 12. Farkas K, Noble RC, Speake BK. Developmental changes in the levels of molecular species of triacylglycerol that contain docosahexaenoic acid in adipose tissue of the chick embryo. Comp Biochem Physiol B Biochem Mol Biol 1996;115:1-6. 13. Stevens LJ,Zentall SS, Deck JL, et al. Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder. Am J Clin Nutr 1995fi2761-768. 14.Innis SM. n-3 Fatty acid requirements of the newborn. Lipids 1992;27879-887. 15. Ascherio A, Katan MB, Zock PL, et al. Trans fatty acids and coronary heart disease. N Engl J Med 1999;3401994-1998. 16. Nelson GJ. Dietary fat, trans fatty acids, and risk of coronary heart disease. Nutr Rev 199856250-252. 17. Simon JA, Fong J, Bernert JT, Browner WS. Serum fatty acids and the risk of stroke. Stroke 1995;26:778-782.

18. Renaud S, de Lorgeril M, Delaye J, et al. Cretan Mediterranean diet for prevention of coronary heart disease. Am J Clin Nutr 1995;61: 36OS376S. 19. Wood CB, Habib NA, Apostolov K, et al. Reduction in the stearic to oleic acid ratio in human malignant liver neoplasms. Eur J Surg Oncol 198531LM7-38. 20.Erikson KL, Hubbard NE, Chakrabarti R. Modulation of signal transduction in macrophages by dietary fatty acids. J Nutr 1995;125: 1683s-16865. 21.van Gee1 BM, Assies J, Haverkort EB, et al. Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with "Lorenzo's oil." J Neurol Neurosurg Psychiatry 1999;67 290-299. 22. Mischoulon D, Fava M. Docosahexanoic acid and omega-3 fatty acids in depression. Psychiatr Clin North Am 2000;23:785-794. 23.Locke CA, Stoll AL. Omega-3 fatty acids in major depression. World Rev Nutr Diet 2001;89:173-185. 24. [No authors listed.] Omega-3 fatty acids in the treatment of depression. Harv Ment Health Lett 2001;184-5. 25.Stoll AL, Damico KE, Daly BP, et al. Methodological considerations in clinical studies of omega 3 fatty acids in major depression and bipolar disorder. World Rev Nutr Diet 2001;

Erasmus U. Fats that heal, fats that kill. Bumaby, Canada: Alive Books, 1986. Murray RK, Granner DK, Mayes PA, Rodwell VW. Harpers illustrated biochemistry, ed 26. Stamford, CT Appleton and Lange, 2003.

Spiller GA. Handbook of lipids in human nutrition. Boca Raton, n: CRC Press, 1996.

88:58-67.

Fish Oils (Omega-3 Fatty Acids, Docosahexanoic Acid, Eicosapentaenoic Acid, Dietary Fish, and Fish Oils) Alexander G.Schauss, PhD, FACN CHAPTER C O N T E N T S Introduction 945 Description 946 Dietary Requirement 946 Explaining Inconsistent Results of Fish Oil SupplementationTrials 948 Pharmacology

Rheumatoid Arthritis 954 Psoriasis 955 Cancer 956 Migraine Headache 958 Diabetes 958 Raynaud Disease 958 Malaria 958

948

Clinical Applications 949 Cardiovascular Disease 949 Elevated Serum Lipids 950 Hypertension 951 Angina Pectoris 951 Stroke 952 Bypass Patients 952 Myocardial Infarction 952 Immune Function 953 Pregnancy and Lactation 953 Nephrotic Syndrome 953 Autoimmune Diseases 954

INTRODUCTION A significant body of scientific evidence indicates that consumption of fish oil rich in dietary omega3 fatty acids is beneficial to human health. The health benefits of fish oil, particularly the association between consumption of omega3 long-chain polyunsaturated fatty acids (PUFAs) and cardiac disease, have long been suspected. Millions of people were given cod liver oil as a fish oil supplement decades ago in the belief that fish oil had health maintenance benefits. Provocative scientific evidence of fish oil’s benefits appeared in the late 1970s when it was claimed that fish oil consumption among Greenland Eskimos and other fish-eating populations might convey a lifetime protective effect against coronary heart disease (CHD).’”

Toxicity 959 Bleeding Time 959 Toxin Contamination 959 Oxidation 959 Measurement of Lipid Oxidation Products in Essential Fatty Acid Supplements 960 Dosage 961 Drug Interactions 961 Conclusion

961

The findings among Greenland Eskimos were particularly intriguing. Greenland Eskimos were found to have low rates of CHD despite a diet rich in saturated animal fats derived from seal and whale meat. It was eventually determined that the Greenland Eskimos’ diet was also rich in fish and that the oil in fish contained large quantities of omega3 fatty acids abundant in docosahexanoic acid (DHA) and eicosapentaenoic acid (EPA). A large study in the United States, the Diet and Reinfarction Trial (DART),”5and two studies in Europe, the GISSI-Prevenzione Trial and the Lyon Diet Heart StudyG8have demonstrated that by increasing dietary omega3 fatty acid intake, a significant decrease in ischemic heart disease occurs.

945

Pharmacology of Natural Medicines

These studies and many others have had a profound effect on public health policy makers' perceptions of the importance of fish and fish oil to human health. For example, on February 8,2002, the U.S. Food and Drug Administration (FDA) announced that it would permit the claim "consumption of omega3 fatty acids may reduce the risk of CHD," to appear on labels of omega3 fatty acid supplements containing a dose level of DHA and EPA of up to 2000 mg per day. The FDA's decision to permit such a claim is sigruficant and timely in that by 2000, one million Americans were reported to suffer heart attacks annually. Approximately one third of these heart attacks, or 300,000, were of the "sudden death" variety, in which individuals die within 2 to 3 hours of their heart attack. A significant body of evidence from the Thrombosis Prevention Trial, the Antiplatelet Trial Collaboration, and the U.S. Physicians Health Study now indicates that including fish rich in omega3 fatty acids with meals just twice a week could significantly reduce the incidence of sudden death from a heart a t t a ~ k . ~On - ' ~the basis of these and several other studies, it is now estimated that this one change in diet could save at least 150,000 people annually from fatal heart attacks.lS1*However, increased daily intake of 5 to 7 servings of fruits, vegetables, and nuts rich in antioxidants may also reduce the incidence of heart attacks. The ratio of omega3 fatty acids to omega-6 (18:2n-6) fatty acids has been the subject of considerable study. Several investigations have shown that a decrease in omega-6 fatty acids combined with an increase in omega3 fatty acids can result in a sigruficant decrease in sudden cardiac death in men.19,20 However, the reduction in risk of a sudden cardiac attack causing death following an increase in omega-3 fatty acid consumption does not occur overnight, but rather after several years of weekly intake. With about 20% to 40% of human body mass being adipose tissue and 15% to 20% of body fat being omega-6 (18:2n-6) in composition, an adult may have more than 3 kg of omega-6 fatty acids in his or her body. This large reservoir of omega-6 may need 3 years to equilibrate with improved dietary lipid intake.21 Hence the recommendation to increase intake of omega3 €atty acids could not come soon enough. Dietary fish oil and fish oil supplements have also been found to ameliorate the signs and symptoms of other diseases and conditions. The EPA and DHA found in fish oil have been shown in various studies to reduce the pain of rheumatoid arthritis by decreasing inflammation, the pain associated with menstrual cramps, the risk of premature delivery in pregnancy, and low birth weights. Beneficial effects have also been reported in the treatment or management of bipolar (manic-depressive) disorder, mild to moderate depression, Raynaud disease, lupus, IgA nephropathy, chronic fatigue syndrome,

Crohn's disease, type 2 diabetes, kidney stones, cystic fibrosis, psoriasis, and ulcerative colitis. Additionally, DHA has been shown to be important for neurogeneses of neuronal synapses and healthy eye development of fetuses and infants.

DESCRIPTION Marine life is generally rich in two omega3 fatty acids (also referred to as n-3fatty acids), EPA and DHA. These long-chained and highly PUFAs contain, respectively, 20 and 22 carbons and 5 and 6 double bonds, also referred to as 20:5n-3 PUFA and 22:6n-3 PUFA. The 20:5n-3 PUFAs and 22:6n-3 PUFAs are abundant in shellfish, sea mammals, and fish, hence the reason Greenland Eskimos' diet is rich in EPA and DHA. By comparison, EPA and DHA levels are low or absent in domesticated land animals. The source of the EPA and DHA found in most marine foodstuffs is phytoplankton, which serves as food for various sea creatures. Fish oil from herring, cod liver, wild salmon, mackerel, and sardines is particularly rich in omega3 fatty acids containing EPA and DHA. Table 94lZ7lists the relative concentration of fatty acids in various common fish species. The habitat in which fish grow has a major impact on their fatty acid composition.22In the wild, fish consume food sources that contain high levels of alpha-linolenic acid (18:3n-3). Fish raised in "fish farms" deserve mention. It has been reported that salmon raised in fish farms receive a steady diet of synthetic pigment to give them a rich pink hue; otherwise, they would be unappetizing given their rather morbid, pale gray appearance. In the natural ocean environment, phytoplankton, which are rich in EPA and DHA, form the basis of the food chain for salmon and contribute to its pink color. Commercial fish foods contain less DHA and EPA and hence lower concentrationsof omega3 fatty acids. Studies have shown that wild fish have higher concentrationsof omega3 fatty acids than pond-reared/cultured fish grown in fish farms and fed commercial feedstuffs that are devoid of EPA and DHA.= For individuals who do not or cannot consume seafood, foods such as tofu, canola oil, black currant oil, flaxseed oil (the best nonfish source), nuts, and soybeans are important sources of alpha-linolenic acid (18:3n-3). However, soy-derived oils and foods and most nuts contain large amounts of omega-6 fatty acids that can reduce some of the therapeutic benefits of the omega3 fatty acids, so finding a prudent balance between omega3 and omegad fatty acids is suggested.

Dietary Requirement Omega3 fatty acid requirements in humans remain controversial. The first suspected case of omega3 fatty acid

Fish Oils ration of fatty acids in fish oils

Oil

Cholesterol (mg/lOO 9)

Unsaturated Mono- ( 5 )

n-3 PUFAs

Poly- (%)

18:3 (5)

205 (I)

22:6 (%)

Cod liver

570

18

51

0.7

9

9.5

Herring

760

19

60

0.6

7.1

4.3

Menhaden

600

34

32

1

Salmon Pilchard

485

24

40

1

-

25

29

Trace

17

9

Mackerel

21

43

Trace

11

11

Anchovy

-

28

29

Trace

17

9

Sardine

-

24

34

Trace

15

10

12.7

8

8

11

Modified from Kinsella JE, Lokesh B, Stone RA. Am J Clin Nutr 1990;52:1-28. PUfAs, Polyunsaturated fatty acids.

deficiency in humans was not reported until 1988.” The patient was a 7-year-old girl with retarded growth who had been fed solely by gastric tube since 3 years of age. A deficiency of omega-3 fatty acid was suspected. Soon after taking cod liver oil and linseed oil supplements, she began to experience normal growth. Some investigators contend that as little as one meal containing fish rich in omega-3 fatty acid a week is sufficient, while others suggest that a much higher intake level of three meals of fish a week is necessary for individuals to benefit from its attributes. An expert workshop held in Europe in 1998 agreed that consumption of omega-3 fatty acids may reduce the risk of CHD.= One year later a similar agreement was published by another expert workshop that addressed the question of what is an adequate intake of essential fatty acids in the United States.26By 2004, evidence was pointing toward the consumption of two to three portions (>8 oz) of fish per week. The United Kingdom Food Standards Agency has recommended that men eat no more than four portions of fish per week and women and children no more than two.* Because the concentration of EPA and DHA in fish can vary depending on its growth environment, fish oil supplements can offer a viable and reliable source of omega3 fatty acid standardized around the content of EPA and DHA. The most popular combination of EPA and DHA found in fish oil supplements remains the brand ”MaxEPA,” which contains 18% EPA and 12% DHA. Eskimo3 is another brand similar to MaxEPA in that it contains 19% EPA and 13% DHA. Other fish oil supplements such as blue-fin tuna oil generally contain ‘Food Standards Agency. Oily fish advice: your questions answered. Available [accessed online at www.food.gov.uWnews/newsarchive/2O~~un/oi/~ishfaq July 7, 20051.

7% EPA and 25% DHA. However, this does not imply that omega-3 fish oil supplements are always derived from pelagic fish (i.e., from deep oceanwater fish), since some freshwater fish contain higher levels of EPA and DHA than some saltwater species (see Table 94-1). Most fish oil capsules contain between 300 and 500 mg of omega-3 fatty acid per gram. Patients using fish oil at the therapeutic levels discussed herein may require between 15 and 30 capsules daily to derive the described benefits, depending on their DHA-to-EPA ratio. At 9 calories/g of oil, this can represent a significant increase in caloric intake and may necessitate an increase in energy expenditure to avoid weight gain. EPA- and DHA-rich fish oil should be kept in capsules (such as soft gelatin with minimal plasticizer contenP; see later discussion on oxidation) capable of providing an oxygen barrier. Otherwise, toxic lipid peroxides (e.g., malondialdehyde)and anisidine isomers may form. Encapsulated liquid sources generally do not have this protection unless they contain antioxidants. Emulsified fish oils are preferred as they are better absorbed in humans. Encapsulated products typically contain fish oil, not fish liver oil. This distinction is important because fish liver oil contains the fat-soluble vitamins A and D, which, if taken in excessive amounts, can cause vitamin A or D toxicity. The lowest consistently reported daily intakes associated with chronic toxicity in adults are 50,000 IU for vitamin A and 10,000 IU for vitamin D. However, there is mounting evidence that vitamin D from sunlight and DHA found in fish oil may reduce the incidence of certain cancers, such as breast cancer. Hence some vitamin D residuals in the fish oil may actually increase its protective value against cancer, as well as CHD. Researchers at the Italian National Cancer Institute completed an investigation aimed at clarifymg

the association between fat intake and breast cancer risk. A total of 4052 postmenopausal women were followed for an average of 5.5 years. During this time 71 cases of invasive breast cancer were diagnosed. The cancer patients were matched with 141 controls. All study participants had blood samples drawn, and red blood cell (erythrocyte) membranes were analyzed for their fatty acid content. The researchers pointed out that erythrocyte membranes are good biomarkers not only for dietary fat intake but also for other dietary and hormonal factors. Women with DHA concentrations in the highest tertile had less than half the risk of breast cancer than did women in the lowest tertile. Polyunsaturated fatty acids overall were also protective, with omega-3 acids being somewhat more protective than omega-6 acids. Saturated fatty acid concentrations were not significantly related to breast cancer risk. A higher concentration of monounsaturated fats, especially oleic acid, was associated with a significantly increased risk. The researchers pointed out that most oleic acid in mammalian tissue is derived from saturated stearic acid through a process involving the enzyme delta 9-desaturase. Saturated fatty acids, cholesterol, carbohydrates, insulin,testosterone, and estrogen all activate this enzyme, whereas dietary polyunsaturated fatty acids and fasting deactivate it. The researchers concluded that the delta 9-desaturase enzyme may be an important link between breast cancer risk and dietary fat c ~ n s u m p t i o n . ~ ~

Explaining Inconsistent Results of Fish Oil Supplementation Trials A number of papers in the fish oil literature have reported equivocal or contradictory results. Many of these differences in outcomes can be explained by the use of olive oil as a placebo or the lack of control for saturated or omega-6 fatty acid intake. Olive oil cannot be considered an inert placebo in trials that investigate effects on platelet function or CHD risk. Several studies have shown that olive oil supplementation has similar inhibitory effects on various aspects of platelet function, including decreased platelet aggregation and thromboxane A2 (TXA2) release, increased platelet membrane oleic acid content, and decreased platelet membrane arachidonic acid c ~ n t e n t .Further, ~,~~ an excess of oleic acid impairs incorporation of arachidonic acid into platelet phospholipids. Another possible complicating factor is the squalene found in olive oil and some deepwater fishes but not in other vegetable 0ils.3~ Other problems include the differing ratios of fatty acids, the position of the fatty acids on the glycerol backbone, and the susceptibility to peroxidation of the various fish oil p r e p a r a t i ~ n s . ~ ~ Also, overprocessing of fish oil supplements can result in a loss of its active constituents and hence an attendant decrease in its efficacy. This has been demonstrated in

at least two studies that looked at such variables as how processing affects levels of triglycerides, cholesterol, lipoprotein(a), atherogenic index, and fibrinogen, following fish oil s ~ p p l e m e n t a t i o n . ~ , ~ ~

PHARMACOLOGY ~~

In general, the effects of supplemental and dietary m a t urated fatty acids appear to be mediated through changes in serum lipids, altered ratios of prostaglandins, decreased platelet aggregation, and modification of cell membrane activity.33 Fish oils appear to reduce undesirable circulating fats and decrease the production of the prothrombotic substance TXA2 by occupying TXA2 receptors and enhancing the production of the platelet antiaggregatory substance prostacyclin. These actions play an important role in inflammation, atherogenesis, thrombosis, and CHD. Fish meals that provide an average of 3.6 g a day of omega-3 fatty acids reduce platelet aggregation and platelet TXB2responses.% Significant decreases in platelet sensitivity to collagen, serum TXB2 levels, and urinary TXB2 metabolites have been observed following omega-3 fatty acid treatment.37EPA supplementation has been shown to decrease synthesis of the omega-6 platelet agonist TXA2 coincident with formation of the inactive omega-3 form, TXA3.38,39 A longitudinal study has shown a pronounced action of dietary omega-3 fatty acids to diminish platelet formation and endothelial deposition that could lead to thrombosis.4o Through the vasodilatory effects of prostacyclin PG13, fish oils may improve peripheral circulation, thereby assisting very low density lipoprotein (VLDL) cholesterol removal. This may be accomplished by altering membrane fluidity in a specific manner, thus affecting the activity of membrane-bound enzymes and resulting in changes in receptor activity, specificity, and signal transduction. Evidence also suggests that fish oils decrease hepatic synthesis of fatty acids and triglycerides and reduce secretion of VLDL cholesterol while displacing arachidonic acid from tissue phospholipids. This results in omega-3 EFA levels that inhibit thromboxane synthesis. Researchers have noted that fish oil effects are selective. EPA and DHA not only displace arachidonic acid from phospholipid pools and inhibit cyclooxygenase, but EPA also becomes a preferred substrate for cyclooxygenase when peroxide tone is high. This results in decreased production of the vasoactive and aggregatory prostacyclin PG12 and increased production of PGI3 that has more potent antiaggregatory effects. According to some researchers, increased bleeding time is due to either less TXA2 or higher prostacyclin I3 levels:' although others contend that EPA conversion to PG13 is the primary cause.42Many researchers believe this

Fish Oils change is one of the primary factors that decreases the risk of atherosclerosis and t h r o m b ~ s i sThese . ~ ~ findings may explain some of the epidemiologic evidence of decreased coronary artery disease and prolonged bleeding time seen in some Eskimos and in those Japanese found eating a diet rich in fish.% Fish oils rich in EPA and DHA have also been found to suppress production of inflammatory mediators found in patients with rheumatoid arthritis and psoriasis. The antiinflammatory effect of the omega3 fatty acids is probably due to reduced production of leukotrienes, interleukin-2, and tumor necrosis factor-alpha (TNF-a), all principal mediators of inflammation. A recent study has found that the ability of fish oil to decrease TNF-a production is influenced by an inherent TNF-a production and by polymorphisms in the TNF-a and lymphotoxin alpha genes (also known as tumor necrosis factor-beta).51 In relation to coronary artery disease, ingestion of fish oil and its effect on platelets, erythrocytes, neutrophils, monocytes, and liver cells are considered to be important in explaining its benefits. The increased concentrations of EPA and DHA from the ingestion of fish oil have been shown to do the following: Decrease production of prostaglandin E2 (PGE2) metabolites Decrease production of TXA, (an active vasoconstrictor and platelet aggregator) Increase prostacyclin PGIB(an active vasodilator and inhibitor of platelet aggregation) Increase production of leukotriene B5 (a weak inducer of inflammation; weak chemotactic agent) Decrease production of leukotriene B4 (a weak inducer of inflammation; inducer of leukocyte adherence and chemotaxis)

CLINICAL APPLICATIONS Cardiovascular Disease The EPA and DHA in fish oil inhibits the development of atherosclerosis, which can increase the risk of primary cardiac arrest?, Evidence from large animal studies indicates that fish oil prevents atherosclerosis by mechanisms other than simply lowering cholesterol, including the following: Stimulation of endothelial production of nitric acid Decrease of cytokine and interleukin-1production Inhibition of monocyte migration into the plague These three events can, when uncontrolled, contribute to the characteristic yellowish plaques (atheromas) that contain the combination of cholesterol, lipophages, and lipoid material seen in the intima and inner media of largeand medium-sized arteries found in atherosclerosis.

Hence the demonstrated ability of fish oil to control all three, combined with its ability to lower VLDL and elevated triacylglycerols, can be a useful approach in the prevention of ventricular fibrillation and sudden death. That fish oil can perform this favorable reduction in risk of sudden death, not shown to be possible by the consumption of linolenic acid or linoleic acid from vegetable oils, has been shown in several double-blind, placebo-controlled, randomized trials conducted in human subjects, especially when compared with vegetable oils.& Increased stiffness in the large arteries can lead to systolic hypertension and increased pulse pressure (which is the difference between diastolic and systolic pressure), both factors that can contribute to increased risk of CHD. Whether DHA or EPA can improve systolic and pulse pressure and vascular resistance has been studied. Thirty-eight middle-aged men and women with elevated plasma total cholesterol consumed a DHA, EPA, or placebo supplement during a 7-week intervention. In contrast to the placebo group, and showed no changes, systemic arterial compliance rose 36% in the EPA group and 27% in the DHA group, and there was a trend toward a reduction in pulse and systolic pressure.'* Also, both the EPA and DHA groups experienced significant declines in plasma total triacylglycerol concentrations. In addition, diets rich in omega-3 fatty acids from fish oil lower triglyceride levels, especially in those with severe hypertriglyceridemia, for whom attempts to correct the cause through exercise, the drug gemfibrozil, or other dietary modifications have proven inadequate. This benefit is not seen with plant source oils containing land-based alpha-linolenic fatty acid-rich polyunsaturated fat sources ( e g , flaxseed oil) or via reduction of saturated animal fatty acids k1take.4~ At a 1994scientificmeeting on the role of fish oil in cardiovascular health, the following favorable mechanisms of action of omega-3 fatty acids in humans were reported inhibition of VLDL triglyceride synthesis; decreased apoprotein B synthesis; enhancement of VLDL turnover with an increased fractional catabolic rate of VLDL; depression of LDL synthesis; and reduction of postprandial li~idemia.4~ The therapeutic use of fish oil supplements is essential in patients with type 5 hyperlipidemia. All benefits of fish oil may not be conferred by only eating fish. Favorable therapeutic and preventive effects may require between 5 and 20 g/day of linolenic acid and fish oil, which is unlikely in contemporary diets consumed in industrialized societies-hence the use of fish oil supplements. The prevention of thrombosis by fish oil consumption is suggested by a number of studies, particularly in patients receiving coronary bypass surgery. In a randomized controlled trial of bypass patients who received

Pharmacology of Natural Medicines ~

warfarin or aspirin as anticoagulants, those subjects who also received fish oil had significantly fewer vein graft

occlusion^.^^ Despite all of these findings related to CHD by 1996, a 1997American Heart Association (AHA) science advisory report on fish oil consumption stated: ”There is no convincing role for fish oil supplements in the prevention of CHD.’” The AHA report did accept mounting evidence that sudden cardiac deaths may be prevented but took the position nevertheless by stating that “further studies are needed to explore the potential of fish oil in the prevention of sudden cardiac death.” Apparently, the AHA’S scientists require ”compelling evidence” before they would recommend general usage of fish oil supplements to reduce CHD or sudden death, despite the conclusion of one of the studies they cited that found that fish oils reduce myriad potential atherogenic processes associated with atherosclerosis, CHD, and sudden cardiac-related deaths.55 Research has focused more on fish oil supplements than on fish consumption. This may be due to dietary surveys that have found that less than half of Australians, Americans, and Canadians regularly eat fish. In addition, fish is a generalized term and some popular species of fish contain low levels of omega-3 fatty acids.

ELEVATED SERUM LIPIDS The most consistent effect of fish oils on serum lipids is a reduction in total triglycerides and VLDL cholesterol, especially in patients with severe hypertriglyceridemia. In general, dietary fish oils appear to both reduce undesirable serum-circulating fats and decrease the production of the prothrombotic thromboxanes. In most studies, fish oil supplementation causes a sigruficant reduction of VLDL cholesterol, plasma triglycerides, plasma cholesterol, and LDL cholesterol. In hypertriglyceridemic patients, fish oil supplementation typically results in a significant decline in VLDL cholesterol levels because large decreases in triglyceride levels lead to a decrease in VLDLS.@~~-~~ Some studies have not found decreases of total cholesterol or LDL cholesterol following fish oil supp l e m e n t a t i ~ nHowever, .~~~ these equivocal studies used olive oil as a placebo, whch, as discussed earlier, is a confounder. For patients with elevated serum cholesterol (>7.75mmol/L) or triglycerides (>5.64mmol/L), there is sufficient evidence to consider fish oil supplementation of 5 to 10 g/day.@In one study of 365 patients, supplementation with 10 ml/day (9.2 g) of MaxEPA resulted in significant reductions in triglyceride levels, which were maintained over a period of 4 years.65Continuing

~~

reductions were observed in persons remaining in the study more than 4 years. The authors concluded: “For triglycerides to remain depressed it seemed necessary to maintain a daily intake of 9.2 g MaxEPA.” In a Canadian study, triglyceride levels decreased 31% in 9 days following fish oil supplementation.66 However, total and HDL cholesterol levels did not change. Nine days after supplementation ceased, triglyceride levels showed a trend of returning to baseline. As total cholesterol and LDL cholesterol levels are predictors of death from cardiovascular and CHD, their control is crucial. Almost all epidemiologic studies show that populations eating fish have a reduced death rate from CHD. By 1990,22 primary and secondary prevention trials demonstrated that lowering serum total cholesterol and LDL cholesterol through either diet or drugs reduced the incidence of CHD among survivors of myocardial infarction. A 10-year prospective study of male mortality rates due to cardiovascular disease found that LDL cholesterol, HDL cholesterol, and total cholesterol levels are the most predictive indices of subsequent mortality from cardiovascular disease among men with and without preexisting cardiovascular disease.67 Support for fish oil intake in the reduction of CHD comes primarily from epidemiologic studies’” and clinical and experimental studies in animals and A 20-year prospective study conducted in the Netherlands found that consuming as little as 35 g/day of fish (0.5 lb/wk) might be of benefit in preventing, and reducing mortality from, CHD.” In contrast, two epidemiologic studies found no relationship between fish consumption and cardiovascular The effect of fish oil consumption on lowering serum lipids may account for the lower mortality rate due to cardiovascular disease found in coastal Alaskan natives, who, compared with mainland Americans, eat a diet rich in fish and other sea creatures. Autopsies on 339 Alaskan natives found that only 10.3% died of cardiovascular causes, compared with 50% of all deaths among those subjects who lived on the American mainland.n The possibility of fewer fatal arrhythmias due to high fish consumption has also been proposed to explain the lower death rate of native Two studies involving rats have shown that ingestion of either as much as 30% or as low as 0.4% of energy in the form of omega-3 fatty acids from fish decreased the incidence of ventricular f i b r i l l a t i ~ n .The ~ ~ ,antiarrhythmic ~~ aspects of PUFAs are supported by a number of clinical and experimental studies in animals and human^.^^-^* Some investigators conclude that fish oil is more effective at reducing ventricular arrhythmias than pharmacologic agents in the prevention and management of cardiovascular disease.”

Hypertension

Another proposed mechanism is that fish oils may facilitate excretion of sodium and fluid by the kidneys. This is supported by a reported but unpublished, double-blind, cross-over study in which researchers placed healthy, nonhypertensive men and women on a diet supplemented with approximately 1 g/day of PUFAs for 28 days.95Each participant received capsules with either fish oil or safflower oil. The fish oil dose was similar to the amount consumed in a single daily serving of tuna, lake trout, or salmon. After 2 weeks, the subjects crossed over to the other supplement. The study found an average 2 to 3 mmHg drop in both diastolic and systolic blood pressure in those who received fish oil supplements. The researchers also found that fish oil increased urine output by approximately lo%, performing much like a low-sodium diet. This resulted in a reduction in fluid volume. Unlike diuretics, the fish oil supplementation did not increase potassium excretion.

There is some evidence from placebo-controlled studies that fish oil reduces blood pressure in a dose-response fashion,especially in patients with hypercholesterolemia and hypertension, but not in subjects with normal blood pressure.83 Fish oil seems to have hypotensive effects, ranging from limited (dosages of 5 g/day or less) to substantially larger d o ~ a g e s ?although ~ , ~ ~ ~ there is some conflicting evidence.93It has been proposed that fish oil depresses vascular response to the hormones involved in hypertension." Another suggestion is that fish oil acts by increasing vasodilatory prostaglandins PGIl and PG13, and that this increase accounts for observed reductions in blood pressure." To test this hypothesis, one study examined the effect of fish oil on blood pressure in men with mild, essential hyperten~ion.9~ One group received 10 ml of fish oil (3 g of omega3 fatty acids), a second group received 50 ml (9 g of EPA and 6 g of DHA), a third group received 50 ml of safflower oil (39 g of omega-6 fatty acids), and a fourth group received 50 ml of a mixture of coconut, olive, and safflower oils. The latter group represented the approximate amount and ratio of fatty acids consumed in the average American diet (39%saturated fat, 46% monounsaturated fat, and 15%polyunsaturated fat). The group receiving the highest dose of fish oil (50 ml) had an average reduction of 6.5 mmHg in systolic pressure and 4.4 mmHg in diastolic pressure. None of the other groups, including the low fish oilsupplemented group, demonstrated blood pressure reductions in the aggregate. The study did not find the expected association between increased production of PGI, and PG13and sustained reduction in blood pressure. This suggests that vasodilatory prostaglandins are probably not the primary mediators of blood pressure reduction by fish oil consumption, although they may play a role.

A number of studies have shown that fish oil supplementation reduces the number of angina attacks and reduces mortality in men recovering from myocardial i n f a r ~ t i o n . 9Significant ~~~ rheological improvements in patients with stable angina pectoris may occur following daily fish oil supplementation with 2.8 g of EPA and 1.8 g of DHA (equivalent to 15 capsules of M ~ X E P A ) . ~ ~ In a double-blind, placebo-controlled study, fish oil supplementation resulted in increased red cell deformability, reduced whole blood viscosity, and prolonged bleeding time compared with olive oil supplementation. The frequency of angina attacks decreased in both groups. However, neither type of oil affected exercise capacity or hemodynamic response to exercise. In 1999 a group of researchers in Italy reported that supplementation with fish oil (containing580 mg of EPA and 290 mg of DHA) sigmficantly reduced mortality among patients who survived a first heart attack.6 This resulted in an editorial comment on the study in the Lancet that wondered if fish oil could protect against ischemic heart disease.%Two years later the researchers reanalyzed their data to determine how fish oil exerts its protective effect.'@They found that the reduction in mortality occurred after only 3 months of supplementation and continued thereafter. The reduction in the incidence of sudden cardiac death accounted for about 57% of the total improvement in mortality rates. At the end of the study 2.7%of the placebo group participants had died from sudden cardiac death as compared with only 2% in the fish oil group. Overall, cardiovascular death (including stroke) at the end of the study was 6.5% in the placebo group versus 5.5% in the fish oil group. There was no statistical significant difference in the incidence of nonfatal heart attacks between the fish oil

Recent evidence also suggests fish oil may prevent cardiovascular disease in Rhesus monkeys and hyperlipidemic pigs despite lack of improvement in serum cholesterol levels.81,82 This retardation in the initiation and progression of atherogenesismay be due to fish oil's depression of inflammatory eicosanoid metabolism in platelets, macrophages, and monocytes. The therapeutic dosage of fish oil for the treatment of cardiovascular disease should be 5 g/day or m0re.4~One researcher has suggested that for both prophylactic and therapeutic applications, the most efficacious use of fish oil would be to concomitantly lower total fat intake to no more than 30%of calories and saturated fatty acids to no more than 30%of total fat, while limiting omega-6 fatty acids (vegetable oils) to a maximum of 10% of total fat intake.49

Angina Pectoris

Pharmacology of Natural Medicines

and placebo groups. The researchers concluded that fish oils exert their protective effect by preventing fatal ventricular arrhythmias rather than through an improvement in cholesterol profile. They did note a small drop in triglyceride levels of 4.6%in the fish oil group but found no significant differences in LDL and HDL cholesterol between the two groups. They also point out that the number of lives per 1000 patients that could be saved every year by giving heart attack survivors fish oil exceeds the number of lives per 1000 patients estimated to be saved by treating heart disease patients with high cholesterol levels with pravastatin. This puts fish oil supplements squarely in the category of a highly effective unpatentable heart drug. Evidence is growing that high blood levels of C-reactive protein (CRP)are associated with an increased risk of CHD and heart attacks. Danish research has revealed that CRP levels can be kept lowered by regular consumption of fish or fish oils.1o1The investigators studied 269 patients with suspected coronary artery disease based on angiography and found that patients with one or more blocked coronary arteries had significantly higher CRP blood levels than patients with no sigrulicant blockages, followed by the observation of an inverse correlation between CRP blood levels and the level of DHA in granulocytes. The level of DHA in granulocytes was found to closely correlate with fish consumption. This led the researchers to conclude that DHA has an antiinflammatory effect that can result in lower CRP levels, thereby suggesting that fish or fish oil consumption may decrease the risk of coronary artery disease.

Stroke A 1995 study found that men who ate fish five or more times a week had a 40% lower risk of experiencing a stroke than men who ate fish less than once a week. A similar study in women by researchers at Harvard Medical School found even more impressive results for women.1o2In this study 79,839 female nurses between the ages of 34 and 59 were followed for 14 years, by which time 574 had experienced a stroke; 303 of the strokes were caused by blood clots, while another 181 were caused by a ruptured artery, and the remaining 90 were of undetermined origin. It was determined that women who ate fish once a week lowered their risk of a stroke of any kind by 22%. However, women who consumed fish five or more times per week reduced their risk by 52%. The investigators concluded that women whose intake of fish oils is 0.5 g per day or more have a 30% lower risk of a stroke than women whose intake is below 0.1 g per day. Of particular interest was the finding that in those women who had a high fish or fish oil consumption, there was no evidence of an increased risk of hemorrhagic stroke. The researchers

concluded that the protective effect of fish oils are due to their ability to inhibit platelet aggregation, lower blood viscosity, suppress formation of leukotrienes, reduce fibrinogen levels, reduce blood pressure, and reduce insulin resistance. Curiously, the beneficial effects were substantially more likely in women who did not take aspirin on a regular basis.

Bypass Patients Some studies have demonstrated that fish oil supplementation may help prevent reclosing (restenosis) of the arteries after angioplasty. In one such study bypass patients were supplemented with 4 g of fish oil a day.Io3 One year later those patients who consumed the fish oil supplements had an occlusion rate of 27%,while control patients had a 33% rate of occlusion, or a 23% relative improvement. On the basis of a postoperative evaluation 3 weeks after patients had cardiac transplants, it was found that patients who consumed fish oil supplements had normal endothelium-dependent coronary vasodilation, which remained abnormal in patients who did not consume fish oil.

Myocardial Infarction

Several studies of rodents have shown that dietary fats modulate the electrical stability of the myocardium. The appropriate fatty acids can reduce the vulnerability to arrhythmia during myocardial i s ~ h e m i a . ~ ~ , ~ ~ , ' ~ Raising the omega-3 fatty acids to higher levels in the myocardium may also prevent postinfarction ventricular fibrflation.7L10531C6 One study evaluated the effect of dietary intervention in 2033 men recovering from myocardial infarction? Patients were randomly allocated to receive one of four types of dietary advice: 1. Lowered intake of dietary fat 2. Consumption of at least two portions of fatty fish (200 to 400 g) a day 3. Supplementation with three capsules (1.5 g) of MaxEPA a day 4. Increased dietary fiber intake At the end of 2 years, the group consuming fish were found to have increased their EPA intake to four times that of other subjects. This group also experienced sigruficantly lower mortality. The fat and fiber advice groups showed no differences in mortality. Although the rate of recurrence of heart attack was similar in all groups, the fish and fish oil group had a 29% reduction in risk of death compared with the other groups. These findings are in direct conflict with an earlier study showing no such benefits.lo7However, it may be sigruficant that the earlier study was conducted over the short period of 6 weeks. Even in patients with no apparent clinical evidence of arterial disease, fish consumption has been shown to

Fish Oils

improve arterial wall function. One study found that in both healthy and non-insulin-dependent diabetes mellitus patients, those who ate fish showed significantly better compliance of their left subclavian artery and femoral arteries.lo8

Immune Function Research in both animals and humans has not yet determined whether fish oil supplementation suppresses or enhances immune function. For example, recent laboratory animal experiments show that supplementation with gamma-linolenic acid or fish oil results in marked changes in the structure and function of leukocyte membranes consistent with improved immune response.10g In addition, animal studies have shown enhancement of the metabolic processes associated with resistance to infection and such diseases as cancer."O However, longterm supplementation with EPA results in pronounced inhibition of the oxidative processes necessary for the immune response. In humans an omega-3enriched, low-fat, low-cholesterol diet suppresses immune function, possibly increasing susceptibility to infection. For example, increasing the typical American diet content of omega-3 fatty acid intake from 1%to 2.5% over a 6-week period results in decreased PGE2 levels, helper cell activity, and other indices of immune function.lWMore research is necessary to clarify the differences in animal and human responses to fish oils.

Pregnancy and Lactation In recent years an extensive number of studies have been published on the effect of DHA and fish oil on pregnancy and During pregnancy, growth of new tissue raises the requirement for essential fatty acids, as mobilization moves polyunsaturated fatty acids from maternal tissue stores to the fetus. A study of 19 normal pregnant women found an increased requirement for omega-3 EFA intake during pregnancy, lactation, and infancy.l17 The authors stated that because omega-3 fatty acids decrease in maternal circulation during pregnancy and remain low for at least 6 weeks after pregnancy, "it may be reasonable to increase the omega-3 PUFA in the diet before, during, and after pregnancy." The authors further suggest that "dietary supplementation may be indicated," since maternal levels of EPA were 42%of normal value. The study further concluded the following: It seems reasonable to suggest that 18:3 omega-3 intake be increased during pregnancy, lactation, and infancy, when requirements for omega-3 PUFA are highest, during the development of the nervous system, which is rich in lipids containing high proportions of omega-3 PUFA.The mental apparatus of the coming generation is developed in utero, and the time to begin supplementation is before conception. A normal brain

cannot be made without an adequate supply of omega3

PUFA, and there may be no later opportunity to repair the effects of an omega-3 fatty acid deficiency once the nervous system is formed. Supplementation with either ALA or EPA may restore EFA levels in such deficient individuals.

In a study of 9000 pregnant women, investigators report that women who consume fish once a week during the first 16 weeks of pregnancy have a 3.6 times lower risk of giving birth to a low-birth-weight infant (>2500 g) or premature delivery (born before 259 days) than those women who ate no fish or seafood during this same time period.118The researchers also found that women whose daily intake of fish was less than 15 g were significantly more likely to give birth to a preterm or underweight baby than women who had higher intakes of fish. This would suggest that even small amounts of fish taken during the early stages of pregnancy can protect against preterm deliveries and low-birth-weight infants. However, recent reports of mercury contamination of some species of fish urge caution. Mercury is a known neuro- and feto-toxic heavy metal. There is no safe intake level of mercury. Fish oil supplements have been found to contain undetectable mercury levels, hence offering a compelling substitute source of omega-3 fatty acids for females of childbearing age. Another study has looked at DHA intake and lactation in lactating women 4 to 6 weeks after delivery.l19 Those women who supplemented their diet with 200 mg of DHA/day had 28% more breast milk than a placebo group consuming 200 mg of a corn/soy oil mixture.

Nephrotic Syndrome Both hypertriglyceridemia and hypercholesterolemia are common in patients with nephrotic syndrome. This association results in an increased risk of CHD. Fish oils have been found to lower serum triglycerides in patients with nephrotic syndrome and may therefore be of clinical benefit.& IgA nephropathy is a kidney disease that can follow a viral infection of the gastrointestinal or upper respiratory tract. The disease has no known cure. Treatment with steroids, antibiotics, anticoagulants, antiplatelet drugs, and phenytoin have been found largely ineffective. About 20% to 40% of all IgA nephropathy patients develop renal failure 5 to 25 years after diagnosis. One study at the Mayo Clinic has found that fish oil supplementation can be effective in slowing down the progression of the disease.120 The progression of the disease was judged by regularly measuring the level of creatinine in blood serum during the 2 years of the trial. A clear difference was observed. The patients in the fish oil group receiving 12 fish oil capsules a day containing 1.9 g of EPA and 1.4g of DHA had an average median increase in serum creatinine of only 0.03 mg/dL, while the patients in the placebo group experienced an increase

placebo control group rather than any improvement by the fish oil Other studies did not suffer from this confounder. A double-blind, placebo-controlled study of patients with rheumatoid arthritis found sigruhcant improvements in several clinical indices during 12 weeks of fish oil supplementati~n,'~~ as did another study of patients Autoimmune Diseases with either rheumatoid arthritis or psoriasis who reported i r n p r o ~ e m e n tPatients .~~ taking 18 g of fish oil Fish oils may play a role in the treatment of autoimmune (containing 153 mg EPA and 103 mg DHA) for 6 weeks disease (e.g., lupus erythematosus, dermatomyositis, reported significant improvement in symptoms. Samautoimmune nephritis, multiple s c l e r ~ s i s ) ~ and ~~-'~~ ples of peripheral blood mononuclear cells from these inflammatory disorders (e.g., rheumatoid arthritis,Iz4 patients showed suppressed synthesis of the two mediapsoriasis,lE atopic dermatitis'). The evidence of fish oil's tors of inflammation, IL-l-@ and TNF-a, compared with possible benefits is derived f?om animal studies using patients receiving placebos. Of particular interest was inbred mice strains.@ Observational studies and anecthe finding that the antiinflammatory effect of the fish dotal reports by lupus patients suggest some benefit. oils continued for up to 4 weeks after cessation of supRheumatoid Arthritis plementation. In another randomized, double-blind, placebo-controlled study conducted over a 24-week Rheumatoid arthritis is uncommon among Eskimos, period, 49 patients with rheumatoid arthritis experiyet by comparison 2% of the world's population suffers enced significant clinical benefit, particularly in tender from rheumatoid arthritis, which is three times prevalent joints, from supplementation of either a low dose of in females more than in males. The disease can strike at 27 mg/kg EPA and 18 mg/kg DHA or a high dose of any age due to inflammation of joint tissues associated with production of toxic substances in the synovium that 54 mg/kg EPA and 36 mg/kg DHA. Interleukin-1 levels can lead to cartilage destruction. (An interesting footnote decreased 54.7% in the high-dose group and 40.6% in the low-dose group.91 is a study from Spain that found decreased levels of In another 15-week study involving 50 patients who omega3 fatty acids in the blood and synovial fluids of male and female rheumatoid arthritis patients compared had been diagnosed with rheumatoid arthritis, fish oil with healthy controls.'26) supplementation was studied. The patients were all The usual symptoms associated with rheumatoid consuming a diet that contained less than 10 g/day of omega-6 fatty acids. These fats are known to promote arthritis are swelling of the affected joints; fatigue; general malaise; and morning stiffness, in particular. inflammation through their eicosanoid metabolites. Half Evidence is mounting that omega3 fatty acids found the patients were given fish oil capsules to provide a in fish oil may beneficially influence the course of treatdaily intake of 40 mg/kg body weight (about 2.8 g for a ment in patients with rheumatoid arthritis due to their 70-kg person); the other half received placebo capsules inhibition of inflammation and incorporation into cell containing 50/50 corn/olive oil. All subjects continued membrane^.'^^ A considerable body of evidence indicates with their regular diet and medications. About half the that rheumatoid arthritis is caused by oxidative stress patients dropped out during the experiment, mainly due involving excessive production of proinflammatorycomto changes in their medications. Complete clinical evalupounds such as interleukin-l-beta (IL-1-p) and TIW-a. ations were carried out at baseline, 4, 8, and 15 weeks. Although there were no significant changes after 4 or Further support comes from a population-based, case-controlled study in women that found a decreased 8 weeks, after 15 weeks major improvements were noted risk of rheumatoid arthritis in those who consumed the in the group receiving fish oil. Particularly impressive most while other studies have shown that fish was the decrease in morning stiffness and overall assessoil supplementation can reduce IL-1-p production, ment of disease activity by both the patients and physiresulting in a reduction in morning stiffness and painful cians. Significant improvements were noted in 6 of the points.'28 9 evaluation parameters in the fish oil group, while no In addition, 14 randomized, controlled clinical trials improvements were noted in the control group. Only have reported significant benefits from fish oil supplethe total number of joints affected, the erythrocyte sedimentation in rheumatoid arthritis patients. A doublementation rate, and the CRP level were unaffected by blind, placebo-controlled study of rheumatoid arthritis supplernentation.lm patients given 1.8 g/day of fish oil showed less morning Dr.Joel Kremer of Albany Medical College in New York stiffness and tender joints. Analysis of this study has concluded that taking 3 to 6 g daily of omega3 fatty showed that the purported benefits of fish oil could have acid fish oils for 12 weeks or more will significantly been due to the unusually high dropout rate of the diminish joint pain and morning stiffness in rheumatoid

of 0.14 mg/dL annually, indicating that their disease was progressing significantly faster. After 4 years, 40% of the patients in the placebo group had died or developed end-stage renal disease compared with only 10% in the fish oil group. No adverse effects of fish oil supplementation were observed.

Fish Oils arthritis patients. Several studies have shown that the improvement in some patients is sigruficant enough to allow them to materially reduce or completely discontinue their use of nonsteroidal antiinflammatory drugs (NSAIDs) such as diclofenac and naproxen. Dr. Kremer also points out that fish oil supplementation has been found to benefit patients with inflammatory bowel disease.131Kremer 's assertion is based on a double-blind, placebo-controlled study involving 66 patients with active rheumatoid arthritis indicated by the presence of at least three of the following symptoms: six or more tender joints; three or more swollen joints; 30 minutes or more of morning stiffness; and a sedimentation rate of 28 mm/hr or higher. The patients were weaned off their antiinflammatory medications and then started on the NSAID diclofenac (75 mg twice a day). After 2 weeks the subjects were randomized into two groups receiving either 130 mg/kg per day of either fish oil (EPA + DHA ethyl esters) or corn oil (an omega-6 fatty acid). The daily dose of fish oil corresponds to about 9 g/day for a person weighing 70 kg. After 18 or 22 weeks, the diclofenac was replaced by a placebo and the fish and corn oil supplementation continued for another 8 weeks, after which all patients were switched to the corn oil plus diclofenac placebo until the end of the study at week 48. The researchers found that the fish oil group achieved a significant lessening of their symptoms from the start of supplementation and until the replacement of diclofenac with the placebo. No statistically significant benefits were observed in the corn oil group. Several patients in the fish oil group maintained their improved status even after diclofenac withdrawal. The researchers concluded that some rheumatoid arthritis patients using fish oil supplementation may be able to discontinue nonsteroidal antiinflammatory drugs without experiencing a flare-up of their disease. They also noted that the benefits achieved from supplementing with 9 g/day of fish oil were no greater than those observed in other studies using only 3 to 6 g/day.

Psoriasis Psoriasis is a skin disease characterized by thick silvery white scales that are surrounded by a red inflamed border. Psoriasis is accompanied by high concentrations of arachidonic acid in the plaques and profound changes in the metabolism of eicosanoids, leading to an increase in proinflammatory agents. Fish oils presumably improve the condition by decreasing the levels of inflammatory leukotriene compounds, especially leukotriene B4r a lipoxygenation product of arachidonic acid. The EPA in fish oil replaces the arachidonic acid in phospholipids, leading to the formation of leukotriene B5rather than Blr resulting in a much weaker inflammatory response.132 This effect has been demonstrated in neutrophils isolated from the peripheral blood of patients given fish oil

to treat their psoriasis.133Patients who showed evidence of clinical response to fish oil therapy for their psoriasis were shown to have higher levels of leukotriene B5 than those failing to improve. Patients with psoriasis (vulgaris) have been successfully treated with a low-fat diet supplemented with fish An impressive 77% (23% were nonresponders) of the patients reported either excellent, moderate, or mild improvement. It was interesting to note that a number of patients did not show improvement until at least 4 months of supplementation. This may indicate the importance of allowing adequate time for clinical improvement after initiating fish oil therapy. Etretinate is a powerful drug used to treat skin disorders such as psoriasis. It can cause serious adverse effects, however, when used in the regularly prescribed dose of about 1 mg/kg per day. One study has shown that a combination of EPA and etretinate at a lower dose (0.3 to 0.5 mg/kg per day) works as well as the pure, high dose and has significantly fewer side effects.lMThe clinical trial included 40 psoriasis patients who were randomly assigned to receive either 20 mg etretinate daily (in capsules) or 20 mg etretinate plus 1800 mg of EPA ethyl ester (in capsules). After 12 weeks the participants were examined to determine the extent of improvement. Forty-five percent of the patients in the combination group showed excellent improvement (>75%)compared with 15%in the pure etretinate group. The time to achieve a 50% improvement in symptoms was also considerably shorter in the combination group (5.1 weeks) than in the monotherapy group (7.6 weeks). Adverse reactions such as inflammation of the lips, dry mouth and eyes, and scaling were observed in both groups but were mild and tolerable. The researchers conclude that the combination regimen is effective in the treatment of psoriasis without marked adverse reactions. Another study investigated whether topical application of fish oil to skin areas affected by psoriasis would alleviate symptoms. The clinical trial involved 25 patients with psoriasis who were randomly assigned to apply either fish oil or liquid paraffin to their psoriatic plaques and leave them covered for 6 hours overnight under an occlusive dressing.135The treatment was repeated daily for a 4-week period. Fish oil proved highly effective in reducing scaling (severity of scaling went from an average rating of 2.91 to 0.32 on a scale from 0 to 4), plaque thickness (from a rating of 2.21 to 0.52), and erythema (from a rating of 2.71 to 0.90). Itching was not relieved by the fish oil treatment. The 4-week liquid paraffin treatment was also effective in reducing erythema but was significantly inferior to the fish oil treatment in reducing scaling and had no significant effect on itching or plaque thickness. Both treatments were well accepted by the patients, and the researchers concluded that they are

both clinically effective with the fish oil treatment being superior to the paraffin treatment.

Cancer Numerous animal studies have demonstrated anticancer activity by fish oil.'% Experimental studies in rats have demonstrated that while corn oil-fed rats show an increased risk for colon cancer, fish oil-fed rats show both decreased risk and slowed progression of this cancer.137Fish oil appears to exert this anticancer effect by altering carcinogen metabolism and modifying prostaglandin synthesis. In Japan, which has the lowest breast cancer rate of any industrialized country, fish consumption is the highest among such countries. Conversely, in those countries where the risk of breast cancer is highest, the proportion of calories in the diet from fish is relatively low. A large epidemiologic study of 23 dietary factors in countries with high and low risks of cancer found a strong association between the percentage of calories from fat and the risk of breast cancer.138Fish consumption was found to have the next most sigruficant association, a negative correlation. A British investigation of the association between a high dietary fat intake and the risk of developing breast and colon cancer revealed interesting findings conceming the incidence of cancer. The study compared cancer mortality rates in 24 European countries, Canada, and the United States with fish consumption and the intake of animal fats.139In countries where the animal fat intake was high, the researchers found a clear inverse correlation between the ratio of fish fat to animal fat and the risk of developing breast cancer in women and colon cancer in both men and women. A similar correlation was found between cancer risk and the ratio of fish fat to total fat intake. This led the investigators to conclude that fish and fish oils not only protect against colon cancer in men but also against colon and breast cancer in women. This protective effect, however, is only apparent in countries where the intake of animal fats is high. In other words, a high intake of fish or fish oils counteracts the detrimental effects of a high animal fat consumption. The researchers further concluded that a 15%decrease in animal fat intake combined with a threefold increase in fish oil intake could possibly reduce male colon cancer risk by as much as 30% in countries with a high animal fat intake. A threefold increase in fish oil intake could be achieved by eating fish three times a week or by taking two standard fish oil supplements containing EPA and DHA. The presence of benign polyps or adenomas is known to be a sigruficant risk factor for the development of fullblown rectal or colon cancer. One study aimed at determining if polyunsaturated fatty acids played a role in the progression of benign polyp adenomas to colon cancer. The study investigators included 27 patients with sporadic

benign polyps of the rectum or colon, 22 patients with cancer of the colon or rectum, and 12 subjects with a normal colon.lmThe researchers measured the fatty acid profile of blood plasma and biopsied samples of the lining of the colon from both diseased and normal areas. They found no differences between polyp patients and those patients with a normal colon as far as plasma profile and normal colon lining profile were concerned. However, there was found a significant difference between the fatty acid profile of normal colon tissue and diseased colon tissue in the adenoma patients. Diseased tissue was found to have higher levels of linoleic acid, dihomogammalinolenic acid, and EPA and lower levels of alpha-linolenic and arachidonic acids. A sigruficant stepwise reduction also existed in EPA content of diseased colon lining from the benign polyp stage to endstage colon cancer. The researchers concluded that there are significant changes in the levels of omega-3 and omega-6 fatty acids early on in the sequence leading from benign polyps to colon cancer and speculated that these changes might participate in the progression to colon cancer. They recommended further work to investigate the benefits of long-term dietary manipulation in view of the finding that low-dose fish oil supplementation normalizes the cell proliferation pattern in patients with sporadic polyps. These kinds of findings have motivated others to conduct intervention trials to see if increasing fish oil via supplementation would reduce the number of abnormal cells in the colon. One such study set out to determine if fish oil supplementation would inhibit the development of benign polyps, the precursors of colon cancer. In this study, 34 men and 26 women who had just undergone surgery to remove benign polyps from their colon were studied.141 Patients were divided into four groups. Group 1was supplemented with 1.4 g of EPA and 1.1 g of DHA/day, group 2 with 2.7 g of EPA and 2.4 g of DHA, and group 3 with 4.1 g of EPA and 3.6 g of DHA. Group 4 received placebo-capsules containing olive oil. Biopsy samples from the lower part of the colon and blood samples were taken and analyzed at the start of the trial and 30 days. Overall, patients in the fish oil groups experienced a significant decline in the number of abnormal cells in their colon lining compared with the placebo group. Further analysis showed that the reduction in the number of abnormal cells was limited to patients who had a large number of abnormal cells at the beginning of the trial. The researchers also noted a significant increase in EPA and DHA levels and a significant drop in arachidonic acid level in the biopsy samples from the fish oil-supplemented patients. A separate 6-month trial involving 15 patients taking 1.4 &day of EPA and 1.1g/day of DHA also showed a significant drop in the number of abnormal colon-lining cells. The researchers concluded that low-dose supplementation with fish oils inhibit the proliferation of those

Fish Oils abnormal cells associated as precursors to polyps in patients at risk for colon cancer and that this effect can be maintained with long-term treatment. Similar to several others studies concerned with oxidation of fish oil in vivo, the authors cautioned that it may be advisable to increase vitamin E intake during fish oil administration. Lung cancer is the leading cause of cancer deaths in Japan even though the incidence and mortality is still less than two-thirds that found in the United States and the United Kingdom. Japanese researchers completed a study aimed at determining the association between lung cancer and diet.’& Their study involved 748 men and 297 women age 40 to 79 years who had been diagnosed with lung cancer and 2964 male and 1189 female cancer-free controls. The researchers found that both men and women who ate cooked or raw fish five times a week or more had half the incidence of lung adenocarcinoma when compared with participants who ate cooked or raw fish less than once a week. Women who consumed tofu (soybean curds) five times a week or more were found to have half the risk of adenocarcinomas compared with women who consumed tofu less than once a week. Frequent consumption of carrots was found to be beneficial for women but detrimental for men, especially smokers. Green vegetables were found to be highly beneficial for men but not statistically so for women. There was also some evidence that increased coffee consumption is associated with an increased risk of squamous cell and small cell lung carcinomas in men. Increased consumption of dried or salted fish was not beneficial for men or women. The researchers speculate that this is because the processing destroys the omega-3 oils present in raw and cooked fish. Animal studies have shown that an increase in fat intake can decrease the number of natural killer (NK) cells found in the blood and spleen. NK cells are an integral part of the natural immune response to virus infections and certain types of cancer. Researchers at Oxford University found that fish oil sigruficantly decreases NK cell activity in healthy human subjects.’43Their clinical trial involved 48 men and women age 55 to 75 years. The participants were randomized to receive one of six supplements for 12 weeks. The supplements were all provided in the form of capsules, three of which were to be taken with each meal. The nine capsules (daily intake) contained either a total of 2 g alpha-linolenic acid, 770 mg gamma-linolenic acid (fromevening primrose oil), 680 mg arachidonic acid, 720 mg DHA, 720 mg EPA+ 280 mg DHA (fish oil), or a placebo (8020 mix of palm and sunflower oils). All the participants had blood samples taken 4 weeks before the start of supplementation, immediately before the start of supplementation, and then every 4 weeks during the trial, as well as after a 4-week washout period. The researchers found no changes in killer cell activity except in the group taking fish oil. The researchers observed an average decline of 20% after

8 weeks and 48% after 12 weeks. The decline was completely reversed after the washout period. The fact that no decline was observed with pure DHA strongly suggests that EPA was responsible. The researchers concluded that excessive EPA intake could have adverse effects for people at risk of viral infections and some cancers. The British researchers’ speculation about fish oils perhaps affecting the effectiveness of NK cells in killing cancer cells is at odds with the results of many other studies. At least a dozen studies show a clear protective effect of fish or fish oil against colon, breast, and prostate cancer. Preliminary evidence indicates that diet can influence the risk of developing melanoma. An estimated 1 in 75 Americans will develop cutaneous malignant melanoma in their lifetime. It is believed that a high intake of omega-6 fatty acids can stimulate the growth of melanoma and other cancers, whereas DHA found in omega-3 fatty acids may suppress the growth of cancer cells. In an in vitro experiment, researchers treated 12 different human metastatic melanoma cell cultures with DHA and observed that more than 50% of these cells stopped growing.’@The investigators urged further testing of their findings in a clinical trial setting. The authors concluded that “if DHA is capable of suppressing cell and tumor growth and metastatic potential in in vivo models of melanoma, a clinical trial of DHA would be warranted as an adjuvant to current surgical and chemotherapeutic interventions.” Cachexia is an abnormal rate of weight loss commonly experienced by many cancer patients, especially those with pancreatic cancer. Several studies have demonstrated that supplementing the diet with around 2.2 g of EPA and 1.4 g of DHA assists stabilization of weight in patients with inoperable pancreatic cancer. One study has shown that such patients can gain weight by consuming a nutritional supplement fortified with fish oils. In this study, 20 patients (age 18 to 80) with inoperable pancreatic cancer were given two cans of a fish-oil enriched nutritional supplement each day, added to their daily food intake. The supplement contained 310 kilocalories per can, composed of 49.7 g of carbohydrate, 16.1 g of protein, 6.5 g of fat, 1 g of EPA, 0.5 g of DHA, and 28 essential vitamins and minerals. After 3 weeks the median weight gain for the group was 1 kilo, and 2 kilos after 7 weeks. A marked improvement in appetite was also noted. Of further interest was the finding that these patients survived an average of 8 months, compared with the expected survival time of 4.1 months, typically reported for patients given ~hemotherapy.’~~ In another study, 18 patients with inoperable pancreatic cancer, including nine patients with stage 4 tumors, were started on a dose of 2 g of fish oils (containing 360 mg of EPA and 240 mg of DHA/day).’% The dose was subsequently increased by 2 g/day every week until the patients’ body tolerance was reached. The average final intake was 12 &day. Before entering the trial,

the mean weight loss among the patients was 2.9 kilos per month. After 3 months of fish oil supplementation, a n average weight gain of 0.3 kilos a month was observed. Overall, 11 patients (61%) gained weight, 3 became weight stable, and 4 continued to lose weight, but at a sigruficantly reduced rate. The concentration of EPA in plasma phospholipids increased from 0% to 5.3% of total fatty acids after 1 month of supplementation, while the concentration of DHA increased to 6.6%from a base level of 3.5%.The researchers concluded that fish oil supplementation arrests weight loss in cancer patients with cachexia. Similar improvements in survival time have also been seen in patients with other end-stage cancers with generalized malignancies. In one study, 60 patients with generalized solid tumors were divided into two groups: one group received 18 g of fish oil containing 170 mg of EPA and 115 mg of DHA per capsule, while the other received a ~ 1 a c e b o .The l ~ ~ fish oil group also received 200 mg of vitamin E daily to reduce oxidation in vivo from the effect of so much fish oil. Each group included 15 well-nourished and 15 malnourished patients. None of the well-nourished patients suffered from cancer cachexia (abnormally low weight and general weakness). The researchers measured the level of T cells, NK cells, and the synthesis of interleukin and TNF before the start of the supplementation and on day 40 of the trial. The study followed all patients until they died. Malnourished patients were found to have a considerably impaired immune function and a decreased production of TNF; both parameters were restored through fish oil supplementation. Malnourished patients overall had a much shorter survival time than well-nourished ones (mean of 213 days vs. 481 days). Both malnourished and well-nourished patients who received fish oil and vitamin E survived significantly longer than did patients on placebo. The researchers speculate that fish oils exert their beneficial effect by decreasing the body’s production of prostaglandin E2, which is believed to play an important role in the initiation and progression of cancer. They concluded that supplementation with dietary omega-3 polyunsaturated fatty acids, specifically fish oils with an antioxidant such as vitamin E, may offer significant palliative support to cancer patients with end-stage metastatic disease. Despite the mounting evidence for a beneficial effect of fish oil in the prevention and treatment of various cancers discussed earlier, some conflicting evidence on the role of fish oil in oncogenic processes requires resolution, particularly for those cancers for which limited research has been performed.=

Migraine Headache Anecdotal reports indicate that patients suffering from migraine headaches who are given 1 g/day of MaxEPA,

particularly males, have significantly less frequent or less intense, or both, episodes. These results might be due to changes in prostaglandin synthesis or reduction, or both, in platelet serotonin release, with resultant reduction in cerebral vasospasm.

Diabetes The incidence of diabetes is also low in Greenland Eskimos. Studies have shown that the type of fat consumed by humans may have a profound effect on insulin action in tissues. Patients with insulin-dependent diabetes mellitus (IDDM) are prone to disorders of lipoprotein and lipid metabolism, especially hyperlipidemias. The combination of low-density lipoprotein (LDL) cholesterol and elevated plasma cholesterol (hypertriacylglyceridemia) is associated with an increased risk of CHD. This combination is a major contributor to the morbidity and mortality associated with non-insulin-dependent diabetes mellitus (NIDDM) patients.148In individuals with NIDDM, fish oil ingestion has been demonstrated to favorably alter arterial wall compliance without adversely affecting cholesterol levels, blood pressure, or fasting blood sugar levels, thereby contributing to a reduced risk of vascular complications seen in IDDM and NIDDM patient^.'^^,'^^ One study has even shown a desirable significant decrease in VLDL triglyceride and cholesterol concentrations in NIDDM patients consuming three fish oil capsules a day containing 320 mg EPA and 530 mg DHA.151

Raynaud Disease Raynaud disease is characterized by periods of disrupted blood flow to the fingers caused by exposure to cold or stress. The condition is usually relieved by warming of the affected body part. Secondary Raynaud disease occurs in association with progressive systemic sclerosis or connective tissue disease. Preliminary evidence indicates that symptoms of Raynaud disease improve in primary but not secondary Raynaud phenomenon, on the basis of a double-blind, placebocontrolled clinical trial involving 32 patients.120Patients were given either 12 one-gram fish oil capsules daily for 12 weeks containing 4 g of EPA and 2.6 g of DHA or a placebo. The group receiving the fish oil supplements reported significant alleviation of symptoms associated with Raynaud disease at the end of the study, including 5 patients, who developed symptoms before the experiment began but could not induce symptoms at all after either 6 or 12 weeks of supplementation.

Malaria Malaria afflicts more than 500 million people worldwide, with about 5% of victims dying each year. Unpublished studies at the U.S. Department of Agricultural Research Service Center in Beltsville, MD, have found evidence

that the omega-3 fatty acids in fish oil may be beneficial in the treatment of malaria.lS2In their research, mice were fed dietary fish oils for 4 weeks and then inoculated with parasites, either Plasmodium yoelii or Plasmodium berghei. As the mice continued to eat the high-fish oil diet, the parasites multiplied as usual. However, after 3 to 4 weeks, the mice were free of the parasites. The researchers suspected that the cause of the parasite’s death was rupture of the parasites’ cell membranes or red blood cell hosts. The researchers theorized that infected cells are more susceptible to rupture because the parasites foster a number of destructive oxidative reactions to which a diet high in fish oils makes them more vulnerable. This finding is particularly promising since there is now a strain of P. berghei that is chloroquine resistant to malaria. The World Health Organization is currently examining the benefits of treating malaria with dietary fish oil and qinghaosu, a Chinese botanical.

(ESKIMO-3: 35% n-3 fatty acids, 18% EPA, and 12% DHA) given for both short (4 weeks) and long (6 months) durations resulted in no changes in bleeding time.46 Another controlled study used 1.5, 3, or 6 g of fish oils (SuperEPA)as a supplement for 3 months and found no effect on bleeding time in 45 healthy male volunteers with normal trig1~cerides.l~~ Evidence as to the degree to which fish oil may affect fibrinolysis is conflicting. Plasma PAI-1 is an inhibitor of fibrinolysis. Increased PAI-1 activity has been linked to the development of myocardial infarction and thrombosis by several investigators. In at least one double-blind, randomized study conducted on an untreated essential hypertensive population, a modest increase in fibrinogen levels was observed after fish oil and corn oil intake was increased by 4 g of omega-3 PUFAs.170However, no change in PAI-1 activity or tissue plasminogen activator (PA) activity was found.

TOXIN CONTAMINATION TOXICITY A review of fish oil supplementation and CHD found that 10 MaxEPA capsules or 25 ml/day of cod liver oil (providing 1.8 g of EPA) is “safe over a long term.”lS3 Long-term studies of potentially adverse effects of fish oil supplementation in humans have not been published. However, this is also true of all other oils, such as vegetable oils and most currently prescribed hypolipidemic drugs.“ Not until 2004 did increased risk and incidence of deaths associated with statius and some other classes of hypolipidemic drugs become well known. Care must also be taken to use fish oil, not fish liver oil, as the latter can be excessively high in vitamins A and D and possibly result in toxicity. Finally, large dosages of fish oil supplements may result in a significant increase in total caloric intake, which can be ameliorated by an increase in energy expenditure.

Although increased bleeding may not be a problem, there may be other risks from increased consumption of fish.171For example, some fish may be contaminated from industrial effluents and toxins. Many of these toxicants, such as polychlorinated biphenyl, are known to increase the risk of cancer. In animal experiments it has been demonstrated that eating such contaminated fish as infrequently as once a week may increase the risk of developing cancer and create a significant risk to pregnant women and i n f a n t ~ . * ” JWith ~ ~ the growth of aqua businesses, or fish farms, it remains unknown whether such exposure is being reduced. Some transgenic fish varieties grow so quickly in fish farms that the opportunity for toxic buildup in organs and fat may be decreased. However, as noted earlier, the EPA and DHA concentration and fatty acid balance of farm fish may be adversely affected by commercial food-fed fish.

Bleeding Time

Oxidation

Concerns have been expressed about prolonged bleeding time in populations having a relatively high intake of fish. Several studies have shown that this effect appears to be dose dependent, although collagen-induced platelet aggregation was not shown to be inhibited.’% Many studies have shown that fish oil supplements prolong bleeding time, inhibit platelet aggregation, and decrease TXA2p r o d u ~ t i o n . ~ ~ f i J ~ ~ ~ @ Recent research suggests that the effect of fish oil supplementation on bleeding time is largely determined by the dosage, duration, and composition of the supplement, and the typical treatment regimens are safe. In one double-blind, placebo-controlled trial, daily supplementation with 30 ml of a Scandinavian fish oil formulation

It has been reported in a pig study that a diet rich in fish oil taken for many months can induce a deficiency of vitamin E, leading to cardiac n e c r o ~ i s . ’ ~For ~ J ~this ~ reason, periodic vitamin E (mixed tocopherol or gamma tocopherol) supplementation may be warranted. However, there is no evidence that the incidence of cardiac necrosis is higher in Eskimos. The omega-3 fatty acids found in fish oil are susceptible to oxidative breakdown. For this reason they must be protected from oxidation by proper extraction and storage, encapsulation, or stabilization with an antioxidant such as vitamin E. Inappropriately stored fish oils (i.e., exposure to oxygen) may result in the formation of toxic lipid peroxides over time.

MEASUREMENT OF LIPID OXIDATION PRODUCTS IN ESSENTIAL FATTY ACID SUPPLEMENTS The consumption of essential fatty acid supplements and vegetable oils is increasing. This is in part due to the perception that consumption of these lipids is beneficial to health. However, the high concentration of unsaturated fatty acids in these products compared with animal fats make these products more susceptible to spoilage and oxidative damage. A number of factors accelerate spoilage of these oils, including the presence of reactive metals, high water content, or high temperatures during processing and storage. Consumers perceive oxidative damage as rancidity or off-flavors and off-odors. Health implications for this damage are important. Oxidative damage diminishes the nutritional value of these oils by destroying vitamins and other nutrients. Oxidative products may also interact with protein and carbohydrates. In addition, the byproducts of lipid oxidation may pose a health risk to consumers. Some edible oils are more resistant to oxidative damage. For example, vegetable oils may naturally contain antioxidants such as tocopherols or vitamin E. Antioxidants prevent the oxidative reactives that can lead to rancidity. Many pathways of oxidation of lipids are not completely understood. Two pathways that have received attention are oxidative and hydrolytic rancidity. Hydrolytic rancidity results in the production of free fatty acids and their salts (soaps). This reaction, also called saponification, is due to a reaction of the lipids with water and typically requires the presence of catalysts or enzymes. Oxidative reactions tend to be more complex, and their byproducts are difficult to measure. Initially, oxygen combines with free fatty acids to form hydroperoxides and free radicals. These reactions are d u e n c e d by many factors: the percentage of unsaturated fatty acids present in the oil; processing and storage temperatures; oxygen concentration; light exposure; presence of antioxidants in the oil; moisture content of the oil; and the presence of reactive transition metals such as iron, nickel, or copper. The primary oxidative products are unstable. Hydroperoxides are rapidly degraded to aldehydes, ketones, alcohols, and hydrocarbons. These secondary products are relatively stable and are responsible for the characteristic flavor and odor associated with rancid oils. Historically, manufacturers of edible oils have relied on two analytic tests to determine the level of oxidation in oil: the free fatty acid percentage and peroxide value. More recently, two additional measures, the anisidine value and the total oxidation value, have been the focus of attention.

The percentage of free fatty acids in oil is an indication of freshness. As oil ages, triglycerides are cleaved to glycerol and free fatty acids through hydrolysis. Free fatty acids are more prone to oxidation than triglycerides, so their presence in oils increases the possibility of rancidity. A fresh, carefully processed oil has a free fatty acid percentage of less than 0.05%. The peroxide value measures the level of hydroperoxides in oil. Hydroperoxides are the primary byproduct of oxidation. Peroxide value alone is not indicative of the actual oxidative state of the oil because hydroperoxides decompose rapidly to secondary byproducts such as aldehydes. Therefore an oil might also have a low peroxide value as a result of extensive oxidation rather than due to low levels of oxidation. In theory, a fresh oil would have a peroxide value of zero. In practice, most vegetable oils have peroxide values ranging from 0.1 to 1. Besides the peroxide value, the anisidine value also must be calculated. The anisidine value is a measure of the amount of alpha- and beta-unsaturated aldehydes. Anisidine is an aromatic amine. Synonyms for anisidine include: aminoanisole, methoxyaniline, methoxyphenylamine, and methoxybenzenamine. Anisidine has two isomeric forms. Both have been reported to enhance mutagenicity in bacterial strains.17hThe ortho-anisidine isomer has been associated with bladder tumors. Data on carcinogenicity is almost exclusively on the ortho-isomer, not the para-isomer, which most companies focus on when they measure anisidine values in fish oils. The total oxidative value (TOV) used to express the extent of oxidation of an oil is the sum of the peroxide value and the anisidine value. Tests for peroxide value should comply with AOCS [American Oil Chemists Society] Oficial Method Cd 8-53 and not exceed a maximum of 5 mEq/kg, while the para-anisidine value should comply with AOCS OfficialMethod 18-90 and not exceed a maximum of 20. Many commercially available oils contain high levels of hydroperoxides and secondary byproducts of oxidation. During the past decade, Shukla and PerkinsIn have analyzed various oils for oxidative stability. The results show that fish oils are more prone to oxidation than vegetable oils. The total oxidation values of fish oils ranged from 20 to 60 compared with 5 to 20 for vegetable oils (Tables 94-2 and 94-3).27 Shukla and Perkins made the following recommendations to prevent oxidation during the manufacturing process28: Always use top-quality, freshly produced raw materials stored in temperature- and humidity-controlled facilities. Prevent exposure to oxygen by using closed, impermeable containers.

Fish Oils

Product

Peroxide value (Px)

Anisidine value (Av)

Total oxidation value (2Px + Av)

Iodine value

Percentage of free fatty acids

5.4 1.5 6.9 3.4

6 4.4 4.8 0

16.8 7.4 18.6 6.8

151.5 146.2 178.6 152

4.1 0.14 0.80

3.7 2.7 20.8 2.2

30.2 14.3 17.9 29.2

37.6 19.7 59.5 33.6

189 196.5 241.7 199.4

0.10 0.09 0.25 0.31

Vegetable oils A

B

C D

1.02

Fish oils

E F

G H

Modified from Kinsella JE, Lokesh B, Stone RA. Am J Clin Nutr 1990;52:1-28

Avoid exposure of raw materials to sunlight. Use stringent quality control. Use stainless steel equipment. Minimize heating of oil during processing. ‘e Use antioxidants to prolong shelf life. When using soft gelatin capsules, choose a shell with the lowest concentration of plasticizer possible.

Country England The Netherlands

By the early twenty-first century, manufacturers of fatty acid supplements and vegetable oils have taken the lead to protect consumers by producing oils with the lowest levels of oxidative byproducts possible. Consumer education and accurate measurement of peroxide and anisidine values are vital to this effort.

DOSAGE The dosages reported to be most effective for most conditions responsive to fish oil are in the range of 5 to 15 g of fish oil/day. EPA and DHA concentrations depend on the intended use. Clinical improvement may require 4 to 6 months to manifest, so patient compliance is important.

DRUG INTERACTIONS Fish oil has eicosanoid-modifying effects. Caution should be taken when recommending fish oil supplementation to pregnant women (studies to date on bleeding time have all been carried out on males). Nearly all fish contain methyl mercury. However, pregnant women can protect their unborn child by not eating large fish that can contain higher levels of methyl mercury, such as king mackerel, shark, swordfish, and tilefish. It is prudent for nursing mothers and young children not to eat these fish as well. Individuals known or suspected to have a bleeding disorder, as well as those prescribed

Denmark United States

Peroxide value (Px)

Anisidine value (Av)

3.8 1.8 3.7 2.2

16.6 34 30.2 20.6

Total oxidation value (2Px + Av)

24.2 37.6 37.6 25

Modified from Kinsella JE, Lokesh B,Stone RA. Am J Clin Nutr 1990;52:1-28.

therapeutic levels of aspirin or warfarin, should consult their physician. Patients may benefit from fish oil when taking cyclosporine.*78Fish oil may also inhibit the cholesterol- and triglyceride-lowering effect of the drugs pravastatin and ~imvastatin?’~

A substantial body of evidence now documents the beneficial effects of fish and fish oil consumption. The link between consumption of dietary long-chain omega-3 fatty acids and cardiac disease was shown when the Physicians’ Health Study in particular demonstrated that fish consumption was inversely associated with the incidence of sudden death ( p = 0.004 before adjustment for potential confounders and p = 0.007 and 0.001 after adjustment for such confounders as aspirin use, body mass index, diabetes, hypertension, hypercholesterolemia, beta-carotene use, and alcohol consumption), similar to the original findings reported for Greenland Eskimos. It is now believed that the omega-3 fatty acids EPA and DHA are the components in fish oil responsible for

its preventative, mitigative, and therapeutic benefits, not only in the management of cardiovascular disease but in the prevention and treatment of various cancers, diabetes, rheumatoid arthritis, and other diseases.’@’ However, determining which source of fish oil (i.e., eating fish or supplementing with fish oil) and which fish species is most desirable is difficult, as the various species and sources have different levels and ratios of eicosanoid metabolites, in addition to the influence of storage, handling procedures, and processing methods. In an effort to resolve the question of which source of fish oil is most beneficial, one study compared the effects of fish oil (4.5 g EPA/DHA) from fish with fish oil supplements in 25 mildly hyperlipidemic men over a 5-week period. Both fish and fish oil supplements lowered serum triglycerides and raised HDL cholesterol. There was no difference between the two treatments in their effects on total cholesterol, apolipoprotein-B, LDL cholesterol, or blood pressure. However, dietary fish did lower fibrinogen (15.6%) and thromboxane (10.5%)and increase bleeding time (10.8%),as compared with both controls and those receiving fish oil supplements.’*’ These findings suggest that although both fish consumption and fish oil supplementation produce desirable

effects on lipids and lipoproteins, fish consumption is more effective in improving several of the hemostatic factors involved in cardiovascular disease. Which fish or fish oil products produce the most desirable combination of therapeutic effects remains unknown. Further research is necessary. In the interim, it s e e m evident that humans can benefit from a diet containing fresh or fresh/frozen fish consumed at least three to five times a week, with additional fish oil supplementationwhen warranted. To ensure that fish is safe for consumption, both continued vigdance by regulatory agencies and effective quality control procedures and standards are required to prevent contaminated fish containing toxicants, such as mercury, from reaching the marketplace. Fish oil supplement manufacturers should provide sufficient information on labels about the source of the fish oil and species to enable consumers to make informed decisions. Information on the fish oil’s source, EPA and DHA concentration and ratio, toxic residual levels (if any), and risk of oxidative activity (total oxidative value) should be provided. Total evidence to date suggests that omega-3 fish oil from dietary fish or fish oil supplements is a beneficial intervention that can be applied to improve population health at reasonable cost and with low risk.la2

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135. Escobar SO, Achenbach R, Iannantuono R, Torem V. Topical fish oil in psoriasis: a controlled and blind study. Clin Exp Dermatol 1992;17159-162. 136. Karmali RA. Fatty acids: inhibition. Am J Clin Nutr 1987;45: 225-229. 137. Reddy BS, Burill C, Rigotty J. Effects of diets high in omega-3 and omega-6 fatty acids on initiation and postinitiation stages of colon carcinogenesis. Cancer Res 1991;51:487-491. 138. Kaizer L, Boyd NF, Kriukov V, Tritchler D. Fish consumption and breast cancer risk an ecological study. Nutr Cancer 1989;1261-68. 139. Caygill CP, Charlett A, Hill MJ. Fat, fish, fish oil and cancer. Br J Cancer 1996;74:159-164. 140. Femandez-Banares F, Esteve M, Navarro E, et al. Changes of the mucosal n-3 and n-6 fatty acid status occur early in the colorectal adenoma-carcinoma sequence. Gut 1996;38:254-259. 141. Anti M, Annelao F, Marra G, et al. Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas. Gastroenterology 1994;107:1709-1718. 142. Takezaki T, Hirose K, Inoue M, et al. Dietary factors and lung cancer risk in Japanese: with special reference to fish consumption and adenocarcinomas. Br J Cancer 2001;&2:1199-1206. 143. Thies F, Nebe-von-Caron G, Powell JR, et al. Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 years. Am J Clin Nutr 2001;73:539-548. 144. Albino AP, Juan G, Traganos F, et al. Cell cycle arrest and apoptosis of melanoma cells by docosahexaenoic acid: association with decreased pRb phosphorylation. Cancer Res 2000;604139-4145. 145 Barber MD, Ross JA, Voss AC, et al. The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer 1999;81:80-86. 146. Wigmore SJ, Ross JA, Falconer JS, et al. The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer. Nutrition 1996;12:S27-S30. 147. Gogos CA, Ginopoulos P, Salsa B, et al. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy. Cancer 1998;82:395-402. 148. Goh YK, Jumpsen JA, Ryan EA, Clandinin MT. Effect of omega-3 fatty acid on plasma lipids, cholesterol and lipoprotein fatty acid content in NIDDM patients. Diabetologia 1997;4045-52. 149. McVeigh GE, Brennan GM, Cohn JN, et al. Fish oil improves arterial compliance in non-insulin-dependent diabetes mellitus. Arterioscler Thromb 1994;14:1425-1429. 150. Luo J, Rizkalla SW, Vidal H, et al. Moderate intake of n-3 fatty acids for 2 months has no detrimental effect on glucose metabolism and could ameliorate the lipid profile in type 2 diabetic men. Diabetes Care 1998;21:717-724. 151. Rivellese AA, Maffettone A, Iovine C, et al. Long-term effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes Care 1996;19: 1207-1213. 152. Anonymous. Fish oil: new hope in fighting malaria. Sci News 1989;135:237. 153. Neutze JM, Starling MB. Fish oils and coronary heart disease. N Z Med J 1986;99:581-583. 154. Ahmed AA, Holub BJ. Alteration and recovery of bleeding times, platelet aggregation and fatty acid composition of individual phospholipids in platelets of human subjects receiving a supplement of cod-liver oil. Lipids 1984;19617-624. 155. Goodnight SH Jr, Harris WS, Connor WE. The effects of dietary omega 3 fatty acids on platelet composition and function in man: a prospective, controlled study. Blood 1981;58880-885. 156. Sanders TA, Roshanai F. The influence of different types of omega 3 polyunsaturated fatty acids on blood lipids and platelet function in healthy volunteers. Clin Sci (Lond) 1983;64:91-99.

157. Ahmed AA, Holub BJ. Alteration and recovery of bleeding times, platelet aggregation and fatty acid composition of individual phospholipids in platelets of human subjects receiving a supplement of cod-liver oil. Lipids 1984;19:617-624. 158. Knapp HR, Reilly IA,Alessandrini P, Fitgerald GA. In vivo indexes of platelet and vascular function during fish oil administration in patients with atherosclerosis.N Engl J Med 1986;314:937-942. 159. Siess W, Roth P, s e r e r B, et al. Platelet-membrane fatty acids, platelet aggregation, and thromboxane formation during a mackerel diet. Lancet 1980;1:441-444. 160. Brox JH, Killie JE, Gunnes S, Nordoy A. The effect of cod-liver oil and corn oil on platelets and vessel wall in man. Thromb Haemost 1981;46604-611. 161. Hirai A, Terano T, Hamazaki T, et al. The effects of the oral administration of fish oil concentrate on the release and the metabolism of 14C-arachidonicacid and 14C-eicosapentaenoicacid by human platelet. Thromb Res 1982;28:285-298. 162. Bradlow BA, Chetty N, van der Westhuyzen J, et al. The effects of a mixed fish diet on platelet function, fatty acids and serum lipids. Thromb Res 1983;29:561-568. 163. Schimke E, Hildebrandt R, Ekitz J, et al. Influence of a cod liver oil diet in diabetics type I on fatty acid patterns and platelet aggregation. Biomed Biochim Acta 1984;43:S351-353. 164. Lands WE, Culp BR, Hirai A, Gorman R. Relationship of thromboxane generation to the aggregation of platelets from humans: effects of eicosapentaenoic acid. Prostaglandins 1985;30:819-825. 165. Von Schacky C, Fischer S, Weber PC. Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans. J Clin Invest 1985;761626-1631. 166. Srivastava KC. Docosahexaenoic acid ( C 2 6 omega 3) and linoleic acid are anti-aggregatory and alter arachidonic acid metabolism in human platelets. Prostaglandins Leukot Med 1985;17319-327. 167. Sanders TA, Hochland MC. A comparison of the influence on plasma lipids and platelet function of supplements of omega 3 and omega 6 polyunsaturated fatty acids. Br J Nutr 1983;50521-529. 168. Croft KD, Beilin LJ, Vandongen R. The effect of dietary fish oil on platelet metabolism of 14C arachidonic acid. Thromb Res 1986; 42~99-104.

169. Blonk MC, Bilo HJ, Nauta JJ. Dose-response effects of fish41 supplementation in healthy volunteers. Am J Clin Nutr 1990;52: 120-127. 170. Toft I, Bonaa KH, Ingebretsen OC, et al. Fibrinolytic function after dietary supplementation with omega-3 polyunsaturated fatty acids. Arterioscler Thromb Vasc Biol1997;17814-819. 171. Foran JA, Glenn BS, Silverman W. Increased fish consumption may be risky. JAMA 1989;26228. 172. Foran JA, Cox M, Croxton D. Sport fish consumption advisories and projected cancer risks in the Great Lakes basin. Am J Public Health 1989;79:322-325. 173. Foran JA, VanderPlwg D. Consumption advisories for sport fish in the Great Lakes basin. J Great Lakes Res 1989;15:476-485. 174. Ruiter A, Jongbloed AW, van Gent CM, et al. The influence of dietary mackerel oil on the condition of organs and on the blood lipid composition in the young growing pig. Am J Clin Nutr 1978;31:2159-2166. 175. Gudbjarnason S, Hallgrimsson J. The role of myocardial membrane lipids in the development of cardiac necrosis. Acta Med %and SUPPI 1976;587:17-27. 176. Thompson DC,Josephy PD, Chu JW, Eling TE. Enhanced mutagenicity of anisidine isomers in bacterial strains containing elevated N-acetyltransferase activity. Mutat Res 1992;279:83-89. 177. Shukla VK, Perkins EG. Rancidity in encapsulated health food oils. Inform 1998;9:955-961. 178. Andreassen AK, Hartmann A, Offstad J, et al. Hypertension prophylaxis with omega-3 fatty acids in heart transplant recipients. J Am Coll Cardiol 1997;29:13241331. 179. Nakamura N, Hamazaki T, Ohta M, et al. Joint effects of HMGCoA reductase inhibitors and eicosapentaenoic acids on serum lipid profile and plasma fatty acid concentrations in patients with hyperlipidemia. Int J Clin Lab Res 1999;29:22-25. 180. Connor WE. Importance of n-3 fatty acids in health and disease. Am J Clin Nutr 2000;71:171S175S. 181. Cobiac L, Clifton PM, Abbey M, et al. Lipid, lipoprotein, and hemostatic effects of fish vs fish-oil n-3 fatty acids in mildly hyperlipidemic males. Am J Clin Nutr 1991;53:1210-1216. 182. Jones PJ, Lau VW. Effect of n-3 polyunsaturated fatty acids on risk reduction of sudden death. Nutr Rev 2002;60407-409.

Flavonoids-Quercetin, Citrus Flavonoids, and Hydroxyethylrutosides Michael T. h4urray. SI) Peter B. Bongiorno, NL), Dip1 Ac CHAPTER CONTENTS Introduction 967

Diabetes 971 Thalassemias 971

Historical Perspective 967 Chemical Descriptions 968 Quercetin 968 Citrus Bioflavonoids 968

Commercially Available Forms 971 Quercetin 971 Citrus Bioflavonoids 971 Dosages 971

Pharmacology 968 Quercetin 968 Citrus Flavonoids 970

Toxicity 972 Drug Interactions 972

Clinical Applications 970 Allergic and Inflammatory Conditions 970 Capillary Fragility, Excessive Bruisability, and Hemorrhoids 971

INTRODUCTION Flavonoids, a group of plant pigments, are largely responsible for the colors of many fruits and flowers. Recent research suggests that flavonoids may be useful in the treatment and prevention of many health conditions. In fact, many of the medicinal actions of foods, juices, herbs, and bee pollen are now known to be directly related to their flavonoid content. More than 4000 flavonoid compounds have been characterized and classified according to chemical structure. Flavonoids are a bit of an enigma to scientists, as they are quite reactive compounds. They can enter into almost any type of reaction known to organic chemistry such as oxidationreduction reactions, carbonyl reaction, acid-base reactions, free-radical reaction, hydrophobic interactions, tautomery, and isomerizations.' As such, characterizationof the many diverse physiologic properties of flavonoids is a considerable challenge to biochemists and researchers alike. This chapter discusses a few representatives of this class of useful clinical agents (quercetin, citrus bioflavonoids, and hydroxyethylrutosides). One of the most beneficial groups of plant flavonoids are the proanthocyanidins(alsoreferred to as procyanidins).

The most potent proanthocyanidins are those bound to other proanthocyanidins. Collectively, mixtures of proanthocyanidin dimers, trimers, tetramers, and larger molecules are referred to as procyanidolic oligorners (PCOs). Chapter 119 discusses PCOs.

HISTORICAL PERSPECTIVE Flavonoids, as well as vitamin C, were discovered by Albert Szent-Gyorgyi (1893-1986), one of the most respected and honored biochemists of the twentieth century. Szent-Gyorgyi received the Nobel Prize in 1937 for his discovery of some of the properties of these molecules. Szent-Gyorgyi discovered the flavonoids while isolating vitamin C. A friend with bleeding gums had stopped the bleeding by taking a crude vitamin C preparation isolated from lemon. When the problem reappeared, Szent-Gyorgyigave his friend a purer form of vitamin C. He expected to observe an even more impressive result, but the purer form of vitamin C did not work. SzentGyorgyi then isolated the flavonoid fraction from the original crude vitamin C preparation, gave it to his friend, and observed complete healing. 967

Szent-Gyorgyi termed his discovery “vitamin P” due to its ability reduce vascular permeability, one of the hallmark features of scurvy. He went on to show that the clinical symptoms of scurvy are the result of a combined deficiency of vitamin C and flavonoids. However, because flavonoids could not fulfill all the requirements of a vitamin, the designation as vitamin P was abandoned. Although flavonoids are often referred to as “semiessential” nutrients, their importance in human nutrition appears to be as important to good health as the essential vitamins and minerals. Good dietary sources of flavonoids include citrus fruits, berries, onions, parsley, legumes, green tea, and red wine. The average daily intake in the United States for flavonoids is estimated to be between 150 and 200 mg.

CHEMICAL DESCRIPTIONS Quercetin Quercetin (Figure 95-1) is a flavonoid that serves as the aglycone for many other flavonoids, including the citrus flavonoids rutin, quercitrin, and hesperidin. These derivatives differ from quercetin in that they have sugar molecules attached to the quercetin backbone. Quercetin is consistently the most active of the flavonoids in experimental studies, and many medicinal plants owe much of their activity to their high quercetin content.

Citrus Bioflavonoids Citrus bioflavonoid preparations can include rutin, hesperidin, quercitrin, and naringin. Most of the clinical research on rutin and crude bioflavonoid complexes occurred before 1970. Since then, most of the clinical research has used a standardized mixture of rutinosides known as hydroxyethylrutosides (HERS). Impressive clinical results have been obtained in the treatment of capillary permeability, excessive bruisability, hemorrhoids, and varicose veins with HERS (discussed later). Citrus bioflavonoids can be viewed as providing similar effects to, but probably not as potent as, HERS or quercetin.

OH

OH

0

Flgure 95-1

Quercetin.

PHARMACOLOGY As a class of compounds, flavonoids have been referred to as ”nature’s biologic response modifiers” because of their ability to mod* the body’s reaction to other compounds such as allergens, viruses, and carcinogens, as evidenced by their antiinflammatory, antiallergic, antiviral, and anticarcinogenic properties? In addition, flavonoids act as powerful antioxidants, providing remarkable protection against oxidative and free radical damage: and have the ability to traverse the blood-brain barrier, thus exerting a neuroprotective effect: Flavonoids are known to form strong ligand complexes with heavy metal ions and may prove to be a good agent of heavy metal detoxification.’ The practical aspect of this antioxidant activity is highlighted by the results of a study in 805 men designed to determine the effect of dietary flavonoids on protecting against heart disease. The study demonstrated an inverse correlation between flavonoid intake and death from a heart a t t a ~ kThis . ~ effect is probably a result of the potent antioxidant effects of the flavonoids preventing, similar to vitamins C and E, the formation of oxidized cholesterol. However, the antioxidant activity of flavonoids is generally more potent and effective against a broader range of oxidants than traditional antioxidant nutrients like vitamins C and E, selenium, and ~ i n c . ~ ! ~ Because different flavonoids tend to provide different benefits, additional and more specific beneficial effects are discussed under the key selected flavenoid categories. There is significant overlap among these flavonoids, however.

Quercetin Quercetin consistently demonstrates the greatest activity among the flavonoids studied in experimental models, particularly in vitro studies. The primary actions that are briefly reviewed here are its antiinflammatoryeffects, inhibition of aldose reductase, antiviral activityrand anticancer properties.

Antiinflammatory Effects Quercetin has demonstrated significant antiinflammatory activity due to direct inhibition of several of the initial processes of inflammation via interaction with calcium channels or calmodulin (the intracellular calcium-binding protein), or both, as well as through other mechanisms such as by inhibiting mast cell and basophil degranulation, neutrophil and monocyte lysosomal secretion, prostaglandin (most notably, leukotriene) formation, lipid peroxidation, and the resultant cascade of effects that are often a result of these processes. For example, it inhibits both the manufacture and release of histamine and other allergic/inflammatory mediators. In addition, it exerts potent antioxidant activity and vitamin C-sparing action.”I4

Flavonoids-Quercetin, Citrus Flavonoids, and Hydroxyethylrutosides

Effect on Histamine Release

Inhibition of Aldose Reductase

The release of histamine and other inflammatory mediators from mast cells and basophils is involved in the pathogenesis of acute allergic and inflammatory responses. Mast cells are widely distributed throughout the human body but are found in higher concentrations in the blood vessels of the subepithelial connective tissue of the respiratory tract, conjunctiva, gastrointestinal tract, and skin. Mast cell and basophil degranulation is an active process that requires calcium influx. Quercetin and many other flavonoids have been shown to be potent inhibitors of mast cell, neutrophil, and basophil degran~lation.'~-'~ A generally accepted hypothesis for this action is that quercetin inhibits receptor-mediated calcium influx, thereby inhibiting the primary signal for degranulation. However, quercetin is also active under conditions in which the calcium channel mechanism is not operative, indicating that other mechanisms are responsible as well.

Quercetin is a strong inhibitor of aldose reductase, the enzyme responsible for the conversion of blood glucose to sorbitol. This compound is strongly implicated in the development of diabetic complications such as diabetic cataracts, neuropathy, and retinopathy.17 The mechanism by which sorbitol is involved in the development of diabetic complications is best understood by considering its involvement in cataract formation. Although the lens does not have any blood vessels, it is an actively metabolizing tissue that continuously grows throughout life. Elevated blood sugar levels result in shunting of glucose to the sorbitol pathway. Because the lens membranes are virtually impermeable to sorbitol and lack the enzyme required to break down sorbitol (polyol dehydrogenase), sorbitol accumulates to high concentrations. These high concentrations persist even if glucose levels return to normal. This accumulation creates an osmotic gradient that results in water being drawn into the cells to maintain osmotic balance. As the water is pulled in, the cell must release small molecules like amino acids, inositol, glutathione, niacin, vitamin C, magnesium, and potassium in order to maintain osmotic balance. Because these latter compounds function to protect the lens from damage, their loss results in an increased susceptibilityto damage. As a result, the delicate protein fibers within the lens become opaque and a cataract forms. Quercitrin, which is hydrolyzed by gut bacteria to yield quercetin and a sugar moiety, was shown to significantly decrease the accumulation of sorbitol in the lens of diabetic animals, effectively delaying the onset of cataracts.18In addition to its effect on aldose reductase, quercetin is also of value in diabetes for its ability to enhance insulin secretion and protect the pancreatic p cells from the damaging effects of free radicals, and for its inhibition of platelet a g g r e g a t i ~ n . ~ , ~

Membrane Stabilization, Antioxidant Activity, and Hyaluronidase Inhibition Quercetin inhibits many of the inflammatory processes attributed to activated ne~trophi1s.l~ This is probably due to its membrane-stabilizing action, potent antioxidant effect (whichprevents the production of free radicals and inflammatory leukotrienes), and inhibition of the enzyme hyaluronidase (thus preventing the breakdown of the collagen matrix of connective tissue and ground substance).Quercetin's membrane-stabilizingeffect could also account for its action in preventing mast cell and basophil degranulation. This effect also inhibits inflammation by decreasing neutrophil lysosomal enzyme se~retion.'~ Neutrophils and monocytes contain lysosomes that, on secretion of their contents, contribute greatly to the inflammatory process.

Effects on Eicosanoid Metabolism Excessive leukotriene formation has been linked to asthma, psoriasis, atopic dermatitis, gout, ulcerative colitis, and possibly cancer.15J6Quercetin has been shown to inhibit many steps in eicosanoid metabolism. Probably of most significanceis its inhibition of phospholipase A2 and lipoxygenase enzymes (see Chapter 149 for diagram).6,7J4 The net result is a significant reduction in the formation of leukotrienes. The leukotrienes C4, D4, and E4 (composing the slow-reacting substances of anaphylaxis [SRS-A]) are derived from arachidonic acid and are 1000 times as potent as histamine in promoting inflammation. Leukotrienes promote inflammation by causing vasoconstriction (thereby increasing vascular permeability) and bronchoconstriction (thus inducing asthma) and by promoting white blood cell chemotaxis and aggregation. The reduction of leukotriene formation has significant antiinflammatory effects.

Androgen Receptor Inhibition The androgen receptor is involved in the development and progression of prostate cancer. In vitro research on androgen-sensitive prostate cancer cell lines using Western blot analyses found quercetin able to inhibit the transcription of the receptor gene in a dose-dependent fashion. Additionally, quercetin inhibited the secretion of the prostate-specific, androgen-regulated tumor markers PSA and hK2. The messenger ribonucleic acid levels of androgen-regulated genes such as PSA, NKX3.1, as well as ornithine decarboxylase, were also downregulated by q~ercetin.'~ Although clinical trials are necessary to evaluate and characterize this effect in men, quercetin may prove to have a beneficial effect on prostate cancer.

Pharmacology of Natural Medicines

Antiviral Activity

Cardiovascular Effects

Flavonoids as a group possess sigruficant antiviral activity, with quercetin having the greatest antiviral activity against herpes virus type I, para-influenzae 3, polio vints type I, and respiratory syncytial virus.2oz Quercetin has been shown, in vitro, to inhibit both viral replication and infectivity. In vivo studies in animals have also shown quercetin to inhibit viral infection.’*23 This would suggest that quercetin may be of some benefit in viral infections including the common cold.

Animal studies have also elucidated other uses for citrus bioflavonoids that beneficially affect cardiovascular risk factors and bone density. Increases in high-density lipoprotein and decreases in low-density lipoprotein cholesterol, total lipid, and triglyceride plasma levels in normolipidemic rats and in rats with diet and induced hyperlipidemia have been observed.29Antihypertensive effects have been demonstrated by evaluating long-term administration of hesperidin and its water-soluble analog, glucosyl hesperidin, to spontaneously hypertensive rats and normotensive rats. Animals were fed diets containing 30 mg/day/kg body weight of either hesperidin or its glucosyl analog for 25 weeks. Blood pressure and heart rate of the hypertensive animals administered the bioflavonoids were measured. Both of these measurements decreased as compared with the control group. In comparison, the blood pressure and heart rate of the controls were not changed by the long-term administration of the bioflavonoid

’

Anticancer Properties Many flavonoids have also been shown to inhibit tumor formation, but again quercetin has consistently been the most effective. In experimental models, quercetin has demonstrated significant antitumor activity against a wide range of cancers including squamous cell carcinoma, leukemia, and cancers of the breast, ovaries, colon, rectum, and brain. Unfortunately, there are no human studies to support the impressive results noted in animal and in vitro studies.2427

Citrus Flavonoids Collagen Matrix Support In addition to possessing antioxidant activity and an ability to increase intracellular levels of vitamin C, rutin, hesperidin, and HER exert many beneficial effects on capillary permeability and blood flow, primarily via strengthening endothelial cells and supporting collagen structures. Collagen, the most abundant protein of the body, is responsible for maintaining the integrity of “ground substance,” as well as the integrity of tendons, ligaments, and cartilage. Collagen is also the support structure of the skin and blood vessels. Citrus flavonoids affect collagen metabolism in several ways. They reinforce the natural cross-linlung of collagen that forms the so-called collagen matrix of connective tissue and protect against free radical damage with their potent antioxidant and free radical scavenging action. They also inhibit enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflammation and microbes during infection. Like quercetin, citrus flavonoids also prevent the release and synthesis of compounds that promote inflammation and allergies such as histamine, serine proteases, prostaglandins, and leukotrienes.8 It is believed that the citrus bioflavonoid hesperidin possesses antihistaminic activity through its metabolite heparitin, a weak inhibitor of cyclooxygenase 2 enzymes. This metabolite is produced as a product of intestinal bacteria, which underscores the need for a balanced intestinal flora in order to gain the antihistamine benefits of citrus bioflavonoids.zs

Bone Metabolism Effects Histornorphometric research on ovariectomized mice has shown that marked decreases in trabecular bone volume and trabecular thickness of the femoral distal metaphysis were sigruficantly prevented by hesperidin. Additionally, calcium, phosphorus, and zinc concentrations in the femur were significantly higher in the hesperidin-fed group while serum and hepatic lipids were lower in mice that consumed the hesperidin-containing diets.31

CLINICAL APPLICATIONS There is much overlap among the clinical uses of flavonoid preparations. Most of the clinical research has focused on HER products.

Allergic and Inflammatory Conditions Largely on the basis of in vitro studies, quercetin appears to be indicated in virtually all inflammatory and allergic conditions including asthma, hay fever, rheumatoid arthritis, and lupus, as well as in diabetes and cancer. However, the main shortcoming is the limited number of clinical studies and poor absorption. Earlier pharmacokinetic studies in animals and humans indicated that little quercetin is absorbed intact, with the majority of the oral dose (53%) being excreted in the f e ~ e s . ~ ~ , ~ ~ One of the main problems in studying the absorption of quercetin and other flavonoids is their degradation by microorganisms in the colon. To sidestep this issue, a recent study examined the absorption of quercetin in healthy ileostomy patients with complete small intestinesM

Flavonoids-Quercetin, Citrus Flavonoids, and Hydroxyethylrutosides The study examined the absorption of quercetin from fried onions (a rich source of quercetin glycosides),rutin, or 100 mg of pure quercetin. Absorption was defined as oral intake minus ileostomy excretion and corrected for degradation within the ileostomy bag. Absorption results were as follows: 52% from onions, 17% from quercetin rutinoside, and 24% for pure quercetin. These results indicate that humans do absorb appreciable amounts of quercetin and that absorption (but not necessarily pharmacologic activity) may be enhanced when quercetin is bound to glucose. In other words, citrus bioflavonoid preparations or HERs, or both, may prove to be more effective clinically.

Capillary Fragility, Excessive Bruisability, and Hemorrhoids

Thalassemias Although it may be difficult to treat the long-term outcomes of thalassemia conditions, it is possible that quercetin may serve to protect abnormally sensitive lymphocytes from common dietary substances. An in vitro study evaluated the effect of food mutagens on the lymphocytes from three different types of thalassemia patients: beta-thalassemia major, beta-thalassemia/Hb E, and an alpha-thalassemia trait with a 3.7-kb deletion. When the mutagen exposure was combined with quercetin, reduced sensitivities among the various thalassemic genotypes were observed in a dose-dependent manner.51 Although human studies are necessary to confirm this beneficial effect, quercetin might be worth a try to attenuate the toxic mutagenic effects commonly found in these susceptible patients.

A deficiency of hesperidin in the diet has been linked with abnormal capillary leakiness, as well as pain in COMMERCIALLY AVAILABLE FORMS the extremities, causing aches, weakness, and night leg Quercetin cramps.35Early studies demonstrated rutin to be effective Quercetin is available alone in powder and capsule in reducing capillary fragility, easy bruising, swelling and bruising after sports injuries, and n0sebleeds.3~~~form. However, if quercetin is being used for its antiinflammatory properties, products that combine with More recent and much more extensive studies have been the pineapple enzyme bromelain may provide addiperformed with HERs. Positive double-blind clinical tional benefit. Bromelain exerts antiallergy and antiinstudies exist in the treatment of venous insufficiency flammatory activity on its own and may also enhance including varicose veins, hemorrhoids, diabetic vascular the absorption of quercetin. Combination preparations disease, and diabetic retinopathy? of protein-digesting enzymes, like bromelain, and In double-blind studies of patients with chronic flavonoids have been shown to potentiate each other's venous insufficiency, HER improves microvascular antiinflammatory activity.52 blood flow and clinical symptoms (pain, tired legs, night cramps, and restless legs) in 73% to 100% of patients.4146 Citrus Bioflavonoids Several studies were conducted on pregnant women, in Mixed preparations of citrus bioflavonoids are the most whom HER was shown to be of great benefit in improving widely used and least expensive flavonoid sources. venous function, as well as in helping to relieve hemorHowever, mixed citrus flavonoids are the least active rhoidal signs and symptoms. In one study, 90% of the and generally the least quantified source of flavonoids, women given HER (1000 mg daily for 4 weeks) had as most commercially available sources of mixed citrus improved symptoms compared with only 12% in the flavonoids only contain 50% flavonoids. Preparations placebo group.47 Similar results in hemorrhoids not containing pure rutin and hesperidin or those that clearly associated with pregnancy have been reported.40,48 state the levels of rutin and hesperidin are better than Diabetes products that do not quantify the amount of the individual flavonoid components. HERs are probably the better Flavonoids appear to be important in the long-term care choice when opting for the benefits in this class of of diabetes. One of the hallmark features of diabetes is a flavonoids. sigruficant disturbance of blood flow through small blood vessels. HERs appear to improve blood flow in diabetics significantly and can be useful in the treatment of diabetic DOSAGES microvascular disease and retinopathy. Flavonoids can The recommended dosage range for quercetin is 200 to also stimulate an otherwise weak insulin effect in several 400 mg 20 minutes before meals (three times/day). If ways. For example, they can influence the protein phosquercetin is being used for its antiinflammatory properphokinases, which modulate second messenger pathways ties and bromelain supplementation is also indicated, known to up-regulate the gene encoding the glucose administration with bromelain may enhance absorption. transporters.' Combination preparations of proteolytic enzymes PCO or bilberry extracts may be better than quercetin, and flavonoids have been shown to have significant citrus flavonoids, and HER in diabetics.4850

Pharmacology of Natural Medicines antiinflammatory activity in experimental studies?* If used with bromelain, the amount of bromelain (1800MCU activity) should be equal to the amount of quercetin. Dosages used for HERS in double-blind clinical studies on the treatment of venous insufficiency and hemorrhoids have ranged from 1000 to 3000 mg daily. This translates to a dosage of citrus bioflavonoids, rutin, and hesperidin of 3000 to 6000 mg daily.

DRUG INTERACTIONS

Quercetin appears to be well tolerated in humans. Carcinogenic and teratogenic studies in rats and rabbits have shown that quercetin is without apparent side effects, even when consumed in large quantities (2000 mg/kg body weight and 5% to 10% of total diet) for long periods In addition, quercetin adminof time (up to 2 istration (up to 2000 mg/kg body weight) to pregnant rats had no teratogenic effects.59As is true of any other compound, allergic reactions may occur. Although uncommon, if they occur, discontinue use. Citrus bioflavonoids, rutin, hesperidin, and HER appear to be extremely safe and without side effects even during ~ r e g n a n c y . ~ , ~ ~

Quercetin, rutin, hesperidin, HER, and green tea polyphenols do not appear to interact with any drug. Citrus bioflavonoid preparations, if they contain naringin, may interact with drugs. This flavonoid is found in grapefruit juice but not orange juice. Naringin has been found to activate phosphoglycoprotein in the epithelial cells of the intestine and suppress the expression of the cytochrome P450 3A4 gene. The phosphoglycoprotein enhances the uptake from the intestine of many drugs including vinblastine, cyclosporine, digoxin, fexofenadine, and losartan' and can increase the oral bioavailability of drugs like nifedipine, felodipine, verapamil, and terfenadine, as well as inhibit the breakdown of various drugs, particularly caffeine, coumarin, and estrogens.60 In addition, the suppressed expression of the P450 gene can enhance oxidative decomposition of some drugs.' Because the drugs mentioned are used frequently in the therapy of cancer, human immunodeficiency virus, immune disorders, hypertension, and other serious conditions, avoidance of grapefruit juice and flavonoid preparations containing naringin is recommended when taking any of these drugs.

1. Havsteen BH. The biochemistry and medical sigruhcance of the flavonoids. Pharmacol Ther 2002;9667-202. 2.Middleton E Jr, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000;52: 673-751. 3. Rice-Evans C. Flavonoid antioxidants. Curr Med Chem 2001;8: 797-807. 4.Youdim KA, Dobbie MS, Kuhnle G, et al. Interaction between flavonoids and the blood-brain barrier: in vitro studies. J Neurochem 2003;85180-192. 5. Hertog MG, Feskens EJ, Hollman PC, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993;3421007-1011. 6. Rice-Evans CA, Miller NJ, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 1996;20933-956. 7. Havsteen B. Flavonoids, a class of natural products of high pharmacological potency. Biochem Pharmacol 1983;32:1141-1148. 8. Ferrandiz ML, Alcaraz MJ. Anti-inflammatory activity and inhibition of arachidonic acid metabolism by flavonoids. Agents Actions 199132283-288. 9. Middleton E Jr, Drzewieki G. Flavonoid inhibition of human basophil histamine release stimulated by various agents. Biochem Pharmacol1984;333333-3338. 10. Middleton E Jr, Drzewieki G. Naturally occurring flavonoids and human basophil histamine release. Int Arch Allergy Appl Immunol 1985;77:155-157. 11. Amella M, Bronner C, Briancon F, et al. Inhibition of mast cell histamine release by flavonoids and bioflavonoids. Planta Med 1985;51:16-20.

12. Pearce FL, Befus AD, BienenstockJ. Mucosal mast cells. III. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal mast cells. J Allergy Clin Immunol 1984; 73:819-823. 13.Busse WW, Kopp DE, Middleton E Jr. Flavonoid modulation of human neutrophil function. J Allergy Clin Immunol 1984;73 801-809. 14. Yoshimoto T, Furukawa M, Yamamoto S, et al. Flavonoids: potent inhibitors of arachidonate 5-lipoxygenase. Biochem Biophys Res CO~UTUII1983;116:612-618. 15. Ford-Hutchinson AW. Leukotrienes: their formation and role as inflammatory mediators. Fed Proc 1985;44:25-29. 16. Ford-Hutchinson AW. Leukotriene involvement in pathologic processes. J Allergy Clin Immunol1984;74:437-440. 17. Chaudhry PS,Cabrera J, Juliani HR,et al. Inhibition of human lens aldose reductase by flavonoids, sulindac and indomethacin. Biochem Pharmacol1983321995-1998. 18.Varma SD, Mizuno A, Kinoshita JH. Diabetic cataracts and flavonoids. Science 1977;195:205-206. 19. Xing N, Chen Y, Mitchell SH, et al. Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis 2001;22409-414. 20. Mucsi I, Pragai BM. Inhibition of virus multiplication and alteration of cyclic AMP level in cell cultures by flavonoids. Experientia 1985; 41:93O-931. 21. Kaul TN, Middleton E Jr, Ogra PL. Antiviral effects of flavonoids on human viruses. J Med Virol1985;15:71-79. 22. Beladi I, Mucsi I, Pusztai R, et al. In vitro and in vivo antiviral effects of flavonoids. In Farkas L, Gdbor M, KBllay F, eds. Flavonoids and bioflavonoids, 1981: proceedings of the International Bioflavonoid Symposium (6th Hungarian Bioflavonoid Symposium)

TOXICITY ~

~~~~

Flavonoids-Quercetin, Munich, F.R.G., September 6-9, 1981. New York Elsevier, 1982 443-450. 23.Guttner J, Veckenstedt A, Heinecke H, et al. Effect of quercetin on the course of mengo virus infection in immunodeficient and normal mice. A histologic study. Acta Virol 1982;26:148-155. 24. Elangovan V, Balasubramanian S, Sekar N, et al. Studies on the chemopreventive potential of some naturally-occurring bioflavonoids in 7,12-dimethylbenz(a)anthracene-inducedcarcinogens in mouse skin. J Clin Biochem Nutr 1994;17153-160. 25.Verma AK, Johnson JA, Gould MN, et al. Inhibition of 7,12-dimethylbenz(a)anthracene- and N-nitrosomethylureainduced rat mammary cancer by dietary flavonol quercetin. Cancer Res 1988;48:5754-5758. 26. Stavric 8. Quercetin in our diet: from potent mutagen to probable anticarcinogen. Clin Biochem 1994;27245-248. 27. Larocca LM, Giustacchini M, Maggiano N, et al. Growth-inhibitory effect of quercetin and presence of type I1 estrogen binding sites in primary human transitional cell carcinomas. J Urol 1994;152: 1029-1033. 28. Lee NK, Choi SH, Park SH, et al. Antiallergic activity of hesperidin is activated by intestinal microflora. Pharmacology 2004;71:174-180. 29. Monforte MT, Trovato A, Kirjavainen S, et al. Biological effects of hesperidin, a citrus flavonoid. (Note II): hypolipidemic activity on experimental hypercholesterolemia in rat. Farmaco 1995;50: 595-599. 30. Ohtsuki K, Abe A, Mitsuzuwi H, et al. Effects of long-term administration of hesperidin and glucosyl hesperidin to spontaneously hypertensive rats. J Nutr Sci Vitamin01 (Tokyo) 2002;48: 420-422. 31. Chiba H, Uehara M, Wu J, et al. Hesperidin, a citrus flavonoid, inhibits bone loss and decreases serum and hepatic lipids in ovariectomized mice. J Nutr 2003;133:1892-1897. 32. Petrakis PL, Kallianos AG, Wender SH, et al. Metabolic studies of quercetin labeled with C14. Arch Biochem Biophys 1959;85:264-271. 33. Gugler R, Leshik M, Dengler HJ. Disposition of quercetin in man after single oral and intravenous doses. Eur J Clin Pharmacol 1975; 9529-234. 34.Hollman PC, de Vries JH, van Leeuwen SD, et al. Absorption of dietary quercetin glycosides and quercetin in health ileostomy volunteers. Am J C l i Nutr 1995;621276-1282. 35. Garg A, Garg S, Zaneveld LJ, et al. Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother Res 2001;15:655-669. 36. Lagrue G, Behar A, Maurel A. [Edematous syndromes caused by capillary hyperpermeability. Diffuse angioedema.] J Ma1 Vasc 1989; 14231-235. 37. Horoschak A. Nocturnal leg cramps, easy bruisability and epistaxis in menopausal patients: treated with hesperidin and ascorbic acid. Del Med J 1959;31:19-22. 38. Cragin RB. The use of bioflavonoids in the prevention and treatment of athletic injuries. Med Times 1962;90:529-532. 39. Beretz A, Cazenave J. The effect of flavonoids on blood vessel wall interactions. In Cody V, Middleton E Jr, Harbome JB, et al, eds. Plant flavonoids in biology and medicine II: biochemical, cellular, and medicinal properties. Proceedings of a Meeting on Plant Flavonoids in Biology and Medicine, Strasbourg, France,August 31-September3, 1987. New York Liss, 1988:187-200. 40. Wadworth AN, Faulds D. Hydroxyethylrutosides. A review of its pharmacology, and therapeutic efficacy in venous insufficiencyand related disorders. Drugs 1992;441013-1032.

Citrus Flavonoids, and Hydroxyethylrutosides 41. Poynard T, Valterio C. Meta-analysis of hydroxyethylrutosides in the treatment of chronic venous insufficiency. Vasa 1994;23:244-250. 42. Boisseau MR, Taccoen A, Garreau C, et al. Fibrinolysis and hemorheology in chronic venous insufficiency: a double blind study of troxerutin efficiency. J Cardiovasc Surg (Torino) 1995;36 369-374. 43.Neumann HA, van den Broek MJ. A comparative clinical trial of graduated compression stockings and 0-(beta-hydroxyethy1)rutosides (HR) in the treatment of patients with chronic venous insufficiency. Z Lymphol1995;19:8-11. 44. Renton S, Leon M, Belcaro G, et al. The effect of hydroxyethylrutosides on capillary filtration in moderate venous hypertension: a double blind study. Int Angiol 1994;13:259-262. 45. MacLennan WJ, Wilson J, Rattenhuber V, et al. Hydroxyethylrutosides in elderly patients with chronic venous insufficiency: its efficacy and tolerability. Gerontology 1994;40:45-52. 46. Bergstein NA. Clinical study on the efficacy of 0-(beta-hydroxyethy1)rutoside(HR) in varicosis of pregnancy. J Int Med Res 1975; 3:189-193. 47.Annoni F, Boccasanta P, Chiurazzi D, et al. [Treatment of acute symptoms of hemorrhoid disease with high dose oral 0-(betahydroxyethy1)-rutosides.] Minerva Med 1986;771663-1668. 48. Wijayanegara H, Mose JC, Achmad L, et al. A clinical trial of hydroxyethylrutosides in the treatment of haemorrhoids of pregnancy. J Int Med Res 1992;20:54-60. 49. Belcaro G, Candiani C. Chronic effects of 0-(beta-hydroxyethy1)rutosides on microcirculation and capillary filtration in diabetic microangiopathy. Curr Ther Res 1991;49:131-139. 50. Agolini G, Cavallini GM. [Long-term therapy of retinal vasculopathies with oral administration of high doses of 0-(betahydroxyethy1)-rutoside.] Clin Ter 1987;120101-110. 51. Ruf AA, Webb J, Anderson D. Modulation by flavonoids of the effects of a food mutagen in different thalassaemia genotypes in the Comet assay. Teratog Carcinog Mutagen 2003;suppl 2: 93-102. 52. Tarayre,’lJ Lauressergues H. Advantages of a combination of proteolytic enzymes, flavonoids and ascorbic acid in comparison with non-steroid anti-inflammatory agents. Arzneimittelforschung 1977;271144-1149. 53. Stoewsand GS, Anderson JL, Boyd JN, et al. Quercetin: a mutagen, not a carcinogen, in Fischer rats. J Toxicol Environ Health 1984;14 105-114. 54. Hirono I, Ueno H, Hosaka S, et al. Carcinogenicity examination of quercetin and rutin in ACI rats. Cancer Lett 1981;13:15-21. 55. Kato K, Mori H, Fujii M, et al. Lack of promotive effect of quercetin on methylazoxymethanol acetate carcinogenesis in rats. J Toxicol Sci 1984;9:319-325. 56. Kato K, Mori H, Tanaka T, et al. Absence of initiating activity by quercetin in the rat liver. Ecotoxicol Environ Saf 1985;10:63-69. 57.Hosaka S, Hirono I. Carcinogenicity test of quercetin by pulmonary-adenoma bioassay in strain A mice. Gann 1981;72:327-328. 58. Hirose M, Fukushima S, Sakata T, et al. Effect of quercetin on twostage carcinogenesis of the rat urinary bladder. Cancer Lett 1983;21: 23-27. 59. Willhite CC. Teratogenic potential of quercetin in the rat. Food Chem Toxicol 1982;20:75-79. 60.Fuhr U, Kummert AL. The fate of naringin in humans: a key to grapefruit juice-drug interactions? Clin Pharmacol Ther 1995;58: 365-373.

Ginkgo biloba (Ginkgo Tree) MichaelT. Murray, ND Joseph E. Pizzorno Jr, ND Peter B. hngiorno, ND, Dip1 Ac CHAPTER CONTENTS General Description 975 Chemical Composition 975 History and Folk Use 976 Pharmacology 976 Tissue Effects 976 Nerve Cell Effects 976 Vascular Effects 977 Platelet Effects 977 Absorption and Distribution of Gingko biloba Extract 977 Clinical Applications 979 Cerebral Vascular Insufficiency and Impaired Mental Performance 979 Alzheimer‘s Disease 981 Tinnitus 981

Ginkgo bilobu (family: Ginkgoaceae) Common names: @go tree, maidenhair tree

GENERAL DESCRIPTION Ginkgo bilobu is a deciduous tree that lives up to 1000 years old and grows to a height of 100 to 122 feet and a diameter of 3 to 4 feet. The ginkgo has short horizontal branches with short shoots bearing fan-shaped leaves that measure 2 to 4 inches across. Because the leaf resembles a maidenhair fern, the @go has been called ”maidenhair tree.” Ginkgo bears an inedible foulsmelling fruit and an edible ivory-colored inner seed that is sold in marketplaces in the Orient. Extracts from the leaves of the &go tree are used medicinally.

CHEMICAL COMPOSITION The active components of ginkgo leaves are the ginkgo-flavone glycosides or ginkgo heterosides (flavonoid molecules with sugars attached, which are

Cochlear Deafness/Ototoxicity 982 Senile Macular Degeneration and Diabetic Retinopathy 982 Peripheral Arterial Insufficiency 982 Sexual Dysfunction 983 Premenstrual Syndrome and Idiopathic Cyclic Edema 983 Antidepressant Effects 983 AllergiedAsthma 984 Raynaud’s Disease 984 High Altitude Sickness 984 Future Applications of Gingko biloba Extract 984 Dosage 984 Toxicity 985

unique to the ginkgo), several terpene molecules unique to ginkgo (ginkgolides and bilobalide), and organic acids.’ The G. bilobu extract (GBE),marketed in Europe under the trade names Tanakan, Rokan, Ginkgobil, Kaveri, Seredrin, and Tebonin, is a well-defined and complex product prepared from the green leaves. Extracts identical to these preparations are available in the United States as food supplements. The culturing, harvesting, and extracting techniques have been thoroughly standardized and require careful control. GBE is standardized to contain 24% flavone glycosides, as these molecules represent a convenient analytic reference group. Although they play a major role in the pharmacologic activity of GBE, other components are also important. The three major backbone flavonoids of the G. bilobu flavonols are quercetin, kaempferol, and isorhamnetine (Figure 96-1). The sugar (glucoside) components are glucose and rhamnose, which are present as single sugars or disaccharides (two attached sugar molecules). 97s

R

OH

0

ComDound

R

R'

R"

Kaempferol Quercetin lsorhamnetine

H OH

OH

OCH3

OH

H H H

OH

Figure 961 The major backbone flavonoids of Gingko biloba extract

The ginkgo is now planted throughout much of the United States as an ornamental tree. The ginkgo, which is the tree most resistant to insects, disease, and pollution, is frequently planted along streets in cities.' The first green growth to reappear at the center of Hiroshima in 1946 was the sprout of a gingko tree that grew to be a normal, full-size tree.2 G. biloba's medicinal use can be traced back to the oldest Chinese materia medica (2800 BC). The @go leaves have been used in traditional Chinese medicine for their ability to "benefit the brain," relieve the symptoms of asthma and coughs, and help the body eliminate filaria. Ginkgo leaf extracts are now among the leading prescription medicines in both Germany and France, where they account for 1% and 1.5%, respectively, of total prescription sales. In America, it was the top-selling botanical medicine in 1999 with $148 million in sales3

PHARMACOLOGY

Figure 96-2

Bilobalide.

Other sigruficant flavonoid components of the extract include proanthocyanidins, largely composed of dimers and oligomers of delphinoidine and cyanidine. The major terpene molecules of GBE, which account for 6% of the extract, are the gnkgolides and bilobalide (Figure 962). These substances are unique to ginkgo and are not found in any other plants. Other constituents of GBE include a number of organic acids. These compounds contribute valuable properties to the extract by making the usually water-insoluble flavonoid and terpene molecules of ginkgo water soluble.

HISTORY AND FOLK USE G. biloba is the world's oldest living tree species. The sole surviving species of the family Ginkgoaceae, the ginkgo tree can be traced back more than 200 million years to the fossils of the Permian period, and for this reason it is often referred to as "the living fossil." Once common in North America and Europe, the @go was almost destroyed during the Ice Age in all regions of the world except China, where it has long been cultivated as a sacred tree. In the late seventeenth century, Engelbert Kaempfer, a German physician and botanist, became the first European to discover and catalog the @go tree. The flavonoid kaempferol is named after Kaempfer. In 1771 Linnaeus named the tree G. biloba. The ginkgo tree was brought to America in 1784 to the garden of William Hamilton near Philadelphia.

The standardized concentrated extract of the leaves of G. biloba (24% @go flavone glycoside content) has demonstrated remarkable pharmacologic effects. Interestingly, the total extract is more active than single isolated component^.',^ This suggests synergism between the various components of GBE, an explanation that is well supported in more than 400 clinical and experimental studies using the extract.'TM

Tissue Effects GBE exerts profound, widespread tissue effects including membrane-stabilizing, antioxidant, and free radicalscavenging effects. GBE also enhances the use of oxygen and g l u c ~ s e . ' , ~ , ~ Cellular membranes provide the first line of defense in maintaining the integrity of the cell. Largely composed of fatty acids (phospholipids), cellular membranes also serve as fluid barriers, exchange sites, and electrical capacitors. These membranes are fragile and vulnerable to damage, especially the lipid peroxidation induced by oxygenated free radicals. GBE is an extremely effective inhibitor of lipid peroxidation of cellular mernbrane~.',~ Red blood cells provide excellent models for evaluating the effects of substances on membrane functions. Red blood cell studies using GBE have demonstrated that, in addition to directly stabilizing membrane structures and scavenging free radicals, GBE also enhances membrane transport of potassium into the cell and sodium out by activating the sodium pump. In essence, GBE leads to better membrane polarization. This effect is particularly important in excitable tissues such as nerve cells.',4

Nerve Cell Effects GBE's membrane-stabilizing and free radical-scavenging effects are perhaps most evident in the brain and nerve

Ginkgo biloba (Ginkgo Tree) cells. Brain cells contain the highest percentage of unsaturated fatty acids in their membranes of any cells in the body, making them highly susceptible to free radical damage. The brain cell is also highly susceptible to hypoxia. Unlike most other tissues, the brain has little energy reserve. Its functions require large amounts of energy, which must be supplied by a constant supply of glucose and oxygen. Diminished circulation to the brain sets off a chain of reactions that disrupt membrane function and energy production and ultimately lead to cellular death. GBE is remarkable in its ability to prevent metabolic and neuronal disturbances in experimental models of cerebral i~chemia.',~,~-'~ It accomplishes this by enhancing oxygen utilization and increasing cellular uptake of glucose, thus restoring energy production. All of the above-mentioned metabolic effects are in addition to GBE's ability to reestablish effective tissue perfusion. Particularly interesting is GBEs ability to normalize the circulation in areas most affected by microembolization, namely the hippocampus and ~triatum.',~ Discussion of additional nervous tissue actions of GBE is incorporated later in the section on clinical indications. Briefly, GBE promotes an increased nerve transmission rate, improves synthesis and turnover of brain neurotransmitters, normalizes acetylcholine receptors in the hippocampus (the area of the brain most affected by Alzheimer disease),l" and inhibits beta-amyloid deposition.l1

Vascular Effects

ischemic vascular area than on a normally perfused area.]* However, despite intense investigation, many of GBE's tonic effects on vascular components are still largely unexplained. Remarkably, GBE can simultaneously combat the phenomena resulting from vascular spasm and, with the same efficiency, restore circulation to areas subject to vasomotor paralysis. The importance of this dual action is becoming more apparent in cerebral insufficiency, as single-direction drugs (i.e., vasodilators)can often aggravate the condition by preferentially dilating the healthy areas, thereby deflecting blood and oxygen away from the ischemic area.

Platelet Effects GBE and isolated pkgolides have profound effects on platelet function including inhibition of platelet aggregation, adhesion, and degran~lation.~ These effects appear to be due to direct membrane and antioxidant effects, increased synthesis of prostacyclin, and an antagonism of a substance known as platelet-activating factor (PAF). GBE and the pkgolides have been shown to be potent inhibitors of I'AF?J3.l5 PAF is a potent stimulator of platelet degranulation and is involved in many inflammatory and allergic processes including neutrophil activation, increasing vascular permeability, smooth muscle contraction including bronchoconstriction,and reduction in coronary blood flow. GBE and ginkgolides compete with PAF for binding sites and inhibit the various events These actions may be responsible induced by PAF.'J~,'~,'~ for many of GBEs clinical effects. Interestingly, despite these effects on PAF, GBE exerts no inhibition of platelet aggregation in humans.

The mechanisms of GBE's vascular effects have been Absorption and Distribution investigated using a number of in vivo and in vitro techof Ginkgo biloba Extract niques (Table 96-1).'t4 Isolated vessel techniques allow The pharmacokinetics (absorption, distribution, and for separation of GBE's effects on different parts of the vascular system (e.g., arterial, arteriolar, microcircula- elimination) of GBE have been studied in rats using radiolabeled extra~ts.'*~5 Following oral administration, tory, venular, and venous components), while in vivo studies provide information on the total circulatory pheat least 60% of the radiolabeled extract was absorbed. Since blood levels peaked after 1.5hours, upper gastroinnomena (i.e., GBE's ability to increase the perfusion rate testinal tract absorption was suspected. to various regions). In general, GBE exerts its vascular effects primarily The flavonoids appear to have an affinity for organs rich in connective tissues such as the aorta, eyes, skin, through its effects on the lining of the blood vessels and lungs. Levels of radioactivity in these tissues are two (vascular endothelium) and the system that regulates to three times higher than those in blood and decrease blood vessel tone. Its vasodilating action is explained by direct stimulation of the release of endothelium-derived little over the course of time. Retained specific activity in the heart is twice that found in the skeletal muscles. relaxing factor (EDRF) and prostacyclin (a beneficial Of the glands, the adrenals retained the greatest level of prostaglandin). In addition, GBE inhibits 3',5'-cyclic radioactivity. GMP (guanosine monophosphate) phosphodiesterase, At 72 hours, the hippocampus and striated bodies an enzyme that results in relaxation of blood vesse1s.l~~ On the venous system, GBE stimulates greater tone, show radioactivity five times greater than that of the blood. This deposition pattern, which parallels the circuthus aiding the dynamic clearing of toxic metabolites lation improvement observed after ischemia due to that accumulate during ischemia (Figure 96-3).'" blood clotting in rats, is alleviated by GBE extracts. GBE normalizes circulation by producing tonic Other areas of the brain such as the cerebral cortex, effects. These effects are much more apparent in an

h

a

e

c

h

a

Release of PG12

Direct membrane effect

Release of EDRF from endothelium

Inhibition of PDE

Cellular and membrane mechanisms explaining Ginkgo biloba's effects

m

Debilitated capillary walls

Increased capillary resistance

Direct membrane effect

Capillary hyperpermeability and plasma

Amelioration of capillary hyperpermeability

Direct membrane effect

Hypoxic vasoparalysis

Diminished accumulation of toxic wastes: K+,COP,and lactate Consequence of venous tonic effect

Mitochondria1 metabolic restart

Vascular atony

Restitution of arterial tone

Direct effect

Potentiation of alphaadrenergic effects'

Exchange area (capillary)

s of the vasoregulatory effects of Ginkgo bi/oba extract

EDRF; Endothelium-derivedrelaxing factor: PDE, phosphodiestefase; PGI,, prostaglandin 12. 'Partly through COMT inhibition.

Potentiation of alpha-adrenergic effects'

Diminished platelet hyperaggregability

s

Vasorelaxation

i

Effects found with Ginkgo biloba extract

n

Arterial thrombosis

Upstream flow (arteriole)

m

Arterial spasm

n

Tissue pathologic condition

~

Site of action

c

Inhibition of PDE (?)

Release of dilating prostaglandins Indirect effect via alphaadrenergic effects

Antagonism of experimental venous spasms

Venular spasms

Direct effect

Venous tonic effect

Venous relaxation and vasoparalysis extravasation

Downstream flow (venous)

Ginkgo biloba (Ginkgo Tree)

Figure 96-3

Gingko biloba extract's impact on ischemia.

brainstem, and cerebellum do not show such high levels of radioactivity.

CLINICAL APPLICATIONS GBE's primary clinical application has been in the treatment of vascular insufficiency. In more than 50 doubleblind clinical trials, both patients with chronic cerebral (brain) arterial insufficiency and peripheral arterial insufficiency have responded favorably to GBE. As described earlier, GBE exerts an extraordinary array of pharmacologic activities that imply a broad spectrum of possible clinical applications, an implication borne out by the new applications of GBE, which are constantly being discovered.

Cerebral Vascular lnsufficiency and Impaired Mental Performance Cerebral vascular insufficiency is an extremely common condition in the elderly of developed countries due to the high prevalence of atherosclerosis (hardening of the arteries). In well-designed studies, GBE has displayed a statistically sigruficant regression of the major symptoms of cerebral vascular insufficiency and impaired mental performance. The following symptoms were reported1,46,1"21: Short-term memory loss Vertigo Headache Ringing in the ears

Lack of vigilance Depression The sigruficant regression of these symptoms by GBE suggests that vascular insufficiency may be the major causative factor accounting for these so-called age-related cerebral disorders versus a true degenerative process. In a comprehensive review, the quality of research on more than 40 clinical studies with GBE in the treatment of cerebral insufficiency was analyzed. The results indicate that GBE is effective in reducing all symptoms of cerebral insufficiency including impaired mental function (senility), and the quality of research was comparable to Hydergine (dihydroergotamine), an FDA-approved drug used in the treatment of cerebral vascular insufficiency and Alzheimer's disease. Eight studies stood out as being extremely well designed and are summarized in Table 96-2.1421 It appears that by increasing cerebral blood flow, and therefore oxygen and glucose utilization, GBE offers relief from these presumed "side effects" of aging and may offer significant protection against their development. Furthermore, G. biloba's antiaggregatory effect on platelets offers additional protection against a stroke. This has been supported in a clinical study of poststroke patients, which demonstrated that GBE improved blood flow and blood viscosity.22 In addition to improving blood supply to the brain, experimental and clinical studies show that GBE increases the rate at which information is transmitted at the nerve cell l e ~ e l . ~One * ~ ~study investigated the

1989 1977 1978

1975

1983 1977 1979 1976 1985 1977

Hofferberth

Moreau

Pidoux

12 20 19 20 112 50 50

CCI

CCI CCT

CCI

Misc

CVA

CCI

30

36 48 27

30 80 99 14 40 47 48 20 25 19

No. of patients

CCI

CVA

D

cos

Senescence

CVA

CCI

CCI

CCI, cv

CCI CCI

Misc

CCI

CCI

Diagnosis

87 47-86 67 59-84 55-94 50 50

84

53-69 72 78

60 40-80 77 65 67 35-80 65-95 62 60 57-88

Age (YO

Placebo (n = 19) Nicergoline (n = 19) DB

Open Open

Open, M

Open

Open

55% 68% 76% 72%

85% 76%

Placebo DB

160 35 (IV) 160 17.5(IV) 120 160 160

Open

79%

Placebo (n= 30) ED ( n = 30) DB

NS

83%

120

Open

Placebo (n = 18)

Placebo (n = 20) DB

DB, CS

Placebo (n = 20) DB

Open

74%

12 2 8 1-3 52 27 27

DB Open

Raubasine + ED ( n = 24)

12

Placebo (n= 14) ED ( n = 19)

DB

Open

Placebo (n = 90)

DB, CS

76% 65% 44% 65% 90% 80% 60% 80% 92% 69%

Placebo (n = 30) Placebo (n = 40)

DB, CS

Efficacy

Compared with:

Type

DB

120 240 120

120 120 120 120 120 120 360 160 120 120

Dosage (mg)

8 8 8

4 7 24 5 5 3 8 5 4 12

Duration (weeks)

CCI, Chronic cerebral insufficiency; COS,cerebral organic syndrome: CS, crossover; CVA, cerebral vascular accident: 0,dementia; D6,double-blind; ED,ergot derivatives; M, multicenter; NS,not specified.

Wackenheim

Vorberg

Terasse

Tea

Safi

Leroy

Israel

Gessner

Eckmann

Dieli

Choussat

1975 1977 1981 1982 1983

1984 1984 1976 1975

Year

Boudouresques

Bono

Augustin

Arrigo

Agnoli

Principal author

Studies demonstrating the significant regression of the major symptoms of cerebral vascular insufficiency through the use of Gingko biloba extract

Ginkgo biloba (Ginkgo Tree)

effects of acute doses of standardized GBE on memory and psychomotor performance in 31 healthy volunteers who were 30 to 59 years old. The study was randomized, double-blind, and placebo-controlled with a five-way crossover design. Gingko improved working memory in all volunteers, especially those who were 50 to 59 years However, GBE’s memory-enhancing effects are not limited to the elderly. In another double-blind study, the reaction time in healthy young women performing a memory test was improved sigruficantly after the administration of GBE.25

Alzheimer’s Disease GBE is showing great benefit in many cases of senility including Alzheimer’s d i s e a ~ e . ~ ,In~ ,addition ~ , ~ ~ to GBE’s ability to increase functionalbrain capacity via the mechanisms described earlier, it has been shown to normalize the acetylcholine receptor in the hippocampus of aged animals, increase cholinergic transmission, inhibit beta-amyloid deposition,” and address many of the other major elements of Alzheimer’s disease.’r4 Although preliminary studies in established Alzheimer’s patients are quite promising, at this time it appears that GBE only helps to reverse or merely delay mental deterioration in the early stages of Alzheimer’s disease. This may help enable the patient to maintain a normal life for a while and avoid being institutionalized. The benefits of GBE in early-stage Alzheimer’s disease are quite evident when looking at the results of two recent double-blind studies. In the first study, 216 patients with Alzheimer’s disease or multiinfarct dementia were given either 240 mg/day of GBE or placebo for 24 weeksz8 Improvements were noted in several clinical parameters including the Clinical Global Impressions (CGI) scale, as shown in Table 96-3. The second study, published in the Journal of the American Medical Association, was the first U.S. clinical study on GBE.29The study was conducted at six research centers. Harvard Medical School and the New York Institute for Medical Research approved the design of the study, in which 202 patients with Alzheimer’s disease

1 cardiovascular performance measures Time of Measurement

Parameter Pain-free walking distance (m)

Week 0

Week 104

62.9

172.4

Rest flow (rnVl00 rnl/rnin)

113.8 1.6

Peak flow (mlll00 mllmin)

3.7

6.9

46.5

72.6

Total walking distance (rn)

Doppler measurement after strain (mmHg)

384

2.7

were given either a modest dose of GBE (120 mg/day) or a placebo for 1 year. GBE not only stabilized Alzheimer’s disease but also led to significant improvements in mental function in 64% of the patients. There were no side effects with GBE. Direct comparison studies on gingko versus standard pharmaceutic regimens have been recently completed. A comparison of placebo-controlled efficacy studies of at least 6 months in duration demonstrated that GBE and second-generation cholinesterase inhibitors (tacrine, donepezil, rivastigmine, metrifonate) were equally effective in treating mild to moderate Alzheimer dementia. In this study, it was observed that no major differences occurred between the four cholinesterase inhibitors and GBE. Additionally, tacrine exhibited a high dropout rate due to adverse drug reactions. In conclusion, the author called for a critical review of the use of new secondgeneration cholinesterase inhibitor prescriptions for mild to moderate Alzheimer’s disease in light of gingko’s equivalent effectiveness.30 A metaanalysis surveyed 50 articles to examine the effect of g d g o on objective measum of cognitivefunction in patients with Alzheimer’s disease.31In the 212 subjects in the placebo and @go groups, a significant overall effect size that was comparable with the benefits of standard cholinesteraseinhibitors was found. In this analysis, standardized measures of cognition were measured including the Alzheimer’s Disease Assessment Scalecognitive subscale. In addition to being beneficial in early-stage Alzheimer’s disease, if the mental deficit is due to vascular insufficiency or depression and not Alzheimer’s disease, GBE is usually effective in reversing the deficit.’tM Importantly,GBE should be taken consistently for at least 12 weeks in order to determine its effectiveness. Although some people with Alzheimer’s disease report benefits within a 2- to 3-week period, most will need to take GBE for a longer period of time.

Tinnitus Permanent, severe tinnitusis an extremely difficult condition to treat. Previous studies have shown contradictory results of GBE in the treatment of tinnitus. For example, in M e y e r ‘ ~study, ~ ~ GBE improved the condition in all patients regardless of prognostic factor. However, in Coles’s3 study, 21 patients with tinnitus took GBE for 12 weeks: 11 reported no change, 4 reported slight to very slight improvement, and 5 reported that their tinnitus was worse. The explanation for these different results is that in Meyer’s study the patients had recent onset tinnitus,while in Coles’s study 18 patients had tinnitusfor at least 3 years. A 1994 study of GBE in tinnitus used a two-part design: the first part was an open part, without a placebo control; the second part was a double-blind, placebocontrolled, cross-over study? The 80 patients in the

open study had been referred to the Department of Audiology, Sahlgren’s Hospital, Goteborg, Sweden, due to permanent severe tinnitus. Twenty patients reporting a positive effect to GBE (14.6 mg twice daily) after 2 weeks were recruited for the double-blind study. Patients were given either the GBE or placebo for 2 weeks and then crossed over into the other group. Evaluation indicated that six patients preferred GBE, seven preferred placebo, and seven had no preference. On the surface, this study seemingly indicates that GBE is ineffective for permanent, severe tinnitus. However, the study was really designed for the GBE to fail. First, the dosage used (14.6 mg twice daily or 29.2 mg daily) is far less than the standard dosage of 40 mg three times daily (or roughly four times the daily dosage used in the study). Secondly, in studies on patients with cerebral vascular insufficiency, it is well established that GBE often takes at least 2 weeks before benefits become apparent. The longer that GBE is used, the more obvious the benefit. In a condition like permanent, severe tinnitus,2 to 4 weeks is simply not enough time. However, given the small, insufficient dosage, it probably would not have mattered if the subjects had been studied for a longer period of time. A more recent study of 1121 healthy people between 18 and 70 years old with tinnitus that was comparatively stable showed no benefit over placebo when given 50 mg of standardized gingko three times a day. Although these data are discouraging, it should be noted that outcome measures were obtained through questionnaires and phoned-in patient reports, without objective audiometric meterh1g.3~ The degree to which GBE is of benefit in permanent, severe tinnitus remains to be determined, but given GBE’s excellent safety profile, it is certainly worth a try.

Cochlear Deafness/Ototoxicity Ischemia is usually the underlying factor in acute cochlear deafness. GBE has improved recovery in cases of acute cochlear deafness due to unknown factors or due to sound trauma or pressure (barotrauma).%GBE has also been shown to be a protective agent against ototoxicity from treatment with the chemotherapeutic agent cisplatin, without decreasing antineoplastic efficacy.37

Senile Macular Degeneration and Diabetic Retinopathy GBE appears to address the multifactorial pathophysiol-

ogy of senile macular degeneration, the most common cause of blindness in adults, quite effectively. In doubleblind studies, GBE demonstrated a statistically significant improvement in long-distance visual acuity in both macular degeneration and diabetic retinopathy.1,4*38 GBE has demonstrated impressive protective effects against free radical damage to the retina in experimental studies. Furthermore, GBE has been shown to prevent

diabetic retinopathy in diabetic rats, suggesting it may have a protective effect in human diabetics as

Peripheral Arterial lnsufficiency Peripheral arterial disease has as its primary lesion the same cholesterol-containing plaque that is responsible for other conditions associated with atherosclerosis (e.g., coronary artery disease, cerebral vascular insufficiency). The arterial obstruction or narrowing causes a reduction in blood flow during exercise or at rest. Clinical symptoms are caused by the consequent ischemia. The most common symptom of peripheral arterial disease is pain during exertion as a result of intermittent claudication. The pain usually occurs in the calf and is described as cramping, tightness, or severe fatigue. The pain is usually bilateral. The cause of the pain is not only reduced oxygen delivery but also an increase in the production of toxic metabolites and cellular free radicals. These free radicals accumulate and react with the lipid constituents of the cell membrane. Pain at rest indicates serious reduction in resting blood flow. It is obviously a sign of severe disease. The pain may be localized to one or more toes, or it may have a stocking-type distribution. The character of the pain is usually described as burning or gnawing and is generally worse at night. Cyanosis or pallor of the extremity is usually apparent. In moderate to severe narrowing of the artery, there are trophic changes including a dry, scaly, and shiny epidermis. The hair may disappear, and the toenails may become brittle, ridged, and deformed. The standard medical approach to peripheral vascular disease and intermittent claudication includes avoidance of tobacco (which causes vasoconstriction), a regular exercise program consisting of walking, and the prescription drugs pentoxifylline (Trental) or cilostazol (Pletal). Surgery is also an option, though most patients with intermittent claudication need not take this risk.’9 Trental has emerged as the “drug of choice” in the standard medical treatment of intermittent claudication.40 A total of 17 placebo-controlled trials have shown that Trental prolongs the total and pain-free walking distance in patients with intermittent claudication. However, the level of improvement (approximately 65% for pain-free walking distance) is less than that achieved with exercise or with GBE. In nine double-blind, randomized clinical trials of GBE versus placebo in two matched groups of patients with peripheral arterial insufficiency of the leg, GBE was shown to be quite active and superior to placebo (eight studies) and equal to pentoxifylline (one ~ t u d y ) . ~ , ~ j , ~ l * Not only did measurements of pain-free walking distance (75% to 110%) and maximum walking distance (52.6% to 119%) dramatically increase, but plethysmographic and Doppler ultrasound measurements also

Ginkgo biloba (Ginkgo Tree)

demonstrated increased blood flow through the affected limb. Blood lactate levels also dropped.g10,12-*8 The demonstration that GBE improves limb blood flow, as well as improved walking tolerance (in studies following strict methodology and with sufficient patients for reliable evaluation), indicates that GBE is far superior to pentoxifylline and standard medical therapy in peripheral arterial insufficiency. This includes other peripheral vascular disorders such as diabetic peripheral vascular disease, Raynaud’s disease, acrocyanosis, and postphlebitis syndrome. Cilostazol is the newest of the drugs used to treat intermittent claudication. Comparison studies between pentoxyfylline and cilostazol have shown greater efficacy for the group treated with cilostazol in a 24-week study.47Although cilostazol and gingko have not been directly compared, evidence indicates that cilostazol’s ability to increase total walking distance (143%) and pain-free walking distance (163%) is inferior to that of gingko’s longer-term record of efficacy (approximately 330% and 271%, respectively). Additionally, patient reports showed no improvement in general health perception for patients taking cilostazol and reported a 34% incidence in headaches at the recommended dosage.@ Importantly, although @go was well tolerated and less expensive than the two FDA-approved drugs, the effect was still somewhat modest, especially compared with exercise pr0grams.4~~ The longer the period over which GBE is used, the greater the benefit. Table 96-3 summarizes a 2-year trial of GBE (160 mg/day) in the treatment of peripheral arterial disease (Fontaine’s stage IIb). Pain-free walking distance increased by more than 270%.’ The usual daily dosage of GBE is 120 mg (40 mg three times a day); however, some of the studies employed a dosage of 160 mg/day, including the study summarized in Table 96-3.

According to preliminary study results, GBE appears to be effective in the treatment of erectile dysfunction due to lack of blood flow. The improvement of the arterial inflow to erectile tissue is assumed to be due to the known effect of GBE on enhancing blood flow through both arteries and veins without any change in systemic blood pressure. Ginkgo’s effects are more apparent with long-term therapy, and better results may have been obtained with a 120 mg/day dose in order to take full advantage of its effect on improving blood flow. With the current epidemic use of antidepressant medications including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and tricyclics for various conditions, antidepressant-induced sexual dysfunction is becoming a prevalent side effect. A study of 33 women and 30 men showed an overall 84% effectiveness rate at curbing symptoms with G. bilobu extract exhibiting a positive effect on all four phases of the sexual response cycle: desire, excitement (erectionand lubrication), orgasm, and resolution This research group also demonstrated the efficacy of @go for these side effects after other management trials of cyproheptadine, yohimbine, amantadine, and buspirone hydrochloride had

Premenstrual Syndrome and Idiopathic Cyclic Edema

Premenstrual syndrome (PMS) is often characterized by fluid retention, vascular congestion, increased capillary permeability, and breast tenderness. A recent doubleblind, placebo-controlled study sought to determine the effectiveness of GBE on these symptoms.54The population studied was a group of 165 women between the ages of 18 and 45 years who had suffered from congestive symptoms for at least three cycles. The patients were then assigned to receive either the &go extract (80 mg twice Sexual Dysfunction daily) or placebo from the sixteenth day of the period to day 5 of the next. On the basis of extensive symptom Most cases of impotence (erectile dysfunction) are due evaluation by patients and physicians, it was concluded to impaired blood flow to erectile tissue. Evidence indithat the GBE was effective against congestive symptoms cates that GBE may be extremely beneficial in the treatment of erectile dysfunction due to lack of blood fl0w.5~ of PMS, particularly breast pain or tenderness. Patients taking the @go extract also noted improvementsin neuSixty patients with proven erectile dysfunction who had ropsychologic assessments. These results indicate that not reacted to papaverine injections up to 50 mg GBE may hold some promise in the treatment of PMS. were treated with GBE in a dose of 60 mg/day for 12 to 18 months. The penile blood flow was reevaluated by Antidepressant Effects duplex sonography every 4 weeks. The ability of GBE to improve general mood in patients The first signs of improved blood supply were seen suffering from cerebral vascular insufficiency in doubleafter 6 to 8 weeks. After 6 months’ therapy, 50% of the blind studies has led researchers to begin investigating patients had regained potency and in 20% a new trial of GBE’s antidepressive effects. In a recent double-blind papaverine injection was then successful; 25% of the study, 40 elderly patients (ranging from 51 to 78 years patients showed an improved blood flow, but papaverold) with depression who had not benefited fully from ine was still not successful. The remaining 5% were standard antidepressant drugs were given either 80 mg unchanged.

of GBE three times daily or a placeb0.5~By the end of the eighth week, the total score of the Hamilton Rating Scale for Depression in the GBE group had dropped from 14 to 4.5. In comparison, the placebo group dropped from 14 to only 13. This study indicated two things: GBE can be used with standard antidepressants. GBE enhance the effectiveness of standard antidepressants, particularly in patients older than 50 years of age. Importantly, the dosage used in the study (80 mg three times daily) is higher than the standard dosage of 40 mg three times daily. See the previous section on "sexual dysfunction" regarding grnkgo's ability to decrease unwanted side effects of standard antidepressant medications.

AllergiedAsthma Mixtures of gmkgolides, as well as the GBE standardized to contain 24% ginkgoflavonglycosides, have shown clinical effects in allergic conditions due to their inhibition of PAF, a key chemical mediator in asthma, inflammation, and allergie~.'~,'~ In one double-blind placebo study, the ability of a mixture of grnkgolides to block the effects of PAF when PAF was injected into the skin was investigated.16Normally, when PAF is injected it causes an immediate formation of a hive (classic wheal and flare reaction). However, if the pkgolide mixture (120 mg) was given before PAF injection, it effectively counteracted the wheal and flare reaction. Specifically, the grnkgolide reduced the flare (reddened) area by a mean of 62.4%and the wheal (hive) volume by a mean of 60%. A study from the Qmgdao Hospital of Integrated Traditional and Western Medicine in Shandong, China assessed the efficacy of an oral gingko liquor to alleviate airway hyperreactivity. It was found that the treatment sigruficantlyreduced airway inflammation and improved pulmonary function and clinical symptoms of asthmatic patients.% Mixtures of gmkgolides, as well as purified gmkgolides, are under investigation in several European countries. The hope is that they will be proven clinically effective in eczema, allergies, and many other conditions in which PAF plays a central r ~ l e . ~ ~ , ~ '

Raynaud's Disease Most common in young women (60%to 90% of reported cases), Raynaud's disease is a condition of vasospastic response that causes areas of the body including the fingers, toes, and tips of the nose and ears to feel numb and cool in response to cold temperatures or stress. During a Raynaud attack, these blood vessels that supply the skin narrow, limiting blood circulation to affected areas. Gingko's vasodilating activity is most likely responsible for its effectiveness in treating this problem.

Given the side-effect profile of pharmaceutic treatments for Raynaud's disease, a recent double-blinded, placebocontrolled study evaluated the use of GBE to treat this difficult condition. A 10-week trial revealed a 56% reduction in the number of weekly attacks, whereas placebo reduced the number by 27Y0.~~ The World Health Organization has recommended the use of ginkgo in Raynaud's disease, acrocyanosis, and postphlebitic syndrome.58

High Altitude Sickness A recent study demonstrated the usefulness of gingko to prevent symptoms of acute mountain sickness. For a Himalayan expedition of moderate altitude with gradual exposure, 44 volunteers were divided into a placebo group and a group that received 80 mg of gingko twice a day. No subject in the gingko group developed acute mountain sickness, unlike 40.9% of subjects in the placebo group. Vasomotor disorders of the extremities were also prevented in the gingko

FUTURE APPLICATIONS OF GINKGO BILOBA EXTRACT Experimental studies, as well as some preliminary clinical evidence, indicate that GBE may be of benefit in cases of angina, congestive heart failure, and acute respiratory distress syndrome. Its action on PAF may also make it useful for a great number of other applications in addition to allergies including various types of shock, thrombosis, graft protection during organ transplantation, multiple sclerosis, and burns.'r4

DOSAGE Most of the clinical research on G. bilobu has used a standardized extract, containing 24% ginkgo flavone glycosides, at a dose of 40 mg three times a day. However, some studies have used the higher dosage of 80 mg two to three times daily. Devising a dosage schedule using other forms of ginkgo is difficult due to extreme variation in the content of active compounds in dried leaf and crude extracts. Whatever form of @go is used, it appears to be essential that it is standardized for content and activity. For example, a standard 1:5 tincture obtained from the highest possible flavonoid content crude ginkgo leaf would require 1oz /day to provide the equivalent dosage level of the standardized extract. Clinical research clearly shows that GBE should be taken consistently for at least 12 weeks in order to determine effectiveness.Although most people report benefits within 2 to 3 weeks, some may take longer to respond.

GBE is extremely safe, and side effects are uncommon. In 44 double-blind studies involving 9772 patients taking GBE, the number of side effects reported was extremely small. The most common side effect, gastrointestinaldiscomfort, occurred in only 21 cases, followed by headache (seven cases) and dizziness (six cases).& Due to its inhibition of PAF, many practitioners are concerned that gingko may increase bleeding risk when used concurrently with warfarin (Coumadin),aspirin, and other antiplatelet therapies. A recent study evaluating the use of @go and warfarin concurrently revealed no change in the international normalized ratio, which is the blood test chosen to monitor the patient's possible bleeding risk in response to anticoagulation therapy@ . '

In contrast to the tolerance of the leaf extract, contact with or ingestion of the fruit pulp has produced severe allergic reactions.61t62Contact with the ginkgolic acids in the fruit pulp causes erythema and edema, with the rapid formation of vesicles accompanied by severe itching. This is similar to an allergic reaction to the poison ivy-oak-sumac group, suggesting cross-reactivity between G. bilobu fruit and this family. Ingestion of as little as two pieces of fruit pulp has been reported to cause severe gastrointestinal irritation from the mouth to the anus. Because the gingko leaf does have a low level of irritative ginkgolic acids, animal studies have been conducted to examine the possibility of adverse reactions from using gingko leaf extract. It was concluded that extracts of G. bilobu taken orally be considered

1. DeFeudis FV,ed. Ginkgo biloba extract (EGb 761). Pharmacological activities and clinical applications. Paris: Elsevier, 1991. 2.Tesch BJ. Herbs commonly used by women: an evidence-based review. Am J Obstet Gynecol2003;188(suppl5):544-S55. 3. Blumenthal M. Herb sales down 3% in mass market retail storessales in natural food stores still growing, but at lower rate. Herbal Gram 2000;49:68. 4. Funfgeld EW, ed. Rokan (Ginkgo biloba). Recent results in pharmacology and clinic. New York: Springer-Verlag, 1988. 5. Kleijnen J, Knipschild P. Ginkgo biloba. Lancet 1992;340:1136-1139. 6. Kleijnen J, Knipschild P. Ginkgo biloba for cerebral insufficiency. Br J C h Pharmacol 1992;34:352-358. 7. Sckaffler VK,Reeh PW.[Doubleblind study of the hypoxia protective effect of a standardized Ginkgo biloba preparation after repeated administration in healthy subjects]. Arzneimittelforschung 1985; 35:1283-1286. 8. Chatterjee SS, Gabard B. Studies on the mechanism of action of an extract of Ginkgo biloba, a drug for the treatment of ischemic vascular diseases. Naunyn-Schmiedebergs Arch Pharmacol 1982; 320R52. 9. Le Poncin Lafitte M, Rapin J, Rapin JR. Effect of Ginkgo biloba on changes induced by quantitative cerebral microembolization in rats. Arch lnt Pharmacodyn Ther 1980;243:236-244. 10. Karcher L, Zagerman P,Krieglstein J. Effect of an extract of Ginkgo biloba on rat brain energy metabolism in hypoxia. Naunyn Schmiedebergs Arch Pharmacol1984;32731-35. 11.Watanabe CM, Wolffram S, Ader P, et al. The in vivo neuromodulatory effects of the herbal medicine gingko biloba. Proc Natl Acad Sci U S A 2001;98:6577-6580. 12. Schmidt U, Rabinovici K, Lande S. Einfluss eines Ginkgo biloba specialextraktes auf doe befomdlickeit bei zerebraler onsufficizienz. Munch Med Wochenschr 1991;133S15-S18. 13. Bruchert E, Heinrich SE, Ruf-Kohler P. Wirksamkeit von LI 1370 bei alteren patienten mit himleistungsschwache. Multizentrische doppelblidstudie des fachverbandes Deutscher Allegemeinaezte. Munch Med Wochenschr 1991;133:59-S14. 14.Meyer B. [Multicenter randomized double-blind drug vs. placebo study of the treatment of tinnitus with Ginkgo biloba extract.] Presse Med 1986,151562-1564. 15. Taillandier J, Ammar A, Rabourdin JP, et al. [Treatment of cerebra1 aging disorders with Ginkgo biloba extract. A longtiudinal

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TOXICITY

study on different levels of investigation. Hum Psychopharmacol 1994;9215-222. 28. Kanowski S,Hermann Wh4, Stephan K, et al. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Phytomedicine 1997;4:3-13. 29. Le Bars PL, Kak MM, Berman N, et al. A placebo-controlled, doubleblind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA 1997;278: 1327-1332. 30. Wettstein A. Cholinesterase inhibitors and Ginkgo extracts-are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months’ duration. Phytomedicine 2000;6:393-401. 31. Oken BS, Storzbach DM, Kaye JA. The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 199855: 1409-1415. 32. Meyer 8. A multicenter randomized doubleblind study of Ginkgo biloba extract versus placebo in the treatment of tinnitus. In results in pharmaFunfgeld EW, Rokan eds.(Ginkgo biloba)-recent cology and clinic. New York Springer-Verlag, 1988:245-250. 33. Coles RRA. Trial of an extract of Ginkgo biloba (EGB) for tinnitus and hearing loss. Clin Otolaryngol1988;13:501-504. 34. Holgers KM, Axelsson A, Pringle I. Ginkgo biloba extract for the treatment of tinnitus. Audiology 1994;3385-92. 35. Drew S,Davies E. Effectiveness of Ginkgo biloba in treating tinnitus: double blind, placebo controlled trial. BMJ 2001;332:73. 36. Bascher V, Steinert W. Differential diagnosis of sudden deafness and therapy with high dose infusions of Ginkgo biloba extract. In Clausen CF, Kirtane MV, Schlitter K, eds. Vertigo, nausea, tinnitus, and hypoacusia in metabolic disorders. Amsterdam: Elsevier Science, 1988575-582. 37. Fukaya H,Kanno H. [Experimental studies of the protective effect of ginkgobiloba extract (GBE)on cisplatin-induced toxicity in rats]. Nippon Jibiinkoka Gakkai Kaiho 1999;102907-917. 38. Lanthony P, Cosson JP. [The course of color vision in early diabetic retinopathy treated with Ginkgobiloba extract.A prelurunary doubleblind versus placebo study]. J Fr Ophtalmol 1988;11:671-674. 39.De Felice M, Gallo P, Masotti G. Current therapy of peripheral obstructive arterial disease. The non-surgical approach. Angiology 199O;41:1-11. 40.Ernst E. Pentoxlfylline for intermittent claudication. A critical review. Angiology 1994;45339-345. 41. Schneider B. [Ginkgo biloba extract in peripheral arterial diseases. Meta-analysis of controlled clinical studies]. Arzneimittelforschung 1992;42:428-436. 42. Thomson GJ, Vohra RK, Carr MH, Walker MG. A clinical trial of Gingko biloba exkact in patients with intermittent claudication. Int Angi01 1990;9:75-78. 43.Saudreau F, Sense JM, Pillet J, et al. Efficacy of Ginkgo biloba extract in the treatment of chronic obliterating arteriopathies of the lower limbs in stage Ill of Fontaine’s classification. J Ma1 Vasc 1989;14177-182.

44.Rudofsky VG. [Effect of Ginkgo biloba extract in arterial occlusive disease. Randomized placebo controlled crossover study]. F0rtscl-u Med 1987;105:397-400. 45. Bauer U.Ginkgo biloba extract in the treatment of arteriopathy of the lower limbs. A 65-week trial.] Presse Med 1986;15:1546-1549. 46.Bauer U.&month doubleblind randomized clinical trial of Ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency.Arznehittelforschung 1984;34:71&721. 47. Dawson, DL, Cutler BS, Meissner MH, Strandess DE Jr. Cilostazol has beneficial effects in the treatment of intermittent claudication. Circulation 1998;98:67&686. 48. Mosby’s Drug Consult. St Louis: Mosby, 2003. 49. Pittler MH,Emst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med 2O00;108:276-281. 50. Jacobs BP, Browner WS. Ginkgo biloba: a living fossil. Am J Med 2OOO;108:341-342. 51. Sikora R, Sohn M, Deutz FJ, et al. Ginkgo biloba extract in the therapy of erectile dysfunction. J Urol1989;141:188A. 52. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther 1998;24:139-143. 53. Cohen AJ, Bartilik BD. Gingko biloba for drug-induced sexual dysfunction. Presented at the American Psychiatric Association Annual Meeting, San Diego, CA, 1997. 54.Tamborini A, Taurelle R. [Value of standardized Ginkgo biloba extract (Egb 761) in the management of congestive symptoms of premenstrual syndrome]. Rev Fr Gynecol Obstet 1993;88: 447-457. 55. Schubert H, Halama P. Depressive episode primarily unresponsive to therapy in elderly patients. Efficacy of Ginkgo biloba (Egb 761) in combination with antidepressants. Geriatr Forsch 1993;3: 45-53. 56. Li M, Yang B, Yu H, B a n g H. Clinical observation of the therapeutic effect of ginkgo leaf concentrated oral liquor on bronchial asthma. Chinese J Integr Med 1997;3264-267. 57. Muir AH, Robb R, McLaren M, et al. The use of Ginkgo biloba in Raynaud’s disease: a double-blind placebollontrolled trial. Vasc Med 2002;7265-267. 58. World Health Organization. WHO monographs on selected medicinal plants, vol 1. Geneva: World Health Organization, 19W154-167. 59. Roncin JP, Schwartz F, DArbigny P. EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure. Aviat Space Environ Med 1996;67445-452. 60.Engelsen J, Nielsen JD, Winther K. Effect of coenzyme QlO and Ginkgo biloba on warfarin dosage in stable, long-term warfarin treated outpatients. A randomised, double blind, placebo-crossover trial. Thromb Haemost 2002;87:1075-1076. 61. Becker LE, Skipworth GB. Ginkgo-tree dermatitis, stomatitis, and proctitis. JAMA 1975;231:1162-1163. 62. Hausen BM. The sensitizing capacity of ginkgolic acids in guinea pigs. Am J Contact Dermat 1998;9:146-148.

Glucosamine Michael T. hlurray, ND Joseph E. Pizzorno Jr, NI> CHAPTER CONTENTS General Description 987

Dosage 991

Available Forms 987 Glucosarnine Sulfate versus Nacetylglucosarnine 987 Glucosarnine Sulfate versus Glucosarnine Hydrogen Chloride 988

Toxicity 991 Drug Interactions 991

Clinical Applications 988 Osteoarthritis 988

GENERAL DESCRIPTION Glucosamine is a simple molecule, manufactured in the body from glucose and an amine. One of the primary physiologic roles of glucosamine is in the joints, where it stimulates the manufacture of glycosaminoglycans (GAGS),key structural components of cartilage. Glucosamine also promotes the incorporation of sulfur into cartilage. Because of this effect, glucosamine sulfate (GS) is thought to be the best source of glucosamine (Figure 97-1). As some people age, they apparently lose the ability to manufacture sufficient levels of glucosamine. The result is that synthesis of GAGS does not keep up with degradation. The inability to manufacture glucosamine at an adequate rate has been suggested to be the major factor leading to osteoarthritis. There are no food sources of glucosamine. Commercially available sources of glucosamine are derived from chitin-the exoskeleton of shrimp, lobsters, and crabs.

AVAILABLE FORMS Glucosamine is commercially available as glucosamine sulfate, glucosamine hydrochloride, and N-acetylglucosamine (NAG). GS, the only form of glucosamine that has been the subject of more than 300 scientific investigations and more than 20 double-blind studies, is the preferred form. GS has also been used by millions of

people worldwide and is registered as an aid in osteoarthritis in some 70 countries. When authors or manufacturers discuss glucosamine hydrochloride or NAG, they often cite references of clinical studies that have used GS or the combination of glucosamine hydrogen chloride (HC1) and chondroitin sulfate. On the basis of currently available clinical evidence, it appears that only GS provides proven clinical effectiveness when administered as an isolated agent (numerous studies show the combination of glucosamine HC1 and chondroitin sulfate to be effective).

Glucosamine Sulfate versus /V-acetylglucosamine NAG differs from GS in that instead of a sulfur molecule, NAG has a portion of an acetic acid molecule attached to it. GS and NAG are different molecules and appear to be handled by the body differently. Companies marketing NAG claim that this form is better absorbed, more stable, and better used than glucosamine sulfate. These contentions are without support in the scientific literature. Detailed human studies on the absorption, distribution, and elimination of orally administered GS have shown an absorption rate of as high as 98% and that, once absorbed, it is then distributed primarily to joint tissues, where it is incorporated into the connective tissue matrix of cartilage, ligaments, and tendons.',* In addition, there are impressive clinical studies on thousands of patients. In contrast, the only clinical study with NAG used it 987

sulfur has been shown to inhibit the various enzymes that lead to cartilage destruction in osteoarthritis (e.g., collagenase, elastases, and hyalur~nidase).~',~~ Because one of the primary effects of GS is to promote OH the manufacture of GAGs, a lack of the sulfur moiety may mean less GAG synthesis when glucosamine HC1 is Figure 97-1 Glucosamine. used. Therefore it is unlikely that glucosamine HC1 will show the same excellent clinical results achieved with as a polymer that is not yet available ~ommercially.~ GS because it lacks this critical element. Polymerization is thought to be necessary due to the In fact, results from double-blind studies indicate that poor oral availability of unbound NAG. glucosamine HC1 may be no more effective than a placebo in relieving osteoarthritis. One double-blind, placeboFurther evidence of the superiority of GS to NAG is controlled, 10-week study examined the effects of gluoffered by studies on laboratory animals. Several studies cosamine HC1 in patients with osteoarthritis of the have demonstrated that glucosamine absorption and utilization is at least twice that of NAG."15 The researchers knee.2I Patients received either 500 mg of glucosamine concluded that glucosamine is a more efficient precursor HCl or a placebo three times daily. Forty-five patients of macromolecular hexosamine (GAG) than NAG. It received glucosamine HC1, while 53 received the placebo. The results indicated that 49% of patients receiving gluis possible that NAG does not penetrate the cell membranes and, as a result, is unavailable for incorporation cosamine HC1 felt they had improved compared with 45% of the placebo group who said they felt improved. into glycoproteins and mucopolysaccharides.6The body preferentially uses GS rather than NAG. This preference However, the difference between the two groups was appears largely due to the active processes that enhance not statistically sigruficant. What these results call into absorption of GS in the intestines.1b question is the viability of glucosamine HC1 as an effective form of glucosamine. The absorption of NAG by humans is poor for several More than 30 published, double-blind clinical trials reasons: with GS have demonstrated a success rate of 72% to 95% NAG is quickly digested by intestinal bacteria. in various forms of osteoarthritis. In osteoarthritis of the NAG binds with dietary lectins in the gut, resulting in knee, the success rate is more than 80%. Clearly, the suca lectin-NAG complex, which is excreted in the feces. cess rate noted by glucosamine HCl in this preliminary A large percentage of NAG is metabolized by intestinal study is much less than the rate reported with glucells. cosamine sulfate. In addition to the question of absorption, several studies have shown that the articular tissue cannot use CLINICAL APPLICATIONS NAG as well as it does glu~osamine.~,~ These absorption The primary use for GS is in the treatment of osteoarthritis. and utilization problems suggest NAG is highly unlikely to possess the same kind of antiarthritic and antiinflamGlucosamine is a safe and effective natural alternative to aspirin and other nonsteroidal antiinflammatory drugs matory properties that GS has been shown to possess. (NSAIDs) in the treatment of osteoarthritis. Clinical and Glucosamine Sulfate versus experimental research indicates that current drugs used Glucosamine Hydrogen Chloride in osteoarthritis may be producing short-term benefit but actually accelerating the progression of the joint Research has shown that sulfur is an extremely impordestruction. NSAIDs tend to inhibit cartilage repair by tant component in the therapeutic effect of GS, and its inhibiting glycosaminoglycan synthesis and the incorposubstitution is likely to decrease the efficacy of supplemental glu~osamine.'~ Sulfur is an essential nutrient ration of sulfur into Because osteoarthrifor joint tissue, where it functions in the stabilization of tis is caused by a degeneration of cartilage, it appears that while NSAIDs are fairly effective in suppressing the connective tissue matrix of cartilage, tendons, and the symptoms, they possibly worsen the condition by ligaments. Even healthy humans have low serum sulfate inhibiting cartilage formation and accelerating cartilage (0.3 to 0.4 mM) and synovial sulfur levels, but in destruction (see Chapter 195 for further d i s c u ~ s i o n ) . 2 ~ ~ ~ osteoarthritis these concentrations are even lower. As far back as the 1930s, researchers demonstrated that indiOsteoarthritis viduals with arthritis are commonly deficient in this essential nutrient.18J9 Restoring sulfur levels brought Numerous double-blind studies have shown GS to about significant benefit to these patient^.'^ In addition produce much better results compared with NSAIDs to sulfur playing a critical role in the manufacture and placebos in relieving the pain and inflammation of of GAGs like chondroitin sulfate and keratan sulfate, osteoarthritis. In one of the classic studies comparing GS

with a placebo, 252 patients with osteoarthritis of the knee were given either a placebo or 500 mg of GS three times daily for 4 weeks.28Results indicated that GS was significantly more effective than the placebo in improving pain and movement after 4 weeks. Previous studies have shown that the longer GS is used, the greater the therapeutic benefit. The rate and severity of side effects with glucosamine did not differ from the placebo. These results are consistent with other double-blind studies versus a p l a ~ e b o . ~A~few - ~ ~studies , ~ ~ have shown no greater benefit than a p l a ~ e b o . ~ , ~ ~ The two longest placebo-controlled trials are of three years in d ~ r a t i o n . ~The , ~ ’results from these studies show quite convincingly that GS slows down the progression of osteoarthritis and in many cases produces regression of the disease, as noted by radiologic improvements. In the first long-term study, 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extensionwere taken at enrollment and after 1and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width (i.e., at the narrowest point) was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOh4AC) osteoarthritisindex. The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of -0.31 mm. No sigruficantjoint-space loss occurred in the 106 patients on GS: -0.06 mm. Similar results were reported with minimumjoint-space narrowing. As assessed by WOMAC scores, symptomsworsened slightly in patients on placebo compared with the clinical improvement observed in the group receiving GS. To investigate the relationship between baseline radiographic severity of knee osteoarthritis (OA) and the importance of long-term joint space narrowing in more detail, a subanalysis of data from the 3-year trial was p e r f ~ r m e dMeasurements .~~ of mean joint-space width (JSW), assessed by a computer-assistedmethod, were performed at baseline and after 3 years, on weight-bearing anteroposterior knee radiographs. Those receiving GS demonstrated a trend for significant reduction in jointspace narrowing in patients in the highest quartile of baseline mean JSW (>6.2 mm). In these patients, a joint space narrowing of 14.9% occurred in the placebo group after 3 years, while patients from the GS group only experienced a narrowing of 6%. Insight into who might best respond to GS was provided in another analysis from this 3-year study that examined the ability of GS to improve a biochemical marker of collagen type I1 degradation (CTX-II).39 At baseline the 212 patients had an average concentration of urinary CTX-II of 222.4 ng/mmol creatinine. This was

sigruficantly above the CTX-I1 levels measured in urine samples from 415 healthy controls (169.1 ng/mmol). Although there was no sigruficant difference in the CTX-II response in the placebo group and the glucosaminetreated group, those with high cartilage turnover presented a sigruficant decrease in CTX-I1 after 12-month glucosamine treatment. The group with CTX-11 concentrations above normal average plus 1standard deviation decreased 15.5% after 12-month therapy. The change in CTX-I1 in these patients correlated with the change in average JSW observed after 36 months. Increased baseline levels of CTX-11 in the placebo group were associated with a worsening of the WOMAC index. These data indicate that measurement of urinary collagen type 11 C-telopeptide fragments enables the identification of patients with high cartilage turnover who appear to be most responsive to GS therapy. In the second study, 202 patients with knee osteoarthritis were randomized to receive oral GS (1500 mg once a day) or placebo. Changes in computed tomography radiographic minimumjoint space width were measured in the medial compartment of the tibiofemoral joint, and symptoms were assessed using the Lequesne and WOMAC. Though symptoms improved more significantly in the GS group, the most telling result was the fact that progressive joint space narrowing with placebo use was -0.19 mm after 3 years, while there was no average change with GS sulfate use (an increase of 0.04 mm was the a ~ e r a g e ) ? ~ Head-to-head, double-blind studies have also shown GS to produce much better results compared with NSAIDs in relieving the pain and inflammation of osteoarthritis, despite the fact that GS exhibits little direct antiinflammatory effect and no direct analgesic or pain-relieving effects.4043Although NSAIDs offer purely symptomatic relief and may actually promote the disease process, GS appears to address the cause of osteoarthritis. By promoting cartilage synthesis, thus treating the root of the problem, GS not only relieves the symptoms but also helps the body to repair damaged joints. The clinical effect is impressive, especially when glucosamine’s safety and lack of side effects are considered. In one of the earlier comparative studies in which GS (1500 mg/day) was compared with ibuprofen (1200 mg/day), pain scores decreased faster in the first 2 weeks in the ibuprofen group. However, by week 4 the group receiving GS experienced a significantly better improvement than the ibuprofen group.4o Physicians rated the overall response as good in 44% of the glucosamine sulfate-treated patients as compared with only 15%of the ibuprofen group. Additional studies designed to further evaluate the comparative effectiveness of GS to NSAIDs provide even better evidence.41“ One study consisted of 200 subjects with osteoarthritis of the knee given either GS (500 mg three times daily) or ibuprofen (400 mg three times daily)

for 4 weeks.4l Consistent with previous studies, the ibuprofen group experienced quicker pain relief. However, by the end of the second week, the group taking GS experienced as good results as the ibuprofen group with one major exception-although the rate of side effects with glucosamine were mild and only affected 6% of the group, ibuprofen produced more significant side effects much more frequently, with 35% of the group experiencing them. In another study, 329 patients were given 1500 mg GS, 20 mg piroxicam, both compounds, or a placebo for 90 days.42The main efficacy variable was represented by the Lequesne index, a standard method of assessing disease activity. As can be seen in Figure 97-2, the results of the study were strikingly in favor of GS alone. These impressive results with GS were achieved without side effects. In fact, patients on GS had fewer side effects than the placebo and no dropouts. (Table 97-1 provides the side effect and dropout values among the four groups.) In another study in osteoarthritis of the knee (Table 97-2) GS showed comparable symptomatic relief, but was better tolerated and produced residual benefit after di~continuation.4~ Another study showed an obvious advantage of GS over ibuprofen in patients diagnosed with temporomandibular joint (TMJ) osteoarthritis. In the doubleblind study, 40 women and 5 men received either GS (500 mg) or ibuprofen (400 mg) three times daily for 90 days. Fifteen patients taking GS (71%)and 11 taking ibuprofen (61%)improved, with positive clinical response taken as a 20% decrease in TMJ pain and function. Between-group comparison revealed that patients taking GS had a significantly greater decrease in TMJ pain with function, effect of pain, and acetaminophen used between days 90 and 120 compared with patients taking ibuprofen.44 In addition to showing benefit in double-blind studies, oral GS was shown to offer significant benefit in an open 121

Dropouts

Placebo

GS

Piroxicam

GS + piroxicam

24.4%

14.8%

40.9%

5.9%

20

3

0

3

GS,Glucosamine sulfate.

Time

Glucosamine sulfate

Ibuprofen

8.42 5.54 3.60 3.26

8.46 5.63 4.18 3.84

1.43 0.77 0.47 0.36

1.48 0.89 0.48 0.54

Knee Pain (Average Score) Before treatment Wk 2 Wk 4

2 wk after treatment Knee Swelling (Average Score) Before treatment Wk 2 Wk 4

2 wk after treatment Clinical Improvement Glucosamine sulfate

Ibuprofen

Effectiveness

After 4 wk

After 6 wk

After 4 wk

After 6 wk

Symptom free

45% 39% 1 1 o/o 5%

55%

32% 45% 15% 8%

36% 41% 14% 9%

Improved Unchanged Worsened Side Effects

32% 7% 6%

Glucosamine sulfate

Ibuprofen

Side effects

6%

Dropouts

0%

16% 10%

Modified from Qiu GX, Gao SN, Giacovelli G, et al. Arzneirnineiiorschung 1998;48: 469-474.

-@U-

Placebo

+Piroxicam -A-

4 0

Incidence of side effects

15

30

60

90

GS + Pir

1 120 150

Day Figure 97-2 Symptom relief (Lequesne index) from glucosamine compared with piroxicam and placebo.

trial involving 252 doctors and 1506 patients in P0rtugal.4~ This large study provides valuable clinical information on the appropriate use of GS. The patients received 500 mg of GS three times daily over a mean period of 50 days. Symptoms of pain at rest, on standing, and on exercise, as well as limited active and passive movements, all improved steadily throughout the treatment period. Objective therapeutic efficacy was rated by doctors as "good" in 59% of the patients and "sufficient" in a further 36%. Although not a controlled study, a 95%

G lucosarnine response rate is impressive. The results with GS were rated by both doctors and patients as being sigruficantly better than those obtained with previous treatment including NSAIDs, vitamin therapy, and cartilage extracts. GS produced good benefit in a significant portion of patients who had not responded to any other medical treatment. In the study, obesity was associated with a significant shift from good to fair. This finding may indicate that higher dosages may be required for obese individuals or that oral glucosamine is not enough to counteract the added stress of obesity on the joints. Patients with peptic ulcers and individuals taking diuretics were also associated with a shift from good to sufficient in efficacy, as well as tolerance. Individuals with current peptic ulcers should take glucosamine sulfate with foods. Individuals taking diuretics may need to increase the dosage to compensate for the reduced effectiveness. The improvement with glucosamine lasted for 6 to 12 weeks after the end of treatment.

GS has an excellent safety record in animal and human studies. On the basis of these studies, many experts have recommended that GS “be considered as a drug of choice for prolonged oral treatment of rheumatic disorders.” Side effects, when they do appear, are generally limited to light to moderate gastrointestinal symptoms including stomach upset, heartburn, diarrhea, nausea, and indigestion. If these symptoms occur, GS should be taken with meals. Regarding people who are “sulfur sensitive,” an important distinction must be made. When patients report they are allergic to sulfur, what they usually mean is that they are allergic to the so-called sulfa drugs or sulfite-containing food additives. It is impossible to be allergic to sulfur, as sulfur is an essential mineral. The sulfate form of sulfur is present in human blood. In short, GS is extremely well tolerated and no allergic reactions have been reported.

DOSAGE

DRUG INTERACTIONS

The standard dosage for GS is 1500 mg daily. It may be administered as a single or divided dosage with equal effectiveness. Obese individuals may need higher dosages on the basis of body weight (e.g., 20 mg/kg body weight daily). Also, individuals taking diuretics may also need to take higher dosages.

Concern has been expressed that glucosamine may influence insulin secretion or action, or both, in humans primarily on the basis of in vitro studies. However, human studies do not support that at recommended levels GS has any impact on insulin secretion or action in either health subjects or those with type 2

1.Setnikar I, Palumbo R, Canali S, Zanolo G. Pharmacokinetics of glucosamine in man. Arzneimittelforschung 1993;43:1109-1113. 2. Setnikar I, Giacchetti C, Zanolo G. Pharmacokinetics of glucosamine in the dog and man. Arzneimittelforschung 1986;36: 729-735. 3. Rubin BR, Talent JM, Kongtawelert P, et al. Oral polymeric N-acetyl-D-glucosamine and osteoarthritis. J Am Osteopath Assoc. 2001;101:339-344. 4. Setnikar I. Antireactive properties of ”chondroprotective” drugs. Int J Tissue React 1992;14:253-261. 5. Karzel K, Domenjoz R. Effect of hexosamine derivatives and uronic acid derivatives on glycosaminoglycan metabolism of fibroblast cultures. Pharmacology 1971;5:337-345. 6. Vidal y Plana RR, Bizzarri D, Rovati AL. Articular cartilage pharmacology. I. In vitro studies on glucosamine and non steroidal anti-inflammatory drugs. Pharmacol Res Commun 1978;10557-569. 7. Capps JC, Shertlar MR, Bradford RH. Hexosamine metabolism. II. Effect of insulin and phlorizin on the absorption and metabolism, in vivo, of D-glucosamine and N-acetyl-D-glucosamine in the rat. Biochim Biophys Acta 1966;127205-212. 8. Capps JC, Shetlar MR, Bradford RH. Hexosamine metabolism. I. The absorption and metabolism, in vivo of orally administered D-glucosamine and N-acetyl-D-glucosamine in the rat. Biochim Biophys Acta 1966;127194204. 9. Shetlar MR, Capps JC, Hem DL. Incorporation of radioactive glucosamine into the serum proteins of intact rats and rabbits. Biochim Biophys Acta 1964;8393-101.

10. Richmond JE. Studies on the metabolism of plasma glycoproteins. Biochemistry 1963;128:676-683. 11. Capps JC, Shetlar MR. In vivo incorporation of D-glucosamine-1-C14 into acid mucopolysaccharides of rabbit liver. Proc SOCExp Biol Med 1963;114:118-120. 12. Shetlar MD, Hem DL, Bradford RH, et al. Fate of radioactive glucosamine administered parenterally to the rat. Proc SOCExptl Biol Med 1962;109:335-337. 13. Kohn P, Winzler RJ, Hoffman R. Metabolism of D-glucosamine and N-acetyl-D-glucosaminein the intact rat. J Biol Chem 1962;237 304-308. 14.McGarrahan JF,Maley F. Hexosamine metabolism. J Biol Chem 1962;2372458-2465. 15. Shetlar MD, Hem DL, Bradford RH, Endecott 8. Incorporation of [1-14C]glucosamine into serum proteins. Biochim Biophys Acta 1961;53:615-616. 16. Tesoriere G, Dones F, Magistro, Castagnetta L. Intestinal absorption of glucosamine and N-acetylglucosamine. Experientia 1972;28770-771. 17. Annefeld M. Personal communication. February 28, 1997, Chicago. 18. Sullivan MX, Hess WC. Cystine content of finger nails in arthritis. J Bone Joint Surg Am 1935;16:185-188. 19. Senturia BD. Results of treatment of chronic arthritis and rheumatoid conditions with colloidal sulphur. J Bone Joint Surg Am 1934; 16119-125. 20. Vignon E, Richard M, Annefeld M. An in vitro study of glucosamine sulfate on human osteoarthritic cartilage metabolism. Manuscript in preparation.

TOXICITY

Pharmacology of Natural Medicines ~

21.Houpt JB, Mch4iUan R, Wein C, et al. Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. J Rheumatol1999;262423-2430. 22. Brandt KD. Effects of nonsteroidal anti-inflammatory drugs on chondrocyte metabolism in vitro and in vivo. Am J Med 1987;83 29-34. 23. Shield MJ. Anti-inflammatory drugs and their effects on cartilage synthesis and renal function. Eur J Rheumatol Inflamm 1993; 13:7-16. 24. Brooks PM, Potter SR, Buchanan WW. NSAID and osteoarthritishelp or hindrance? J Rheumatol 1982;93-5. 25. Newman NM, Ling RS.Acetabular bone destruction related to nonsteroidal anti-inflammatory drugs. Lancet 1985;2;11-14. 26. Solomon L. Drug-induced arthropathy and necrosis of the femoral head. J Bone Joint Surg Am 197355246-251. 27.Ronningen H, Langeland N. Indomethacin treatment in osteoarthritis of the hip joint. Acta Orthop S a n d 1979;50:169-174. 28.Noack W, Fischer M, Forster KK, et al. Glucosamine sulfate in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;251-59. 29. Crolle G, DEste E. Glucosamine sulfate for the management of arthrosis: a controlled clinical investigation. Curr Med Res Opin 1980;7104-109. 30.Pujalte Jh4,Llavore EP, Ylescupidez FR. Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. Curr Med Res Opin 1980;7110-114. 31. Drovanti A, Bignamini AA, Rovati AL. Therapeutic activity of oral glucosamine sulfate in osteoarthrosis: a placebecontrolled doubleblind investigation. Clin Ther 1980;3:260-272. 32. DAmbrosia E, Casa B, Bompani R, et al. Glucosamine sulphate: a controlled clinical investigation in arthrosis. Pharmatherapeutica 1982;2:504-508. 33. Braham R, Dawson B, Goodman C. The effect of glucosamine supplementation on people experiencing regular knee pain. Br J Sports Med 2003;37:45-49. 34. Hughes R, Carr A. A randomized, double-blind, placebocontrolled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. Rheumatology 2002;41:279-284. 35. Rindone JP, Hiller D, Collacott E, et al. Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee. West J Med 2000;17291-94. 36. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial. Lancet 2001;357251-256.

~

~~~

37. Paveka K, Gatterova J, Olejarova M, et al. Glucosamine sulfate use and delay of progression of knee osteoarthritis:a >year, randomized, placebocontrolled, double-blind study. Arch Intern Med 2002;162: 2113-2123. 38. Bruyere 0, Honore A, Ethgen 0, et al. Correlation between radiographic severity of knee osteoarthritis and future disease progression. Results from a 3-year prospective, placebo-controlled study evaluating the effect of glucosamine sulfate. Osteoarthritis Cartilage 2003;l:l-5. 39. Christgau S, Henrotin Y, Tank0 LB, et al. Osteoarthritic patients with high cartilage turnover show increased responsiveness to the cartilage protecting effects of glucosamine sulphate. Clin Exp Rheumatol 2004;22:36-42. 40.Lopes Vaz A. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulfate in the management of osteoarthrosis of the knee in out-patients. Curr Med Res Opin 1982;8:145-149. 41. Muller-Fassbender H, Bach GL, Haase W, et al. Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. Osteoarthritis Cartilage 1994;2:61-69. 42. Rovati LC, Giacovelli G, Annefeld M, et al. A large, randomized, placebo controlled, double-blind study of glucosamine sulfate vs piroxicam and vs their association, on the kinetics of the symptomatic effect in knee osteoarthritis. Osteoarthritis Cartilage 1994;2 (suppl 1):56. 43. Qiu GX, Gao SN, Giacovelli G, et al. Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. Armeimittelforschung 1998;48:469-474. 44. Thie NM, Prasad NG, Major PW. Evaluation of glucosamine sulfate compared to ibuprofen for the treatment of temporomandibular joint osteoarthritis: a randomized double blind controlled 3 month clinical trial. J Rheumatol2001;28:1347-1355. 45. Tapadinhas MJ, Rivera IC, Bignamini AA. Oral glucosamine sulfate in the management of arthrosis: report on a multi-centre open investigation in Portugal. Pharmatherapeutica 1982;3:157-168. 46. Monauni T, Zenti MG, Cretti A, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49:926-935. 47. Scroggie DA, Albright A, Harris MD. The effect of glucosaminechondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163: 1587-1590.

Glutamine Peter B.Bongiomo, ND, Dip1 Ac CHAPTER CONTENTS introduction 993 Food Sources 993 Forms 993 Physiologic Effects 993 Clinical Applications 995 Intestinal Permeability-Related Conditions 995 Infectious Diarrhea 995 Postsurgical Complications of the Gastrointestinal Tract 995 Chemotherapy and Radiation Side Effects 996 Cachexia 997

INTRODUCTION Glutamine (Figure 98-1) is the most abundant amino acid in the blood and muscle tissue. It comprises approximately 6% of mixed whole body protein and is unique among amino acids in that it is a preferred fuel of rapidly dividing cells such as intestinal and immune cells and is important in maintaining pancreatic function.’” Glutamine is involved in the transport of circulating amino nitrogen and is an important intermediary that allows for accelerated gluconeogenesis from amino acids that are released by the skeletal muscle during stress state^.^ In addition, glutamine is used as a precursor for DNA and glutathione ~ynthesis.~ As one of the principal fuels used by the cells of the intestinal lining, it accounts for 35% of enterocyte energy production. Although readily available in the diet and synthesized in the body from glutamate and ammonia, supplementation is known to enhance the energy metabolism of the gastrointestinal mucosa, thus stimulating regeneration.6 Although glutamine is not considered essential in healthy people, there is evidence that the increased need for glutamine in stressed states such as burns, septicemia, endotoxemia, intestinal failure, and critical illness may result in it being ”conditionally e~sential.”~,~,~

Human ImmunodeficiencyVirus 997 Peptic Ulcers 998 Severe Burns 998 Low-Birth-Weight Infants 998 Exercise and Weight Lifting 998 Cardiac Disease 999 Other Conditions 999 Dosage 999 Toxicity

1000

Drug Interactions 1000

Food Sources Typical food sources of glutamine include animal and plant proteins. Typical foods are cabbage, beef, chicken, fish, legumes, miso (a salty, fermented bean product), and dairy products.

Forms The nomenclature of L-glutamine and glutamine are used interchangeably. Dglutamine is the stereoisomer of L-glutamine and does not have any known biologic activity. L-glutamine is not very soluble in water, and aqueous solutions are unstable at temperatures of 22 to 24 degrees Celsius. As a result, the more soluble and more stable dipeptides such as alanyl-glutamine are used as delivery forms of L-glutamine in total parenteral nutrition s o l u t i ~ n s . ~ J ~

Physiologic Effects Intestinal Repair and Protection Animal and human studies suggest that glutamine stimulates intestinal mucosal growth1’ and protects from mucosal atrophy. Glutamine prevents intestinal mucosal damage and has been shown to decrease bacterial leakage across the intestines after they are damaged, presumably by stimulating repair.12 Glutamine is thought to accomplish this by strengthening epithelial tight 993

0

0

NH, Figure 98-1

L-glutamine.

junctions and also by preventing paracellular permeabilities through an epidermal growth factor receptordependent mechanism. In one tissue culture experiment, intestinal epithelium cells were treated with acetaldehyde in order to compromise barrier function. These cells were treated with L-glutamine, D-glutamine, L-asparagine, L-arginine, L-lysine, or L-alanine. Only the L-glutamine demonstrated a benefit by decreasing aldehyde effects on transepithelid resistance. Furthermore, L-glutamine-treated cells had decreased permeability that was dose dependent. L-glutamine reduced the acetaldehyde-induced disturbance of transmembrane structures such as occludin, zonula occludens-1, E-cadherin, and beta-catenin from the intercellular junctions. Lastly, L-glutamine induced a rapid increase in the tyrosine phosphorylation of epidermal growth factor receptor. No other amino acids demonstrated this effect.l3

Acid Base Balance Glutamine plays an important role in acid-base homesta as is.^^ Glutamine is synthesized from glutamate and the toxic alkaline waste product ammonia by the enzyme glutamine synthetase, which requires magnesium and adenosine triphosphate. When ammonia levels are elevated, the body effectively removes ammonia from the blood by synthesizing glutamine. Conversely, if the blood is too acidic, the glutamine can be broken down into glutamate and ammonia, which increases blood pH. Ammonia can bind hydrogen ions to produce ammonium cations, which are excreted in the urine along with chloride anions. Bicarbonate ions are simultaneously released into the bloodstream. Clinical studies have shown that relatively small oral doses of glutamine can elevate plasma bicarbonate concentrations in healthy adults. In one study 2 g of glutamine were dissolved in a cola drink and ingested over a 20-minute period 45 minutes after a light breakfast. Control subjects were given soda only. Blood samples were taken 1 week before, at baseline, and subsequently at three separate 30-minute intervals after ingestion of the glutamine drink or placebo. Eight of nine subjects responded to the oral glutamine load with a sigruhcant increase in plasma glutamine at 30 and 60 minutes before returning to the baseline value at 90 minutes. Ninety minutes after the glutamine was

administered, plasma bicarbonate concentration was found to be increased. Additionally, circulating plasma growth hormone concentration was elevated as well. Concomitant with enhanced renal acid secretion, glutamine ingested also caused an increase in glomerular filtration rate.15 The authors of this study explained that their results show that it is unlikely L-glutamine is a direct precursor of bicarbonate. Instead, L-glutamine appears to play an indirect role in accelerating acid secretion through mechanistic changes in the kidneys. Human studies have shown that urinary ammonium excretion is altered by changes in glutamine intake.16 Chronic metabolic acidosis is a common clinical problem encountered in catabolic states such as sepsis, shock, and diabetes and is a major factor in many biologic derangement^.'^ Because glutamine becomes an essential amino acid in catabolic states when the increased demand exceeds the body’s capability to synthesize it,’* glutamine supplementation may be quite useful to maintain pH homeostasis in patients with acidotic conditions.

Glutathione Repletion Glutathione is a tripeptide consisting of glutamate, cysteine, and glycine. As a reservoir source for glutamate in the body, the availability of glutamine appears crucial for the regeneration of glutathione stores in the liver during hepatic injury; in skeletal muscle following major trauma, sepsis, or surgery; and in chemotherapy-injured heart muscle.1Y-21 Glutamine can enhance intracellular repletion of glutathione, an important scavenger of reactive oxygen species.= Rat studies have demonstrated that during 5-flurouracil-induced free radical-mediated hepatic injury, glutamine increases glutathione biosynthesis and preserves the glutathione stores in hepatic tissue.19Human studies of 17 patients undergoing a standardized surgical procedure were prospectively given 0.56 g/kg body weight/day of glutamine or a placebo. Employing percutaneous muscle biopsies and blood samples, it was observed that 24 and 72 hours after an operation, there were no significant decreases in total or reduced glutathione in the glutamine-supplemented group. In contrast, the placebo group experienced total muscle glutathione losses of 47”/0k 8% and 37%f 11%, as well as reduced glutathione decreases of 53% f 10% and 45%f l6%, at 24 and 72 hours, respectively.

Protein Sparing Glutamine is a regulator of muscle prote0lysis,2~and supplementation can attenuate loss of protein in the muscle. Experiments using animal cancer models have demonstrated decreased protein loss and simultaneous protection of immune and gut-barrier function during radiation therapy in patients with advanced c a n ~ e r . ~

Glutamine In children with severe muscle wasting, 5 hours of oral glutamine has shown to have protein-sparing effect (see later discussion on cachexia).24

Immune Support Although poorly understood, it appears that glutamine has an immune-modulating effect by enhancing interleukin (1L)-6 levelsz and lymphocyte function?6 IL-6 plays an essential role in the final differentiation of beta cells into immunoglobulin-secreting cells, nerve cell differentiation, and acute phase reactants in hepatocytes. Exercise by itself is known to induce an elevenfold increase in plasma IL-6.Glutamine supplementation further enhances IL-6 levels.= The ability of lymphocytes to proliferate and generate lymphokine-activated killer cell activity in vitro has been found to be glutamine dependent.27Additionally, glutamine-enriched parental nutrition has demonstrated enhanced lymphocyte activity in patients undergoing high doses of chemotherapy after stem cell transplantation for hematologous malignancy.

CLINICAL APPLICATIONS Intestinal Permeability-Related Conditions A number of conditions are linked to intestinal permeabilities including chronic urticariaF8 inflammatory bowel disease (Crohn's disea~e)F~-~I celiac liver and biliary cirrhosis and cases of portal hypertension,=a systemic scler0sis,3~ rheumatologic disordersP7J8cystic alcohol overuse,4oadult and child asthma:' human immunodeficiency virus (HIv)/ acquired immune deficiency syndrome,42nonsteroidal antiinflammatory drug-treated arthritis patients,a moderate to major burn injuries,"" corticosteroid use,& cardiopulmonary bypass patient^,^,^^ and acute metal toxicities.48 In order to evaluate these permeabilities, sucrose has served as a marker for gastroduodenal permeability and the urinary lactulose/mannitol ratio for intestinal permeability, after administration of these sugars.28From a naturopathic perspective, the underlying cause of many of these conditions may stem from food allergies, which contribute first to chronic inflammation in the intestinal tract28and then to systemic endotoxemia.Certain conditions such as cardiopulmonary bypass can cause intestinal i~chemia:'~which is then the primary insult that causes permeabilities in these patients. The use of glutamine can help heal these permeabilities, thus removing a mode of pathogenesis in these variegated conditions.

Infectious Diarrhea Animal models have definitely shown the usefulness of glutamine in diarrhea to augment sodium and water absorption and to enhance blood glucose and body weight.%A rat model of cholera toxin-induced diarrhea has shown that glutamine was able to improve water

and electrolyte intestinal absorption even better than the traditional glucose solutions.10One placebocontrolled, double-blind, randomized trial human study evaluated glutamine to treat acute diarrhea in 128 otherwise healthy children. O f these 6- to 24month-olds, 63 received 0.3 g/kg/day of glutamine and 65 controls received a placebo for 7 days. The average duration of diarrhea in the glutamine-treated group was signhcantly shorter than that of the placebo group (3.40 f 1.96 days vs. 4.57 f 2.48 days, respectively). However, no differences in serum IL-8 and secretory immunoglobulinA were found between groups at the beginning of treatment or 1week later.5l Clearly, glutamine holds promise for enhancing repair of mucosal injury caused by a wide range of infections or toxic agents and thus has great potential as a nutritional therapeutic for patients with enteric

Postsurgical Complications of the Gastrointestinal Tract Patients undergoing abdominal surgeries such as gastrectomies, sigmoidectomies, cholecystectomy, colectomies, and rectal resections are at risk for the development of intestinal failure or short bowel syndrome (SBS). In SBS a serious malabsorption of fluid, electrolytes, and other nutrients can occur, placing the patient at higher morbidity and mortality r i ~ k . 5 Trauma ~ from abdominal surgery may also compromise the intestinal mucosa to the point where bacteria and endotoxins can easily transfer through the intestinal wall and invade tissue and blood in an event called bacterial translocation. Through inflammatory mechanisms, bacteria, and endotoxic septic conditions, the intestinal mucosal barrier can be adversely affected and cause further damage, thus forming a vicious circle. Severe cases result in systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS).% In a regimen that includes growth hormone and diet changes, glutamine can help difficult cases to enhance bowel adaptation. In one study of 10 patients with SBS who had previously failed to adapt to enteral nutrients, 8 subjects received exogenous growth hormone, supplemental glutamine, and a modified high-carbohydrate, high-fiber diet. Two patients were treated with the modified diet alone. Three weeks of treatment with growth hormone, glutamine, and a modified diet sigruficantly increased total caloric absorption from approximately 60%to 75%, protein absorption from 48.8%to 63%, and carbohydrate absorption from 60% to 81.5%. Water absorption increased from 45.7% to 65%, and sodium from 49% to 69%. Fat absorption did not change. Diet alone did not influence nutrient absorption or stool output. After 28 days of therapy, the patients were discharged and instructed to continue the diet and glutamine treatment.55It is unknown whether glutamine and

Pharmacology of Natural Medicines diet changes alone, without concomitant growth hormone administration, would have the same positive effect. In a second study, 20 patients having just undergone abdominal surgery were randomized into two groups receiving oral administration of 30 g of glutamine or a placebo in divided doses for 7 days. Serum glutamine concentration was significantly decreased in the placebo group and increased in the glutamine group after 7 days. Markers of intestinal permeability were sigruficantly increased in the placebo group and decreased in the glutamine group. Additionally, the serum markers of endotoxin, diamine oxidase, and malondialdehyde concentrations were sigruficantly decreased in the glutamine group compared with those in the placebo group. Temperatures, heart rates, and white blood cell counts were also sigruficantly lower in the glutamine group.% Ischemia-reperfusion of the gut is also a common event in various clinical conditions such as trauma, burn, septic shock, cardiac or aortic surgery, and liver or small bowel transplantation and is associated with a high death rate. Intestinal ischemia-reperfusion can cause edema and disruption of the structural integrity and function of the intestinal mucosa and associated vascular tissue. It may set the stage for endotoxemic translocation of a number of bacterium, including Escherichia coli, Enterococcus, Pseudomonas, Proteus, and Staphylococcus. Studies of animal models demonstrate that glutamine, when supplemented as total parenteral nutrition, protects the intestines from morphologic and functional mucosal injury after intestinal ischemia-reperfusion. Furthermore, intestinal permeabilities and the incidence of bacterial translocation in the intestinal ischemiareperfusion animals are also prevented by glutamine supplementation.56 The gastrointestinal tract is susceptible to SBS, severe intestinal permeabilities, ischemia perfusion damage, systemic inflammatory response during trauma, various medical conditions, and abdominal postoperative periods. Glutamine can decrease intestinal permeability, maintain an intestinal barrier, and attenuate systemic inflammatory response in early postoperative patients.

Chemotherapy and Radiation Side Effects Standard cancer therapies often include the use of chemotherapy and radiation, which can injury rapidly dividing intestinal cells. It has been shown that during chemotherapeutic and radiotherapy insult, glutamine can reduce degeneration of intestinal mucosa in rats, prevent intestinal mucosal injury,%protect liver function through enhanced glutathione biosynthesis and storage in hepatic tissue, increase immune function, and reduce permeability of the g ~ t . ~ ~ 3 In one investigation, 70 patients with colorectal cancer were randomly assigned to oral glutamine at 18 g/day or placebo before the first regimen of 5-flurouracil and

folinic acid administered intravenously for 5 days. Glutamine was given 5 days before, during, and after chemotherapy. Using D-xylose urinary excretion and cellobiose-mannitol evaluation, damage to the intestines was assessed at baseline, as well as 4 and 5 days after the end of the first cycle of chemotherapy. After one cycle of chemotherapy, the reduction in Dxylose absorption and reduction of mannitol was sigruficantly greater in the placebo group (7.1%vs. 3.8%and 9.2% vs. 4.5%, respectively). Urinary recovery of cellobiose was not different between the study arms. Accordingly, the cellobiosemannitol ratio increased more in the placebo treatment group. Furthermore, diarrhea parameters, as well as the average number of antidiarrheal opiate loperamide tablets needed, were reduced in the glutamine arm, thus supporting the positive clinical effect of this low-cost supplement." Oropharyngeal mucositis, or mouth sores, and accompanying swallowing difficulty are other untoward results of radiotherapy and can be a major source of suffering in patients with head and neck cancer. Glutamine during and after chemotherapy appears to be an excellent way to safely decrease the incidence of mouth sores. One investigation of 17 patients with head and neck cancer who received primary or adjuvant mouth irradiation for 5 days a week were randomized to either adjunctive glutamine suspension of 16 g in 240 ml normal saline or a saline placebo. Patients were instructed to swish the test solutions (30 ml) four times daily. The duration of objective oral mucositis was sigruficantly shorter in the glutamine arm.57A second randomized, double-blind crossover trial observed 24 patients who were given a glutamine or placebo suspension to swish and swallow on days of chemotherapy administration and for at least 14 days following. Significant improvement was observed in the glutamine group. Additionally, the duration of mouth pain was 4.5 days less in chemotherapy courses with concomitant glutamine supplementation. The severity of oral pain was reduced so significantly when glutamine was used that a patient could venture past soft foods 4 days sooner compared with placebo.% Glutamine studies validating its use are also beginning to emerge in other areas of oncology. In a study of esophageal cancer patients, 13 patients were randomized into two groups, control and a group that received oral glutamine supplemented at a dosage of 30 g/day for 4 weeks. It was observed that supplementation of glutamine enhanced lymphocyte mitogenic function and reduced permeability of the gut during radiochemothe rap^.^ Patients undergoing bone marrow transplant and myelosuppressive chemotherapy for acute myeloid leukemia have also found that parenteral glutamine therapy can improve neutrophil recovery, although no change in neutropenic fever had been shown.59Given that glutamine improves the structure and function of

Glutamine

the gut, it is understandable that multiple parameters and markers of healthy physiologic function will improve with its use. It should be noted that glutamine’s efficacy may depend on a number of other factors, including the specific chemotherapeutic prescribed and dosage. A study of 65 patients with advanced breast cancer receiving doxifluridine were prescribed 30 g a day of glutamine in three divided doses of 10 g each or a placebo for 8 consecutive days during each interval between chemotherapy, which was administered from days 1 to 4. In this case there was no statistical difference with regard to diarrhea morbidity, nor did glutamine affect the severity and duration of tumor growth.@Interestingly, a study of bone marrow transplant patients found that allogeneic transplant patients (those receiving bone marrow from another individual) did not have the same beneficial mouth pain reduction that autologous transplant patients (those who donated their own marrow) experienced when receiving glutamine support. However, in the work mentioned previously, the amounts of glutamine were less than those used in other studies. It was also theorized that methotrexate use in the allogeneic patients may be responsible for the decreased protection. Nevertheless, in the allogeneic patients, the 28-day survival was still increased.61A third multicenter study of 129 patients found no protection against diarrhea when used adjunctively with pelvic radiation therapy. These patients received 4 g of glutamine or a placebo by mouth, which is also a significantly lower dose than the more successful studies employed.62 Although intestinal function is greatly compromised with chemotherapy and radiation treatment, cardiac function is commonly affected as well. The use of doxorubicin therapy for breast cancer is often limited by cardiomyopathic heart changes that often result in congestive heart failure. One rat study simulated doxorubicin treatment with and without glutamine support and found that oxidative damage to the heart was diminished in the glutamine-treated group, probably as a result of glutamine’s ability to maintain cardiac tissue glutathione levels (see later discussion on cardiac disease)?l

Cachexia Cancer-related cachexia is caused by a diverse combination of accelerated protein breakdown and slowed protein synthesis.63 There has been considerable interest in giving supplemental glutamine to cancer patients because glutamine is taken up by the growing tumor, and any subsequent deficiency of glutamine in the host may cause cancer cachexia? One animal study found that glutamine levels in plasma and skeletal muscle were indeed decreased in tumor-bearing rats, while glutamine production and the conversion of arginine to glutamine were increased.

In rats supplemented with glutamine, total parenteral nutrition demonstrated a reduced whole-body protein breakdown rate during chemotherapy5 A clinical study of patients with stage lV solid malignancies who had demonstrated weight loss of at least 5% were randomly assigned in a double-blind fashion to either a control mixture of nonessential amino acids or treatment of 14 g of glutamine/day, along with the leucine metabolite betahydroxy-beta-methylbutyrate (3 g/day) and L-arginine (14 g/day). Within 4 weeks, the patients supplemented with the glutamine mixture gained 0.95 f0.66 kg of body mass, whereas control subjects lost 0.26 k 0.78 kg during the same time period. This effect continued over the 24 weeks with no negative effect of treatment on the incidence of adverse effects or quality of life measures.63 Because the glutamine derived from skeletal muscle is trapped by the tumor, there is a theoretic concern that glutamine supplementation in cancer patients could potentially encourage tumor growth. One research group, however, has shown that glutamine supplementation does not appear to enhance DNA content in tumor Additionally, some tissue culture studies provide evidence that glutamine may even inhibit cancer promotion.65Although research is necessary to clarify this point, given the immediate risk of mortality due to protein loss in cancer patients, it still would seem prudent in those patients at greater immediate risk of cachexia-related death.

Human ImmunodeficiencyVirus Loss of body cell mass and drug-associated gastrointestinal problems often occur in patients with HIV infection. In these cases the patient’s ability to survive can be affected in the long term. Given the role glutamine plays in cachexic body mass loss (see earlier discussion), reversal of malabsorption,66and protection of the small intestine:’ glutamine deficiency is a probable causal factor in HIV-associated wastinga Preliminary clinical studies suggest improvements in HIV-positive patients dosed at 8 g a day with regard to intestinal permeability and intestinal absorption. The authors of this study correctly suggest that at least 20 g/day may be necessary for more significant improvement~A . ~ double-blind, ~ placebo-controlled trial of 26 patients with greater than 5% weight loss since their disease onset used a glutamine and antioxidant regimen including 40 g of glutamine/day in divided doses or 40 g of a glycine placebo for 12 weeks. Over 3 months, the glutaminelantioxidant group gained 2.2 kg in body weight or 3.2%, whereas the control group gained only 0.3 kg or 0.4%. The glutamine-antioxidant group gained 1.8 kg in body cell mass, whereas the control group gained 0.4 kg. Of note, the intracellularwater increased in the glutamineantioxidant group but not in the control

Pharmacology of Natural Medicines Glutamine can help HIV patients decrease the severity of iatrogenic diarrhea. Twenty-five patients suffering for more than a month from nelfinavir-associated diarrhea were randomized in a double-blind, placebo-controlled, crossover trial to receive L-glutamine at 30 g/day or a placebo for 10 days. In this study the L-glutamine significantly reduced the severity of nelfinavir-associated diarrhea and produced improved quality of life compared with placebo.71

Another study of 45 severely bumed adults found that those randomized to receive enteral glutamine experienced a reduction in blood infection by a factor of 3, and mortality risk was lowered.” Another investigation of burned patients whose total body surface bums ranged from 50% to 80% and third-degree burns ranged from 20% to 40% but who did not have respiratory injuries found improved gut permeability, initially decreased plasma endotoxin levels, and reduced ho~pitalization.7~

Peptic Ulcers

Low-Birth-Weight Infants

Cabbage juice, a key source of glutamine, has been well documented as having remarkable success in treating peptic ulcers. One liter per day of the fresh juice, taken in divided doses, resulted in total ulcer healing in an average of only 10 days. Further research has shown that the high glutamine content of the juice is probably responsible for the efficacy of cabbage in treating these ulcers. In a double-blind clinical study of 57 patients, 24 using 1.6 g/day of glutamine and the rest using conventional therapy (antacids, antispasmodics, milk, and bland diet), glutamine proved to be the more effective treatment. Half of the glutamine patients showed complete healing (according to radiographic analysis) within 2 weeks, and 22 of the 24 showed complete relief and healing within 4 weeksu Although the mechanism for these results is unknown, it is postulated by the authors to be due to the role of glutamine in the biosynthesis of the hexosamine moiety in certain mucoproteins. These moieties may stimulate mucin synthesis, which would benefit peptic ulcer patients.

Infants with a birth weight of less than 1000 to 1500 g may be especially susceptible to glutamine depletion, as nutritional supply of glutamine is limited in the first weeks after birth. This may increase morbidity by contributing to problems with gut integrity, as well as immune suppre~sion.~ One study of 35 ill preterm neonates of less than 1000 g were randomized to receive either glutamine-supplemented parenteral nutrition or standard parenteral nutrition. Although there were no significant differences between the groups in white cell count, differential white cell count, blood urea nitrogen, plasma ammonia, lactate, pyruvate, plasma glutamine, or glutamate, the median time to achieving full enteral nutrition was shorter in the glutamine group (13 days vs. 21 days). Parenteral glutamine was well tolerated and considered safe for these preterm neonates.75 However, other studies have found that formula supplemented with glutamine in growing preterm infants is entirely metabolized in the gut and does not have a discernable effect on whole-body protein and nitrogen kinetic^.'^ A large multicenter, double-blind, randomized trial of infants with a birth weight of 401 to 1000 g were given either a control or 20% isonitrogenous solution by parenteral nutrition for up to either 120 days of age, death, or discharge from the hospital. Of the 721 infants who were assigned to glutamine supplementation, 370 (51%)died or developed late-onset sepsis, as compared with 343 of the 712 infants (48%) assigned to control. Although no adverse effects were noted as a result of being given glutamine, this study demonstrated that glutamine did not decrease mortality. This study and others also found no reduction in the incidence of sepsis in these young patient^.^,^^

Severe Burns Plasma glutamine levels have been demonstrated to be profoundly decreased after severe bums in adults. This may at least partially explain the impaired cellular immunity that is seen in bum patients. Bum victims given glutamine have shown better intestinal repair, a higher quality of wound healing, and reduced hospitalization. In one study, 48 severe bum patients were randomly divided into two groups: a control group that took a placebo and a glutamine-treated group that received 0.5 g of glutamine/kg body weight/day, both for 14 days. After taking glutamine for 14 days, plasma glutamine concentration was sigruf~cantly increased in the glutamine group than in the control group. In addition, a greater quality of wound healing as well as shorter hospital stays were experienced in the glutamine-treated bum patients.“ In another study, dosage of L-glutamine at 0.6 g/kg/ day did not result in an immediate whole body protein gain (an important factor in a bum patient’s convalescence) and resulted in an insignificant increase in plasma glutamine? However, this study measured only the first 48 hours, which may not have been enough time to show a long-term benefit.

Exercise and Weight Lifting Glutamine is considered to have an anabolic effect on skeletal muscle. Given the benefits on glutathione reserves, protein catabolism, and intestinal integrity, some glutamine enthusiasts believe that glutarnine supplementation may be useful for exercise and strength training as well. One small study suggests that oral glutamine increases growth hormone re1ea~e.I~ Even so, clinical trials studying glutamine as an exercise performance enhancer are not encouraging.

A double-blind, placebo-controlled, crossover study had six resistance-trained men lift weights after the ingestion of glutamine or glycine at 0.3 g/kg body weight or a placebo. One hour after ingestion, subjects performed four total sets of exercise to momentary muscular failure including two sets of leg presses at 200% of body weight and two sets of bench presses at 100% of body weight. Despite glutamine's possible role in exercise, there were no actual differences in the average number of maximal repetitions performed in the leg press or bench press exercises among these three groups.79Other studies using 0.3 to 0.9 g per kilogram of body weight also demonstrated no changes in exercise performance, body composition, or muscle protein degradation in young healthy adults.8°,81It is possible that beneficial effects of glutamine are best detected only in patients with chronic illness and those with compromised physiology instead of normal, healthy individuals.

Cardiac Disease Cardiac disease is a recognized stress on the physiology of the gastrointestinal and immune system. Animal studies have supported the notion that glutamine can help recovery from cardiac ischemia and help the heart recover after reperfusion injury.82,83As noted earlier, glutamine can protect the heart from damage due to chemotherapy regimens by its glutathione-replenishing effect (see earlier discussion on chemotherapy and radiation side effects).19Also noted earlier are the benefits to the gastrointestinal system in those heart patients experiencing ischemic gut episodes after cardiac by pas^.^"^ Animal research shows that greater levels of plasma glutamine also prevent decreases in the ratio between adenosine triphosphate to adenosine diphosphate in myocardial tissue.83 Unfortunately, little research has been done to evaluate the clinical use of glutamine in various cardiac situations. One investigation of patients with chronic stable angina received a single 80 mg/kg oral dose of glutamine or a placebo in a double-blind, random fashion 40 minutes before a standard exercise test. This single dose of glutamine significantly increased plasma glutamine concentration from 419 to 649 pmol/L. Moreover, the glutamine appeared to encourage positive changes in ST depression on the echocardiogram.83 Clearly, more research is required, but given that heart disease is the leading reason for mortality, natural and safe treatments like glutamine should be further explored.

Other Conditions A number of other medical conditions such as alcoholism, pancreatitis, and brain injury will further adversely affect the health of a patient who already has protein and energy

needs and is more susceptible to infection. Although more studies are necessary, the following includes a few interesting conditions not mentioned earlier. In alcoholics, glutamine supplementation (1 g/day) has been shown to reduce voluntary alcohol consumption in uncontrolled human studies and experimental animal ~ t u d i e s . ~ Despite -~' the fact that this research is about 50 years old, there has never been any follow-up to these preliminary studies. This is unfortunate, as the results were quite promising, finding glutamine to be safe and relatively inexpensive. Related to alcoholism in many patients, individuals with acute pancreatitis have also benefited from parenteral glutamine treatment with improvement in immune function, decreased systemic inflammation, and a trend toward shorter hospital stays.' In an interesting study of 20 brain injury patients, 10 subjects were randomized to receive either an early enteral diet or the same formula with glutamine and probiotic added for a range of 5 to 14 days. The infection rate was found to be loo%, but only 50% in the glutamine group. The median number of infections per patient was significantly greater in the control group compared with the study group. Critical care stay and ventilation requirements were more than halved in the treatment group (10 days vs. 22 days, and 14 days vs. 7 days, respectively). Interestingly, probiotics were also used in the treatment group. This synergistic enhancement in gut flora may be useful to augment the already known benefits of glutamine.88

DOSAGE The typical oral dosage of glutamine is 100 mg three times a day, although the delivery method and actual effective dosage should be condition specific, meaning dosages are often much higher. The following points serve as guidelines: Severebums: enteral dosage for individuals with severe burns has been approximately 0.5 g/kg/day in most studies Preventing and treating the side effects of chemotherapy involves the following: Patients treated with 5-flurouracil have received up to 18 g/day 5 days before, then during, and 5 days after treatment" High-dose chemotherapy after stem cell transplantation: total parenteral nutrition enriched with glutamine 20 gZ6 Oral mucositis: 16 g in 240 ml normal saline is mixed, and 30 ml is swished four times a d a y 7 Esophageal cancer radiotherapy: was given with a successful adjunctive oral glutamine supplement of 30 g/day for 4 weeks5

Cachexia patients have been tested with dosages of 14 g/day combined with other amino acids63 Pediatric oncology patients: 0.65 g/kg was found to be a safe dose of glutamine to use in a clinical study in pediatric oncology patientss9 Children with acute diarrhea: 0.3 g/kg/day has been used suc~essfully~~ Peptic ulcers: drinking 1 L a day in divided doses is sufficient or 1.6 g/day for 1 monthB HIV patients: 30 to 40 g glutamine/day to prevent medication associated diarrhea, and to improve intestinal permeability70*71; coadministration of antioxidants may also be helpful Postabdominal surgeries: glutamine can be dissolved in warm water and taken orally or by gastric tube after the operation at 30 g/day for 7 daysM

In one pediatric oncology patient, a single dose of 0.75/kg was found to raise the blood ammonia level to an unacceptably high limit. Related to this, it was difficult to disperse the glutamine adequately at this dose, resulting in the suspension being found unpalatable.

Glutamine, even at high doses, is without apparent side effects and is well tolerated.4S2

In cancer treatment, glutamine does not appear to change the efficacy of cancer drugs, rate of relapse, or progression of malignancy.61Some animal studies suggest that glutamine supplementation may even preferentially increase tumor retention of methotrexate, thus increasing the therapeutic window of this drug?O Many antiseizure medications including phenobarbital, phenytoin, carbamazepine, primidone, and valproic acid work to block glutamate activity in the brain. Because glutamine can convert to glutamate, clinicians should be cautious when using glutamine in patients using these medications.

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TOXICITY

Glutamine standard peptide-based feeding in critically ill patients. Am J Clin Nutr 1996;64:615-621. 25. Hiscock N, Petersen EW, Krzywkowski K, et al. Glutamine supplementation further enhances exercise-induced plasma IL-6.J Appl Physiol2003;95145-148. 26. Piccirillo N, De Matteis S, Laurenti L, et al. Glutamine-exuiched parenteral nutrition after autologous peripheral blood stem cell transplantation: effects on immune reconstitution and mucositis. Haematologica 2003;88192-200. 27. Noyer CM, Simon D, Borczuk A. A doubleblind placebo-controlled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS.Am J Gastroenterol1998;93972-975. 28. Buhner S,Reese I, Kuehl F, et al. Pseudoallergicreactions in chronic urticaria are assodated with altered gastroduodenal permeability. Allergy 2004;591118-1123. 29. Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors.Autoimmun Rev 2004;3394-400. 30. Peeters M, Geypens B, Claus D, et al. Clustering of increased small intestinal permeability in families with Crohn‘s disease. Gastroenterology 1997;113802-807. 31. Puspok A, Oberhuber G, Wyatt J, et al. Gastroduodenalpermeability in Crohn’s disease. Eur J Clin Invest 1998;2867-71. 32. Smecuol E, Bai JC, Vazquez H, et al. Gastrointestinal permeability in celiac disease. Gastroenterology 1997;112:1129-1136. 33. Di Leo V, Venturi C, Baragiotta A, et al. Gastroduodenaland intestinal permeability in primary biliary cirrhosis.Eur J Gastroenterol Hepatol2003;15967-973. 34.Campillo B, Pemet F’, Bories PN, et al. Intestinal permeability in liver cirrhosis: relationship with severe septic complications.Eur J GastroenterolHepatol1999;11:755-759. 35. Catanoso M, Lo Gull0 R, Giofre MR, et al. Gastro-intestinalpermeability is increased in patients with limited systemic sclerosis. Scand J Rheumatol2001;30:77-81. 36. Vaarala 0. The gut immune system and type 1 diabetes. Ann N Y Acad Sci 2002;958:39-46. 37. Katz JP, Lichtenstein GR. Rheumatologic manifestations of gastrointestinal diseases. Gastroenterol Clin North Am 1998;27 533-562. 38. Parke AL. Gastrointestinal disorders and rheumatic diseases. Curr Opin Rheumatol1991;3160-165. 39. van Elburg RM, Uil JJ, van Aalderen WM, et al. Intestinal permeability in exocrine pancreatic insufficiencydue to cystic fibrosis or chronic pancreatitis. Pediatr Res 1996;39:985-991. 40.KeshavarzianA, Holmes EW, Pate1 M, et al. Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am J Gastroenterol1999;94200-207. 41. Hijazi 2, Molla AM, Al-Habashi H, et al. Intestinal permeability is increased in bronchial asthma. Arch Dis Child 2004;89227-229. 42. Uil JJ, van Elburg RM, van OverbeekFM, et al. Clinical implications of the sugar absorption test intestinal permeability test to assess m u d barrier function. Scand J Gastroenterol Suppll997;223:70-78. 43. Weber P, Brune T, Ganser G, et al. Gastrointestinal symptoms and permeability in patients with juvenile idiopathic arthritis. Clin Exp Rheumatol2003;21:657-662. 44.Deitch EA. Intestinal permeability is increased in burn patients shortly after injury. Surgery 1990;107411-416. 45. Kiziitas S, Imeryuz N, Gurcan T, et al. Corticosteroid therapy augments gastroduodenal permeability to sucrose.Am J Gastroenterol 1998;932420-2425. 46.Riddington DW, Venkatesh B, Boivin CM, et al. Intestinal permeability, gastric intramucosal pH, and systemic endotoxemia in patients undergoing cardiopulmonary bypass. JAh4A 1996;275 1007-1012. 47. Sindair DG, Haslam PL, Qumlan GJ, et al. The effect of cardiopulmonary bypass on intestinal and pulmonary endothelial permeability. Chest 1995;10871&724.

48. Gotteland M, Araya M, Pizarro F, et al. Effect of acute copper exposure on gastrointestinalpermeability in healthy volunteers. Dig Dis Sci 2001;46:1909-1914. 49. Videm V, SvennevigJL, Fosse E, et al. Plasma endotoxin concentrations during cardiac surgery may be related to atherosclerosis. Perfusion 2000;15:421426. 50. Brooks HW,White DG, Wagstaff AJ, et al. Evaluation of a glutamine-containing oral rehydration solution for the treatment of calf diarrhea using an Escherichia coli model. Vet J 1997;153: 163-169. 51. Yalcin SS,Yurdakok K, Tezcan I, et al. Effect of glutamine supplementation on diarrhea, interleukin-8 and secretory immunoglobulin A in children with acute diarrhea. J Pediatr Gastroenterol Nutr 20O4;38494501. 52. Majamaa H, Isolauri E, &elin M, et al. Lactic acid bacteria in the treatment of acute rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr 1995;20333-338. 53. Matarese LE, Seidner DL, Steiger E. Growth hormone, glutamine, and modified diet for intestinal adaptation. J Am Diet Assoc 2004;104:1265-1272. 54.QUan ZF, Yang C, Li N, et al. Effect of glutamine on change in early postoperative intestinal permeability and its relation to systemic inflammatory response. World J Gastroenterol 2004;lO: 1992-1994. 55. Byme TA, MorrisseyTB, Nattakom TV,et al. Growth hormone, glutamine, and a modified diet enhancenutrient absorption in patients with severe short bowel syndrome. JF’EN J Parenter Enteral Nutr 1995;19296-302. 56. Wu GH, Wang H, Zhang YW, et al. Glutamine supplemented parenteral nutrition prevents intestinal ischemia-reperfusioninjury in rats. World J Gastroenterol2004;10:2592-2594. 57. Huang EY, Leung SW, Wang CJ, et al. Oral glutamine to alleviate radiation-induced oral mucositk a pilot randomized trial. Int J Radiat Oncol Biol Phys 2OOO;46535-539. 58. Anderson PM, schrwder G, Skubitz KM. Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy.Cancer 1998;831433-1439. 59. Scheid C, Hermann K, Kremer G, et al. Randomized, double-blind, controlled study of glycyl-glutamine-dipeptidein the parenteral nutrition of patients with acute leukemia undergoing intensive chemotherapy.Nutrition 2004;20249-254. 60.Bozzetti F, Biganzoli L, Gavazzi C, et al. Glutamine supplementation in cancer patients receiving chemotherapy: a double-blind randomized study. Nutrition 1997;13748-751. 61. Anderson PM, Ramsay NK,Shu XO, et al. Effect of low-dose oral glutamine on painful stomatitisduring bone marrow transplantation. Bone Marrow Transplant 1998;22339-344. 62. Kozelsky TF, Meyers GE, Sloan JA. North Central Cancer Treatment Group. Phase III double-blind study of glutamine versus placebo for the prevention of acute diarrhea in patients receiving pelvic radiation therapy. J Clin Oncol2003;21:1669-1674. 63. May PE, Barber A, DOlimpio JT, et al. Reversal of cancer-related wasting using oral supplementation with a combination of betahydroxy-beta-methylbutyrate,arginine, and glutamine. Am J Surg 2002;183471-479. 64.Klimberg VS, Souba WW, Salloum RM, et al. Glutamine-enriched diets support muscle glutamine metabolism without stimulating tumor growth. J Surg Res 1990;48:319-323. 65. Kaufmann Y, Kornbluth J, Feng 2,et al. Effect of glutamine on the initiation and promotion phases of DMBA-induced mammary tumor development.JPEN J Parenter Enteral Nutr 2003;27411-418. 66. Dwyer JT. Nutrition support of HIV+ patients. Henry Ford Hosp Med J 1991;39:60-65. 67. Klimberg VS, Souba WW, Dolson DJ, et al. Prophylactic glutamine protects the intestinal mucosa from radiation injury. Cancer 1990;6662-68.

Pharmacology of Natural Medicines 68. Shabert JK, W h o r e DW. Glutamine deficiency as a cause of human immunodeficiencyvirus wasting. Med Hypothe~e~ 1996;46:252-256. 69. Noyer CM,S i o n D, Boruuk A, et al. A double-blind placebocontrolled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS. Am J Gastroenterol 199893: 972-975. 70. Shabert JK, Wmlow C, Lacey JM, et al. Glutamineantioxidant supplementationincreases body cell mass in AIDS patients with weight loss: a randomized, double-blind controlled trial. Nutrition 1999; 15860-864. 71. Huffman FG, W a l ME. ~ L-glutamine supplementation improves nelfinavir-associated diarrhea in HIV-infected individuals. HIV C l i Trials 2003;4324329. 72. Peng X, Yan H, You Z, et al. Effects of enteral supplementation with glutamine granules on intestinal mucosal barrier h c t i o n in severe burned patients. Bums 2004;30:135-139. 73. Garrel D, Patenaude J, Nedelec B, et al. Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med 200331:2444-2449. 74. Zhu M, Tang D, Zhao X, et al. [Impact of glutamine of gut permeability and clinical prognosis on the aging patients undergoing gastric-intestinal operation.] Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2000;22:425-427. 75.Thompson SW, McClure BG, Tubman TR. A randomized, controlled trial of parenteral glutamine in ill, very low birth-weight neonates. J Pediatr Gastroenterol Nutr 200337550-553. 76. Parimi PS,Devapatla S, Gruca LL, et al. Effect of enteral glutamine or glycine on whole-body nitrogen kinetics in very-low-birthweight infants. Am J Clin Nutr 2004;79:402-409. 77. Poindexter BB, Ehrenkranz RA, Stoll BJ, et al. National Institute of Child Health and Human Development Neonatal Research Network. Parenteral glutamine supplementation does not reduce the risk of mortality or late-onset sepsis in extremely low birth weight infants. Pediatrics 2004;113:1209-1215.

78. Vaughn P, Thomas,'F Clark R, et al. Enteral glutamine supplementation and morbidity in low birth weight infants. J Pediatr 2003;142:662-668. 79. Antonio J, Sanders MS, Kalman D, et al. The effects of high-dose glutamine ingestion on weightliftingperformance. J Strength Cond R ~ s2002;16157-160. 80. Candow DG, Chilibeck PD, Burke DG, et al. Effect of glutamine supplementation combined with resistance training in young adults. Eur J Appl Physiol2001;86:142-149. 81. Haub MD, Potteiger JA, Nau KL, et al. Acute L-glutamine ingestion does not improve maximal effort exercise. J Sports Med Phys Fitness 1998;38:240-244. 82. Khogali SE, Harper AA, LyaU JA, et al. Effects of L-glutamine on post-ischaemic cardiac fundion: protection and rescue. J Mol Cell Cardiol199830819-827. 83. Khogali SE, Pringle SD, Weryk BV, et al. Is glutamine beneficial in ischemic heart disease? Nutrition 2002;18:123-126. 84. Rogers LL, Pelton RB, Williams RJ. Voluntary alcohol consumption by rats following administration of glutamine. J Biol Chem 1955;214503-506. 85. Rogers LL, Pelton RB. Glutamine in the treatment of alcoholism; a preliminary report. Q J Stud Alcohol 1957;18581-587. 86. Ravel JM, Felsing B, Lansford EM, et al. Reversal of alcohol toxicity by glutamine. J Biol Chem 1955;214497-501. 87. Rogers LL, Pelton RB, Williams RJ. Voluntary alcohol consumption by rats following administration of glutamine. J Biol Chem 1955;214503-506. 88. Falcao de Arruda IS, de Aguilar-Nascimento JE.Benefits of early enteral nutrition with glutamine and probiotics in brain injury patients. Clin Sci (Lond) 2004;106:287-292. 89. Ward E, Picton S, Reid U, et al. Oral glutamine in pediatric oncology patients: a dose finding study. Eur J Clin Nutr 2003;57 31-36. 90. Rubio lT,Cao Y, Hutchins LF, et al. Effect of glutamineon methotrexate efficacy and toxicity. Ann Surg 1998;227772-778,

Glycyrrhiza glabra (Licorice) Mchael T. Murray, ND Joseob E. Pizzorno Jr, ND

C H A P T E R C 0 N T E N TS General Description 1003 Chemical Composition 1003 History and Folk Use

1004

Pharmacology 1004 Estrogenic Activity 1004 Pseudoaldosterone Activity 1004 Antiinflammatory and Antiallergic Activity 1004 lmmunostimulatory and Antiviral Effects 1005 Anticancer Effects 1005 Antibacterial Activity 1005 Antihepatotoxic Activity 1005 Memory-EnhancingEffect 1005 Antinephritic Activity 1005 Clinical Applications

Oral Licorice Preparations Containing Glycyrrhizin 1007 Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome 1007 Hepatitis 1007 Acute Intermittent Porphyria 1007 Obesity and Syndrome X 1008 Addison's Disease 1008 Inflammation 1008 Sweetening Agent 1008 Topical Applications 1008 Eczema and Psoriasis 1008 Herpes Simplex 1008 Melasma 1008 Dosage 1008 Dosage Instructions for Deglycyrrhizinated Licorice 1009

1005 Side Effects and Toxicology

Deglycyrrhizinated Licorice 1006 Gastric Ulcers 1006 Duodenal Ulcers 1006 Aphthous Ulcers 1006

Glycyrrhiza glabra (family: Leguminosae) Common names: licorice, glycyrrhiza

GENERAL DESCRIPTION Glycyrrhiza glabra is a perennial, temperate zone herb or subshrub, 3 to 7 feet high, with a long, cylindrical, branched, flexible, and burrowing rootstock with runners. The parts used are the dried runners and roots, which are collected in the fall.

CHEMICAL COMPOSITION The major active component of licorice root is the triterpenoid saponin glycyrrhizin (also known as glycyrrhizic acid or glycyrrhizinic acid, Figure 99-l), which is usually

1009

Drug Interactions 1009

found in concentrations ranging from 6% to 10%. The intestinal flora is believed to hydrolyze glycyrrhizin, yielding the aglycone molecule (glycyrrhetinic acid) and a sugar moiety, resulting in absorption of both.' A processed licorice extract, deglycyrrhizinated licorice (DGL), which is used in the treatment of peptic and aphthous ulcers, is made by removing the glycyrrhizin molecule. The active components of DGL are flavonoids. These compounds have demonstrated impressive protection against chemically induced ulcer formation in animal studies? Other active constituents of licorice include isoflavonoids (e.g., isoflavonol, kumatakenin, licoricone, glabrol), chalcones, coumarins (e.g.,umbelliferone, herniarin), triterpenoids and sterols, lignins, amino acids, amines, gums, and volatile oils?

1003

Pharmacology of Natural Medicines

from soy) are known to possess estrogenic effect. The estrogenic activity of the isoflavones appears to be more sigrulicantthan the estrogen antagonism of glycyrrhetinic acid? Interestingly,these same components inhibit breast cancer cell

Pseudoaldosterone Activity Figure -1

Glycyrrhizinicacid.

HISTORY AND FOLK USE The medicinal use of licorice in both Western and Eastern cultures dates back several thousand years. It was used primarily as a demulcent, expectorant, antitussive, and mild laxative. Licorice is one of the most popular components of Chinese medicines. Its traditional uses include treating peptic ulcers, asthma, pharyngitis, malaria, abdominal pain, insomnia, and

PHARMACOLOGY Licorice is known to exhibit many pharmacologic actions including the following? Estrogenic Aldosterone-like action Antiinflammatory (cortisol-likeaction) Antiallergic Antibacterial, antiviral, and antitrichomonas Antihepatotoxic Anticonvulsive Choleretic Anticancer Expectorant Antitussive activities The majority of these actions are discussed individually later. Although much of the pharmacology focuses on glycyrrhizin and glycyrrhetinic acid, it is worth remembering that licorice has many other components such as flavonoids, which may have significant pharmacologic effects.

Estrogenic Activity Most herbalists generally believe that glycyrrhiza exhibits alterative action on estrogen metabolism (i.e., when estrogen levels are too high, it inhibits estrogen action, and when estrogens are too low, it potentiates estrogen action when used in greater amounts)! Glycyrrhetinic acid has been shown to antagonize many of the effects of estrogens, particularly exogenous e~trogens.~ The estrogenic action of glycyrrhiza is due to its isoflavone content, as many isoflavone structures (e.g., daidzein and genistein

The chronic ingestion of glycyrrhiza in large doses leads to a welldocumented pseudoaldosteronism syndrome (i.e., hypertension,hypokalemia, sodium and water retention, low plasma renin activity, and suppressed urine and serum aldosterone levels).813In normal subjects, the amount of glycyrrhizin needed to produce these side effects is between 0.7 and 1.4 g, which corresponds to approximately 10 to 14 g of the crude herb? Although glycyrrhiza possesses mineralocorticoid activity (about four orders of magnitude lower than aldosterone) and binds to aldosterone receptors, it is largely without effect in adrenalectomized animals or in patients with severe adrenocorticoid insufficiency. Therefore it can be concluded that its primary effects are largely as a result of glycyrrhetinic acid inhibiting the breakdown of aldosterone in the 1i~er.l~ Glycyrrhizin and glycyrrhetinic acid have been shown to suppress 5-beta-reductase, the main enzyme in humans responsible for inactivating cortisol, aldosterone, and progesterone. These effects can be put to good use in the treatment of Addison disease, a severe disease of adrenal insuffi~iency.'~

Antiinflammatory and Antiallergic Activity Glycyrrhiza has signhcant antiinflammatoryand antiallergic activity.15J6 Although both glycyrrhizin and glycyrrhetinicacid bind to glucocorticoid receptors, and much of glycyrrhiza's antiinflammatory activity has been explained by its "cortisol-like effects," many of the effects of glycyrrhiza actually antagonize or counteract Included are antagonism to such actions of cortisol as activation of tryptophan oxygenase, accumulation of hepatic glycogen, stimulation of hepatic cholesterol synthesis, inhibition of thymus atrophy, and inhibition of ACTH synthesis and secretion. Glycyrrhizin does, however, reinforce cortisol's inhibition of antibody formation, stress reaction, and inflammation. Like its mineralocorticoid effect, glycyrrhiza'smajor influence on glucocorticoid metabolism is probably related to its suppression of 5-beta-reductase activity, thus increasing the half-life of cortisol. Glycyrrhetinic acid can also increase the conversion of cortisol to the more powerful cortisone.18 Glycyrrhiza'smajor cortisol-likeeffect relates to its ability to inhibit pho~pholipase-A2.~~ This enzyme is responsible for cleaving lipids from biomembranes for eicosanoid metabolism. In addition to this effect, glycyrrhizin has also been shown to inhibit cyclic adenosine monophosphate (CAMP)-phosphodiesterase,thereby raising CAMP levels and prostaglandin formation by activated

Glycyrrhiza glabra (Licorice)

peritoneal macrophages from rats.20f21Glycyrrhizin has been shown to inhibit experimentally induced allergenic reactions such as the Arthus’ phenomenon, the Schwartzman’s phenomenon, and Forssman’s anaphylaxis and to be an antidote against many toxins including diphtheria, tetanus, and tetrodotoxin.21*22 Glycyrrhizin has exerted antithrombotic effects but does not potentiate the inhibitory activity of antithrombin I11 or heparin cofactor I1 toward thrombinB

lmmunostimulatory and Antiviral Effects Glycyrrhizin and glycyrrhetinic acid have been shown to induce i n t e r f e r ~ nThe . ~ ~induction of interferon leads to significant antiviral activity, as interferons bind to cell surfaces, where they stimulate synthesis of intracellular proteins that block the transcription of viral DNA. The induction of interferon is also followed by activation of macrophages and augmentation of natural killer cell activity. Glycyrrhizin has been shown to directly inhibit the growth of several DNA and FWA viruses in cell cultures (vaccinia, Epstein-Barr, Herpes simplex, Newcastle disease, vesicular stomatitis viruses, SARS-associated coronavirus, and human immunodeficiency virus [HIV]) and to inactivate herpes simplex virus 1 (HSV-1) irreversibly.2528Administration of glycyrrhizin to mice suffering from herpetic encephalitis increased their survival rate on average about 2.5 times, while it reduced HSV-1 replication in the brain to 45.6% of the control.29 Glycyrrhizin, as stated earlier, also inhibits the thymolytic and immunosuppressive action of cortisone. Other licorice components have exerted immunomodulatory effects as well.30

strains), Streptococcus mutans, Mycobacterium smegmatis, Bacillus subtilis, Streptococcus pyogenes, Haemophilus influenzae, Moraxella catarrhalis, and Candida a l b i ~ a n s . ~ ~ , ~ ~ The majority of the antimicrobial effects are due to isoflavonoid components, with the saponins having a lesser antibacterial effect.

Antihepatotoxic Activity Glycyrrhetinic acid inhibits carbon tetrachloride and galactosamine-induced liver damage. The mechanism of action is prevention of nonenzymatic lipid peroxidation and inhibition of the production of free radicals by the enzymatic action of NADPH-cytochrome P450 reductase on CC14.40

Memory-Enhancing Effect Licorice may exert some memory-enhancing effects. In a study in mice, licorice was shown to enhance learning and memory in mice as determined by the elevated plus-maze and passive avoidance paradigm. Furthermore, licorice significantly reversed the amnesia induced by diazepam and scopolamine. Although antiinflammatory and antioxidant properties may contribute favorably to the memoryenhancement effect, since scopolamine-induced amnesia was reversed as well, it is possible that the beneficial effect on learning and memory was due to facilitation of cholinergic transmission.4l

Antinephritic Activity Glabridin, an isoflavan isolated from G. glabra, improved urinary protein excretion, total cholesterol, serum creatinine, and blood urea nitrogen levels after its oral administration to mice with glomerular disease.42

Anticancer Effects

CLINICAL APPLICATIONS

Licorice components exert a wide range of anticancer effects.31The most active appear to be the flavonoids and coumarins. For example, isoliquiritigenin has been shown to suppress colon cancer in mice via markedIy decreasing both prostaglandin E2 and nitric oxide (NO) production in mouse macrophage Isoliquiritigenin was also shown to significantly inhibit the proliferation of prostate and breast cancer cell lines in dosedependent and time-dependent manners.7~~~ Isoliquiritigenin also signhcantly reduced pulmonary metastasis in mouse renal cell carcinoma and prevented the leukocytopenia caused by administration of 5-fl~orouracil.~ A coumarin compound, identified as licocoumarone, was shown to the factor in licorice that induces a p o p t ~ s i s . ~ ~

Licorice is a component of more traditional Chinese and Japanese herbal formulas than any other herb. Though extremely pharmacologically diverse, the current clinical applications of licorice can be divided into three main categories:

Antibacterial Activity Alcohol extracts of glycyrrhiza have displayed antimicrobial activity in vitro against Helicobacter pylori, Staphylococcus aureus (including antibiotic resistant

Use of DGL Use of oral licorice preparations containing glycyrrhizin Use of topical preparations containing glycyrrhetinic acid The key use of DGL is in ulcerative conditions of the gastrointestinal tract (e.g., peptic ulcers, canker sores, inflammatory bowel disease), while the key uses of oral licorice containing glycyrrhizin include viral infections (e.g., the common cold, HIV, and acquired immunodeficiency syndrome (AIDS), viral hepatitis); premenstrual syndrome (PMS) and menopause; acute intermittent porphyria; Addison’s disease; inflammation; syndrome X; and as a sweetening agent. Topical preparations

containing glycyrrhetinic acid can be used in eczema, psoriasis, herpes, and melasma.

DEGLYCYRRHIZINATED LICORICE By far, the most popular medicinal use of licorice in the United States is in the treatment of peptic ulcers with DGL (deglycyrrhizinated licorice). Although glycyrrhetinic acid was the first drug proven to promote healing of gastric and duodenal ulcers,43most physicians using licorice in the treatment of peptic ulcers now use DGL. DGL was actually shown to be more effective than glycyrrhetinic acid, without side effects.44 DGL's mode of action is different than that of current drugs such as antacids and H2-receptor antagonists, which focus on reducing gastric acidity. Though effective, these treatments can be expensive, carry some risk of toxicity, disrupt normal digestive processes, and alter the structure and function of the cells that line the digestive tract. The latter factor is just one of the reasons why peptic ulcers develop again if antacids, cimetidine, ranitidine, and similar drugs are used. Rather than inhibit the release of acid, DGL stimulates the normal defense mechanisms that prevent ulcer formation and stimulate healing of the damaged mucous membranes. Specifically,DGL increases the following45,&: The blood supply to the damaged mucosa The number of cells producing the mucous that protects the mucous membranes The amount of mucous the cells produce The life span of the intestinal cell

In addition, several flavonoid components of G. glubra have shown significant activity against H.pylori including antibiotic-resistant strains.%

Gastric Ulcers Nunemus clinical studies over the years have found DGL to be an effective antiulcer compound. DGL has been shown to be extremely effective in the treatment of gastric In one study, 33 gastic ulcer patients were ulcer~.4~-~l treated with either DGL (760 mg, three times a day) or a placebo for 1 month.50There was a sigruficantly greater reduction in ulcer size in the DGL group (78%)than in the placebo group (34%).Complete healing occurred in 44% of those receiving DGL, but only in 6% of the placebo group. In several head-to-head comparison studies, DGL has been shown to be more effective than cimetidine (Tagamet), ranitidine (Zantac), or antacids in both shortterm treatment and maintenance therapy of peptic u l ~ e r s . 4 ~However, ,~5~ although these drugs are associated with sigruficant side effects (see earlier), DGL is extremely safe and is only a fraction of the cost. Subsequentstudieshave shown DGL to be as effective as Tagamet and Zantac for both short-term treatment and

maintenance therapy of gastric For example, in a head-to-head comparison with Tagamet, 100 patients received either DGL (760 mg, three times a day between meals) or Tagamet (200 mg, three times a day, and 400 mg at bedtime).4sThe percentage of ulcers healed after 6 and 12 weeks were similar in both groups. Whereas Tagamet is associated with some toxicity, DGL is extremely safe to use. Gastric ulcers are often a result of using alcohol, aspirin or other nonsteroidal antiinflammatory drugs, caffeine, and other factors that decrease the integrity of the gastric lining. As DGL has been shown in human studies to reduce the gastric bleeding caused by aspirin, DGL is strongly indicated for the prevention of gastric ulcers in patients requiring long-term treatment with ulcerogenic drugs such as aspirin, nonsteroidal antiinflammatory agents, and corticosteroids.5l

Duodenal Ulcers DGL is also effective in duodenal ulcers. This is perhaps best illustrated by one study in patients with severe duodenal ulcers: 40 patients with chronic duodenal ulcers of 4 to 12 years' duration and more than six relapses during the previous year were treated with All of the patients had been referred for surgery because of relentless pain, sometimes with frequent vomiting, despite treatment with bed rest, antacids, and anticholiiergic drugs. Half of the patients received 3 g of DGL daily for 8 weeks; the other half received 4.5 g/day for 16 weeks. All 40 patients showed substantial improvement, usually within 5 to 7 days, and none required surgery during the 1year follow-up. Although both dosages were effective, the higher dose was sigruficantly more effective than the lower dose. In another more recent study, the therapeutic effect of DGL was compared with that of antacids or cimetidine in 874 patients with confirmed chronic duodenal ulcers.52 Ninety-one percent of all ulcers healed within 12 weeks; there was no sigruficant difference in healing rate in the groups. However, there were fewer relapses in the DGL group (8.2%) than in those receiving cimetidine (12.9%) or antacids (16.4%).These results, coupled with DGL protective effects, suggest that DGL is a superior treatment of duodenal ulcers.

Aphthous Ulcers Recurrent aphthous stomatitis (canker sores) is a common problem. DGL may be effective in promoting healing. In one study, 20 patients were instructed to use a solution of DGL as a mouthwash (200 mg powdered DGL dissolved in 200 ml warm water) four times daily? Fifteen of the 20 (75%)experienced 50%to 75%improvement within 1 day, followed by complete healing of the ulcers by the third day. DGL in tablet form may produce even better results.

Glycyrrhiza glabra (Licorice)

The result of glycyrrhizin in HIV-positive and AIDS patients is almost immediate improvement in immune function. In one study, nine symptom-free HIV-positive patients received 200 to 800 mg glycyrrhizin in vitro The most popular use of oral licorice preparations containing glycyrrhizin is in the treatment of viral illnesses, daily. After 8 weeks, the groups had increased T helper cells, improved helper /suppressor ratios, and improved particularly the common cold. Licorice has long been liver function.60 used in this application. This historical use is justified by In another study, six AIDS patients received 400 to its immune-enhancing and antiviral effects. In addition, licorice components were shown to exert antibacterial 1600 mg glycyrrhizin in vitro daily61After 30 days, five of the six showed a reduction or disappearance of the action against the common pathogens Streptococcus pyogenes, Haemophilus influenzae, and Moraxella ~atarrhalis.5~ P24 antigen, which indicates active disease. The results of these studies and others in HIV-positive and AIDS Another popular use of licorice is in the treatment of patients are encouraging. gynecologic issues, primarily PMS and menopause. Regarding PMS, because glycyrrhizin and glycyrrhetinic Hepatitis acid possess antiestrogeniceffect and suppress the breakSome studies of HIV patients used an intravenous glydown of progesterone, administration of licorice 2 weeks cyrrhizin-containingp d u c t , Stronger NeominophagenC before the onset of menstruation (the midluteal phase) (SNMC), consisting of 0.2% glycyrrhizin, 0.1% cysteine, may help to reduce PMS symptomatology. Clinical trials and 2.0%glycine in physiologic saline solution. This prcdhave shown that taking licorice containing herbal combiuct is used in Japan primarily for the treatment of hepanations is useful in dysmenorrhea.% Isoflavones from glycyrrhiza have shown an ability to inhibit serotonin titis. The other components, glycine and cysteine, appear to modulate glycyrrhizin's actions. Glycine has been reuptake and therefore may also exhibit some antideshown to prevent the aldosterone effectsof glycyrrhizin, pressant effects in PMS.57 while cysteine aids the liver in detoxification reactions. Human ImmunodeficiencyVirus and In addition to AIDS,SNMC has demonstrated benefiAcquired Immunodeficiency Syndrome cial results in treating chronic hepatitis B and c, often difficult infections for the body to clear.22,62-61 Specifically, Glycyrrhizin-containing preparations are showing promise in the treatment of HIV-related diseasesincluding SNMC has been shown to improve liver function and lower levels of liver enzymes. Glycyrrhizin therapy AIDS. Although much of the research has featured intraappears particularly helpful in patients with chronic venous administration, this route of administration may hepatitis C who fail to respond to interferon and in those not be necessary, as glycyrrhizin and glycyrrhetinic acid who cannot be treated with it for various reasons. are easily absorbed orally and are well tolerated. This is most evident in a recent double-blind study on the clinical effectiveness of glycyrrhizin by long-term oral adminis- Acute Intermittent Porphyria This disorder of heme biosynthesis is characterized by tration to 16 hemophiliac patients with evidence of HIV recurrent attacks of neurologic and psychiatric dysfuncinfection.58Patients received daily doses of 150 to 225 mg tion. The symptoms include the following: of glycyrrhizin for 3 to 7 years. Helper and total T-lymphocyte numbers, other immune Abdominal complaints of nausea, vomiting, and colicky system parameters, and glycyrrhizin and glycyrrhetinic pain, occasionallysevere enough to present as an acute acid levels in the blood were monitored. The results indiabdomen without fever or leukocytosis cated that orally administered glycyrrhizin was converted Variable neurologic signs and symptoms (e.g., paresinto glycyrrhetinic acid, which was detected in sera, thesia, hypesthesia, neuritic pain, wrist or foot drop, without manifesting any side effect. None of the patients loss of deep tendon reflexes) given the glycyrrhizin had progression of immunologic Variable mental and emotional disturbances, typically abnormalities or development to AIDS. In contrast, the restlessness, disorientation, and visual hallucinations group not receiving glycyrrhetinicacid showed decreases (seen in one third of patients) in helper and total T-cell counts and antibody levels. Two of the 16 patients in the control group develAs estrogens are known to exacerbate or induce acute oped AIDS. intermittent porphyria (AIP), it is quite possible that In another study, 10 HIV positive patients without some of the so-called PMS symptoms are exacerbations AIDS took 150 to 225 mg glycyrrhizin daily.59After 1to of AIP due to the midcycle estrogen surge. A partial (50%) deficiency of uroporphyrinogen I 2 years, none developed symptoms associated with AIDS synthase results in increased inducibility of aminoleor Armrelated complex (ARC), while 1 of 10 patients vulinic acid (ALA) synthase by drugs and foreign chemof a matched control group developed ARC and 2 proicals and by 5-beta-reductase steroid metabolites (potent gressed to AIDS and subsequently died.

ORAL LICORICE PREPARATIONS CONTAINING GLYCYRRHIZJN

inducers of ALA synthase). AIP is also associated with a marked deficiency in the activity of 5-alpha-reductase, resulting in increased 5-beta-reductase activity? Glycyrrhetinic acid and glycyrrhizin have been shown to sigruficantly reduce 5-beta-reductase while increasing 5-alpha-red~ctase.~ (Lead also increases 5-beta-reductase activity, resulting in a presenting picture similar to AIP.& Chronic or acute lead toxicity must be ruled out in these patients.)

Obesity and Syndrome X Preparations containing glycyrrhetinic acid may be effective in reducing various issues related to syndrome X or metabolic syndrome. For example, in a preliminary study, 15 normal-weight subjects (7 males, 22 to 26 years old, and 8 females, 21 to 26 years old) who consumed for 2 months 3.5 g a day of a commercial preparation of licorice containing glycyrrhetinic acid reduced body fat mass by 1.2%in men and 2.8% in w0men.6~This weight loss may be mediated not only via suppressing renin activity and aldosterone levels via inhibition of ll-betahydroxysteroid dehydrogenase, but also via improving blood glucose control-a key goal in syndrome X.@-’O In another study, supplementation of a licorice root extract to moderately hypercholesterolemic patients for 1 month reduced plasma susceptibility to oxidation (by 190/,).It also increased resistance of plasma LDL against three major atherogenic modifications: oxidation (by 55%), aggregation (by 28%), and retention (by 25%). It reduced plasma cholesterol levels (by 5%), which was due to a 9% reduction in plasma LDL cholesterol levels, and reduced (by 14%) plasma triglyceride levels. Licorice extract supplementation also reduced systolic blood pressure by

Addison’s Disease As described earlier, licorice exerts an ”aldosterone-like effect” that is useful in treating Addison‘s disease.

Inflammation Virtually any inflammatory or allergic condition may be reduced by licorice by the mechanisms discussed earlier in the section on pharmacology. Historically, licorice has been successfully used for treating asthma and other atopic c~nditions.~**~ Licorice has been shown to enhance the action of corticosteroids like prednisone and prednisolone, as well as the levels of the body’s own corticosteroids.R,n In one study, six subjects received an intravenous dose of prednisolone with or without 200 mg glycyrrhizin. Glycyrrhizin was found to increase significantly the concentration of total and free prednisolone by inhibiting its breakdown. Furthermore, the effects of prednisolone appeared to be potentiated by glycyrrhizin.”

Sweetening Agent As glycyrrhizin is 50 to 100 times sweeter than sucrose, licorice can be used as a sweetening or flavoring agent to mask the bitter taste of other medications3

TOPICAL APPLICATIONS Eczema and Psoriasis Glycyrrhetinicacid exerts an effect similar to that of topical hydrocortisone in the treatment of eczema, contact and allergic dermatitis, and psoriasis. In fact, in several studies, glycyrrhetinic acid was shown to be superior to topical cortisone, especially in chronic cases. For example, in one study of patients with eczema, 93% of the patients applying glycyrrhetinic acid demonstrated improvement compared with 83% using cortisone.74 In another study, a topical gel containing 2% glycyrrhetinic acid was shown to be effective for treatment of atopic dermatitis and was more effective than in reducing the scores for erythema, edema, and itching over 2 weeks compared with preparations containing 1% glycyrrhetinic acid.75 Glycyrrhetinic acid can also be used to potentiate the effects of topically applied hydrocortisone by inhibiting the ll-beta-hydroxysteroid dehydrogenase, which catalyzes the conversion of hydrocortisone to an inactive ~ O I T I It - Ialso . ~ ~increases ,~ the permeation of topically applied steroids. In one study, glycyrrhetinic acid in a concentration of 0.1% in gel increased diclofenac sodium flux value 10-fold compared with a control gel.78

Herpes Simplex Clinical studies have shown topical glycyrrhetinic acid and derivatives to be quite helpful in reducing the healing time and pain associated with cold sores and genital herpes.m*sO As mentioned earlier, glycyrrhizin inactivates HSV-1 irreversibly and stimulates the synthesis and release of interferon.25

Melasma Two components, glabrene and isoliquiritigenin, can inhibit tyrosinase-a key enzyme in melanin biosynthesis.8I Dermatologic disorders such as melasma, age spots, and sites of actinic damage arise from the accumulation of melasma. Glabrene and isoliquiritigenin may serve as candidates for skin-lightening agents.

DOSAGE The dosage of licorice for most clinical applications is based on the content of glycyrrhetinic acid. The exception is in the treatment of peptic ulcer. In this application, deglycyrrhizinated licorice (DGL) is preferred, as it

Glycyrrhiza glabra (Licorice)

produces equally effective results compared with glycyrrhetinic acid but is free from any side effects. For most purposes, the goal is to achieve a high level of glycyrrhetinic acid in the blood without producing side effects (discussed later). In general, the following dosages three times a day are safe and effective in raising glycyrrhetinic acid levels: Powdered root: 1to 2 g Fluid extract (1:l):2 to 4 ml Solid (dry powdered) extract (4:l): 250 to 500 mg In the treatment of AIDS, pure glycyrrhetinic acid products or extracts standardized for glycyrrhetinic acid are recommended. Toxicity can become a problem for patients taking licorice for any period longer than 1month (see Side Effects and Toxicology).

Dosage Instructions for Deglycyrrhizinated Licorice In order to be effective in healing peptic ulcers, it appears that DGL must mix with saliva. DGL may promote the release of salivary compounds, which stimulate the growth and regeneration of stomach and intestinal cells. DGL in capsule form has not been shown to be effective?2,83 The standard dosage for DGL is two to four 380-mg chewable tablets between or 20 minutes before meals. Taking DGL after meals is associated with poor results.84 DGL should be continued for 8 to 16 weeks, depending on the response.

SIDE EFFECTS AND TOXICOLOGY The main hazards of licorice administration are due to the aldosterone-like effects of glycyrrhetinic acid. If ingested regularly, licorice root (>3 g/day for more than 6 weeks) or glycyrrhizin (>lo0 mg/day) may cause sodium and water retention, hypertension, and hypokalemia.8,9,s87 Individuals with existing hypertension may be more predisposed to this effect via increased sensitivity to the inhibition of 11-beta-hydroxysteroiddehydrogenase by glycyrrhetinic acid.fsJ”’ Monitoring of blood pressure and electrolytes and increasing dietary potassium intake is suggested, as the pseudoaldosterone effects can be quite sigruficant. The maximal effect on blood pressure with chronic ingestion is observed after 2 weeks of use?9 There is great individual variation in the susceptibility to the symptom-producing effects of glycyrrhizin, primarily due to differences in pharmacokinetics and conversion to the more potent glycyrrhetinic acid (100 to 200 times more active in suppressing 11-beta-hydroxysteroid-dehydrogenase).90Adverse effects are rarely observed at levels below 100 mg/day, while they are

quite common at levels above 400 mg/day9 However, some persons may be susceptible to chronic dosages at even lower levels, especially if the more potent glycyrrhetinic acid is available in free form. One study determined a no-effed level of glycyrrhetinic acid as 2 mg/kg, from which an acceptable daily intake (ADI) of 0.2 mg/kg body weight can be extrapolated with a safety factor of 10. This translates to a consumption of 12 mg glycyrrhetinic acid/day for a person with a body weight of 60 kg?I Prevention of the side effects of glycyrrhizin may be possible by following a high-potassium, low-sodium diet. Although no formal trial has been performed, patients who normally consume high-potassium foods and restrict sodium intake, even those with high blood pressure and angina, have been reported to be free from the aldosterone-like side effects of glycyrrhi~in.~~ Licorice should probably not be used in patients with a history of hypertension or renal failure or in those who currently use digitalis preparations. Licorice preparations containing glycyrrhizin may reduce serum and salivary testosterone levels in men. In one study, men consuming the equivalent of 500 mg of glycyrrhizin experienced a drop of 26% in serum testosterone le~els.9~ However, in another study, no sigruficant effect was noted.% Licorice intake during pregnancy is generally regarded safe unless hypertension becomes an issue. There has been one detailed study on maternal consumption of glycyrrhizin and how it affects birth ~ e i g h t . 9 Glycyrrhizin ~ intake was calculated from detailed questionnaires on licorice consumption.Glycyrrhizin exposure was grouped into three levels: low ( ~Large - ~ ’ dosages are therefore required

for efficacy and contribute to increased expense, large number of tablets or capsules required, and poor patient ~ o m p l i a n c e . ~Furthermore, ~>~ pancreatin can cause hyperuricosuria and renal damage in large doses owing to its high purine contenLMAlthough H2receptor antagonists such as cimetidine are often used along with pancreatin to lessen intragastric ina~tivation,5~$~ this approach is unsuccessful in improving lipid digestion in many patients57and carries the risk of possible adverse side effects. Various forms of enteric-coated pancreatin (i.e., enteric-coated capsules, tablets, granules and microspheres) are formulated to dissolve above pH 5.5-6.0 and are intended to protect orally administered pancreatin against gastric a~idity.5~3 These often lack optimum efficacy, however, because most patients with pancreatic insufficiency have hyperacidity in the upper small intestine owing to decreased bicarbonate secretion. As a result, enteric-coated tablets or capsules often fail to dissolve and deliver their enzymes in the duodenum or jejunum as h1tended.5~In addition, phthalate derivatives and other excipients required for enteric coatings may cause reactions in chemically sensitive individuals. By contrast, a lipase preparation from A. oryzae is resistant to inactivation by gastric acidity and is enzymatically active in pH ranging from 2 to 10. It digests dietary fat, beginning in the stomach and continuing in the small intestine.52,60It is water-soluble, heat-stable, nontoxic, and free of some of the potential drawbacks of pancreatin replacement therapy?

CLINICAL APPLICATIONS Malabsorption and Steatorrhea Chronic panmatitis and cystic fibrosis are the most common causes of pancreatic exocrine insufficiency. Pancreatogenic steatorrhea results from failure of fat digestion, leading to lipid malabsorption, impaired nutrition, weight loss, and considerable social embarra~sment.4~6~ Lipase preparations from fungal sources have been shown to be highly effective in treating malabsorption and steatorrhea under a wide variety of conditions.m*626 A 1985 crossover control clinical trial compared the effectiveness of 10 teaspoons of a conventional pancreatic enzyme preparation (360,000 lipase units) with that of 10 capsules of enteric-coated pancreatin (100,000 lipase units) and 10 capsules of acid-stable fungal enzymes (75,000 lipase units) in patients with chronic pancreatitis, severe pancreatic exocrine insufficiency, and steatorrhea.60Seventeen patients in the study were divided into two treatment groups on the basis of surgical status. Nine patients had undergone Whipple’s procedure (bowel resection with partial duodenopancreatectomy)

3 to 8 months before the study (group A). This group had shown a preoperative reduction in stimulated pancreatic enzyme secretion to less than 10% of normal. In the remaining eight, nonsurgical patients (group B), stimulated secretion was reduced to between 4% and 28% of normal. All patients were given a diet containing 100 g fat/day; 5 days after discontinuation of all medications (pancreatic enzymes, antacids, and H2receptor antagonists), stools were collected for 72 hours. Thereafter, each group was started on identical 2-week periods of treatment using enteric-coated pancreatin first, then conventional pancreatin, and, finally, acid-stable fungal enzymes. Stools were collected for the last 3 days of each treatment period and analyzed for stool weight, fat concentration, and total fecal fat excretion. Before treatment, atl fecal parameters were pathologically elevated in all 17 patients, diarrhea and characteristic abdominal symptoms were present, and the patients had a tendency to lose weight. All three treatment protocols led to a significant reduction in total daily stool weight and total daily fecal fat excretion in comparison with controls in both groups. Perhaps more importantly, all patients in both groups became virtually symptom-free with each of the three treatment protocols. Table 108-1 shows fecal fat excretion and stool weight for controls and for each treatment protocol in group A and group B. Individual patient results in each group have been averaged together. It is interesting to note that the fungal lipase controlled signs and symptoms about as well as a 33% larger dose of entericcoated pancreatin and a 380% larger dose of conventional pancreatin. A 1988 placebo-controlled, randomized, crossover study in England compared the effectiveness of 400 mg (4800 lipase units) of acid-stable lipase from A. oryzue with that of 10,000 mg (60,000 lipase units) of pancreatin in the treatment of chronic pancreatic exocrine insufficiency in dogs.52Eleven dogs (weighing 15 to 21 kg) used in the study underwent total pancreatectomy to produce pancreatic exocrine insufficiency. All animals received intrasplenic autografts of islet of Langerhans

tissue to preserve pancreatic endocrine function. Animals served as their own controls through the use of preoperative data. The dogs were maintained on fixed diets containing 46 g/day fat. Each treatment protocol lasted 3 weeks, beginning and ending with weighing of animals and %day specimen collections for determination of fecal fat excretion and stool volume. Dogs in the untreated placebo group experienced sigruficant weight loss (p < 0.01) due to malabsorption averaging 0.9 kg over a 3-week period. Dogs receiving either 400 mg/day of A. oryzue lipase or 10,000 mg/day of pancreatin did not show significant weight loss. Similarly, both fecal fat excretion and stool volume were pathologically elevated in the placebo group. Significant reductions occurred in both fecal fat and stool volume, with no sigruficant difference between fungal lipase and pancreatin treated animals. A significant finding of the English study was the fact that a small dose of acid-stable lipase from A. oryzue (400 mg) was as effective as a dose of conventional pancreatin 25 times larger (10,000 mg) in the treatment of malabsorption, malnutrition, and steatorrhea due to pancreatic exocrine insufficiency in dogs. Unlike pancreatin, A. oryzue lipase delivers enzyme activity in the broad range from pH 2 to 10. It safely digests dietary fat, beginning in the stomach and continuing in the small intestine, and may be more effective than pancreatin in the abnormal acidic conditions commonly found in the duodenum and jejunum of patients with pancreatic insufficiency.

Lactose Intolerance Lactose intolerance produces symptoms such as abdominal pain, bloating, cramping, flatulence, belching, and diarrhea.&Maldigestion of lactose is a common problem in children and adults, occurring in 76% of apparently healthy children in one study and 56% in another singleblind, controlled trial.67Lactose maldigestion can result from genetic nonpersistence of intestinal lactase activity at some time after weaning as well as from secondary lactase deficiencies. It may or may not produce symptoms of lactose

Stool weight and fecal fat in patients with steatorrhea Fecal Fat (glday)

Stool Weight (@day)

Group A

Group B

Group A

Group B

180

82

906

675

Entericcoated pancreatin (1 00,OOOlipase units)

75

39

494

324

Pancreatin (360,000lipase units)

55 87

48

437

345

48

51 9

316

Treatment protocol Control

Fungal lipase (75,000lipase units)

The upper limit of the normal range for fecal fat excretion is 7 @day, and for stool weight is 250 @day.

Microbial Enzyme Therapy

A lactase enzyme derived from A. oryzae is effective in the treatment of lactose maldigestion and lactose intolerance when taken orally at the time of milk Moreover, this enzyme aids in the in vivo digestion of milk sugar even in healthy individuals classified as normal lactose digesters. Furthermore, the A. oryzae-derived lactase is more effective in the digestion of lactose than a similar enzyme derived from the yeast Kluyveromyces l a c t k g It is known that milk prehydrolyzed in vitro by being incubated under refrigeration with lactase is effective in the prevention of lactose intolerance in susceptible individuals. A 1986 single-blind, controlled study was designed to determine whether ingestion of lactase at mealtime was equally as effective in the treatment of lactose intolerance as prehydrolyzed milk, because the latter requires refrigeration, which is difficult to obtain in ”underdevelopedff parts of the world. The hydrogen breath test was used as an accurate and sensitive measurement of lactose digestion in vivo (see Chapter 25). The study included 48 healthy Guatemalan preschool children. The ability of participants to digest lactose from ingested whole cow’s milk was tested against four treatment protocols as follows (each protocol included 240 ml of whole cow’s milk containing 12 g of lactose): 1.Whole, intact cow’s milk 2. Milk prehydrolyzed in vitro with lactase enzyme 3. Varying amounts of lactase from K. lactis administered orally with milk 4.Varying amounts of lactase from A. oryzae administered orally with milk

Twenty-seven of the children (56%) proved to be maldigesters of lactose from the ingestion of intact milk. Twenty-five of these lactose maldigesters (93%) were found to show no lactose maldigestion (i.e., successfully treated) after the ingestion of milk prehydrolyzed with lactase in vitro for 24 hours. Rehydrolyzed milk was used as the standard for successful treatment in comparing the effectiveness of lactase enzymes derived from A. oryzue and K. 1actis.g All experimental dosages of in vivo lactase from both A. oryzae and K. lactis si@cantly reduced the volume of post-challenge hydrogen excretion as compared with intact milk (p < 0.05). However, la@ from A. oryzue was found to be equally as effective as prehydrolyzed milk, whereas K. lactis lactase was only 82%as effective. This research supports the addition of microbial betagalactosidase (lactase) to milk at mealtimes as effective in the prevention of signs and symptoms of lactose maldigestion. Ingestion of lactase with milk at mealtime avoids the inconvenience of refrigerated 24hour incubation as well as the sweeter flavor produced when milk is prehydrolyzed. In a somewhat surprising result, A. oryzae lactase was also found to improve the extent of lactose digestion in

the 21 children classified as normal, complete digesters. This finding demonstrates that the capacity for lactose digestion is actually a continuum, even in lactasepersistent subjects, rather than an all-or-none phenomenon. The efficacy of these enzymes in lactose-intolerant children and adults has now been replicated in several ~tudies.~,~~

Vascular Disease Numerous crossover, single-blind and placebo-controlled studies have confirmed the effectiveness of a proteolytic enzyme derived from A. oryzae in treating chronically obstructed arteries in humans.29-333,37,7478 In fact, intravenous therapy with fungal protease from A. oryzue is dramatically more effective than anticoagulant therapy (e.g., heparin, warfarin) at recanalizing obstructed arteries and improving blood flow through stenosed arterial ~ e g m e n t s . ~ 3 ~ , ~ ~ A 1978 controlled, single-blind crossover study evaluated the effectiveness of protease from A. oryzae versus anticoagulant therapy and placebo in 18 patients (ages 63 to 75 years) with stable intermittent claudication of at least 6 months’ duration.%Patients were divided into two groups, and a full assessment of each patient was carried out before testing. Translumbar aortogram, Doppler ultrasonographic scanning, and peripheral systolic blood pressure were used to assess the patency of eight different arterial segments in each patient (a total of 72 segments in each group). Anticoagulation therapy with warfarin was introduced after assessment and continued throughout an observation period of 3 months and subsequent trial periods. Assessment of peripheral circulation was repeated after the %month observation period of anticoagulant therapy. Thereafter, a series of six intravenous infusions of fungal protease and normal saline was given to experimental and control groups, respectively, at regular intervals over the next 2 weeks. Assessment of peripheral circulation was repeated at the end of the protease infusion treatment. No other form of therapy was given, except warfarin for anticoagulation. On admission to the study, the first group of patients receiving fungal protease therapy showed 27 obstructed segments (completely obstructed), 34 stenosed segments (partially obstructed), and only 11 patent arterial segments. The 9 patients receiving saline (placebo) showed 25 obstructed,26 stenosed, and 21 patent arterial segments before treatment (Table 108-2). At the end of the %month observation period (anticoagulation therapy only), no changes in Doppler ultrasonography findings or ankle/arm blood pressure ratios were found in either group. At the end of the 2-week trial period, 3 of the 72 arterial segments in the saline group had progressed to increased obstruction (i.e., 4% worse). In contrast, treatment with the fungal protease infusion improved patency of 33 of 72 arterial

segments after placebo or fungal

Placebo Arterial status

Treated

Initial

Final

Initial

Final

No. patients

21

21

11

27

No. stenosed

26

23

34

35

No. obstructed

25

28

27

10

segments (i.e., a 46% improvement). These changes were sigruficant at the 0.1% level (p c 0.001). The saline group was offered the opportunity to receive a further course of treatment without disclosure of a change in regimen from saline to fungal protease infusion. Five patients declined further treatment, but four patients with 32 arterial segments subsequently received the crossover fungal protease infusion protocol. After treatment, 5 completely obstructed segments were found to have recanalized. This research demonstrated that 3 months of anticoagulant therapy produced no improvement whatsoever in peripheral nor did subsequent infusions of saline (placebo) during a 2-week period. Six intravenous infusions of a fungal protease derived from A. oryzue given within 2 weeks sigruficantly improved peripheral circulation in more than half of the chroNcally obstructed arterial segments in these patients. Furthermore, detailed analysis of study results suggested that an increase in the number and/or dosage of protease infusions might have resulted in even greater improvement in obstructed and stenosed arterial segments. Other studies have shown fungal protease to be effective in the treatment of arterial obstruction in patients with more advanced conditions, such as gangrene and other severe ischemic disea~e?’,~,~

Celiac Disease It has been known since the 1950s that the gluten found in wheat, rye, and other grains is the cause of intestinal damage in celiac disease, with the gliadin fraction of gluten being the source of its toxicity.79” By the 1970s, fractionation studies had succeeded in identifying the components of gliadin involved in the toxic mechanism. The carbohydrate moiety, consisting mainly of glucose, galactose, xylose, and arabinose, is the source of gluten’s gastrointestinal toxicity in the patient with celiac disease, rather than the protein fraction as had been previously suspected?l* Carbohydrase enzymes from microbial sources are effective in vitro in the treatment of celiac disease, because they enzymatically cleave the toxic carbohydrate portion of gliadin. Fungal carbohydrase preparations

render grains like wheat and rye virtually harmless to individuals with gluten enteropathy?1fi2 A 1977 study attempting to identdy the source of gliadin toxicity used a preparation of amylytic enzymes from Aspergillus niger to remove the carbohydrate portion of gliadin in vitro.8l To ascertain the variables being tested, native gliadin underwent chromatography, which showed that carbohydrate was associated with four main protein bands. When the carbohydrase-treated gliadin underwent chromatography, no alteration was detected in the protein pattern, but carbohydrate was completely absent. To further establish that the protein makeup remained unchanged compared with native gliadin, peptide mapping of the treated gliadin was carried out with electrophoresis followed by chromatography. Peptide maps showed no differencebetween the treated and untreated gliadins, confirming that no alteration had occurred in the primary structure of the protein. Gliadin treated in this manner was baked into loaves of bread made with gluten-free flour. The study compared the effect of bread with treated versus untreated gliadin on four patients with previously diagnosed celiac disease. All four patients had been following gluten-free diets for at least 3 months before the study and were virtually symptom-free. Previously, their clinical and physical signs and symptoms had included the diarrhea, malabsorption, decreases in body weight and height, anemia, tetany, impaired Dxylose absorption, decreased intestinal mucosal enzyme secretion, flattened mucosal brush border, and subepithelial tissue lymphocytosis typical of celiac disease. During the test period, patients 1,2, and 3 received a total of 50 g of treated gliadin baked into loaves of bread (10 g gliadin/450-g loaf). Xylose absorption tests and intestinal biopsies from jejunal villi were performed before and after each test period. The celiac patient receiving untreated gliadin (patient4) experienced a return of signs and symptoms of celiac disease-diarrhea, abdominal pain, low values on xylose absorption studies, decreased mucosal enzyme secretion (alkaline phosphatase, lactase, sucrase) and characteristic histologic damage (mucosal lymphocytosis and loss of enterocyte height). The patients who received the treated gliadin remained symptom free during the test period and showed no abnormalities in histologic parameters (i.e., general morphology, epithelial cell height, and tissue lymphocytes were normal in these patients). This study demonstrated that carbohydrate-digesting enzymes from Aspergillus spp. can be used in vitro to remove the toxicity of gluten to patients with celiac disease and supports the hypothesis that carbohydrate components of gliadin are responsible for its toxicity rather thanthe protein components previously suspected.

Microbial Enzyme Therapy

It appears that no controlled studies have been performed to evaluate the effectiveness of amylytic fungal enzymes at reducing gluten toxicity to patients with celiac disease by administering these enzymes with gluten-containing foods at mealtime. It should be noted that although patients with celiac disease show intolerance to the carbohydrate portion of gliadin, this is likely not the only source of gluteninduced disease. A number of studies suggest that protein components of gluten produce systemic allergic manifestations in some patients.* It appears that both gastrointestinal intolerance and immunologic hypersensitivity are capable, either individually or in concert, of producing disease symptoms in susceptible individuals. Future studies may also show that both pathologic mechanisms are amenable to treatment by hydrolysis of the offending portions of gluten with the appropriate orally administered fungal enzymes. This possibility, however, remains to be proven.

including the increased supply of dietary antigens that leak into the blood stream as a result of inadequate protein digesti~n.lJt~t~-~*,~ By digesting dietary protein, fungal enzymes administered orally at mealtime work to decrease the supply of antigenic macromolecules available to leak into the blood stream. In addition, orally administered fungal enzymes that have themselves been absorbed intact may help ”digest” antigenic dietary proteins that they encounter in the blood stream. Further research is needed to evaluate the role of fungal enzymes in the treatment of food allergies.

SUMMARY

‘References 1, 2. 9, 10, 14, 84, 85.

Although the intact absorption of orally administered protein, including enzymes, can no longer be reasonably denied, the quantitative significance of this process requires additional study. It appears unlikely that this route of absorption is sigrufrcant from the standpoint of overall nutritional status, but considerable evidence supports the biologic and therapeutic importance of intact protein absorption and the role of fungal enzyme therapy. The emerging field of fungal enzyme therapy holds promise as an effective therapy or adjunct in a wide range of conditions, including maldigestion, malabsorption, pancreatic insufficiency, steatorrhea,celiac disease, lactose intolerance, arterial obstruction, and thrombotic disease.

1. Gardner ML. Gastrointestinal absorption of intact proteins. Ann Rev Nutr 1988;8:329-350. 2. Gardner ML. Intestinal assimilation of intact peptides and proteins from the diet-a neglected field? Biol Rev Camb PMOSSoc 1984; 59289-331. 3. Warshaw AL, Walker WA, Isselbacher KJ. Protein uptake by the intestine: evidence for absorption of intact macromolecules. Gastroenterology 1974;66987-992. 4. Udall JN, Walker WA. The physiologic and pathologic basis for the transport of macromolecules across the intestinal tract. J Pediatr Gastroenterol Nutr 1982;1:295-301. 5. Loehry CA, Axon AT, Hilton PJ, Hider RC, Creamer B. Permeability of the s m a l l intestine to substances of different molecular weight. Gut 1970;11:466-470. 6. Hemmings WA, Williams EW. Transport of large breakdown products of dietary protein through the gut wall. Gut 1978;19715-723. 7. Menzies IS. Transmucosal passage of inert molecules in health and disease. In Skadhauge E, Heintze K, eds. Intestinal absorption and secretion. Lancaster, PA MTP Press, 19W527-543. 8. Gardner MLG, Steffens KJ, eds.Absorption of orally administered enzymes. Berlin: Springer-Verlag, 1995. 9. Ferguson A, Carswell F. Precipitins to dietary proteins in serum and upper intestinal secretions of coeliac children. Br Med J 1972;1:75-77. 10. Husby S, Foged N, Host A, Svehag SE. Passage of dietary antigens into the blood of children with coeliac disease: quantification and size distribution of absorbed antigens. Gut 1987;281062-1072.

11. Husby S, Jensenius JC, Svehag SE. Passage of undegraded dietary antigen into the blood of healthy adults: further characterization of the kinetics of uptake and the size distribution of the antigen. Scand J Immunol1986;24447-455. 12.WaUcer WA. Antigen absorption from the small intestine and gastrointestinaldisease.Pediatr Clin North Am 1975;22:731-746. 13. Hamilton I, Fairris GM, Rothwell J, et al. Small intestinal permeability in dermatological disease. Q J Med 1985;56.559-567. 14. Lambert MT, Bjamason I, Connelly J, et al. Small intestine permeability in schizophrenia.Br J Psychiatry 1989;155619-622. 15. Heatley RV, et al. Inflammatory bowel disease. In Losowsky MS, Heatley RV, eds. Gut defenses in clinical practice. Edinburgh Churchill Livingstone, 1986225-277. 16. Shorter RG, Huizenga KA, Spencer RJ. A working hypothesis for the etiology and pathogenesis of nonspecific inflammatory bowel disease. Am J Dig Dis 1972;1710241032. 17. Jackson PG, Lessof MH, Baker RW, et al. Intestinal permeability in patients with eczema and food allergy. Lancet 1981;1:1285-1286. 18.Hemmings WA. The absorption of large breakdown products of dietary proteins into the body tissues including the brain. In Hemmings G, Hemmings WA, eds. The biological basis of schizophrenia. Lancaster, PA h4TP Press,1978239-257. 19. Jakobsson I, Lindberg T, Lothe L, et al. Human alpha-ladalbumin as a marker of macromolecular absorption. Gut 1986;271029-1034. 20.Bockman DE, Winborm WB. Light and electron microscopy of intestinal ferritin absorption: observations in sensitized and non-sensitized hamsters. Anat Rec 1966;155:603-622.

Food Allergies Antigen sampling by subepithelial immune tissue in the gut helps, under normal conditions, to program the body’s defenses and protect against exposure to “foreign” dietary proteins and polypeptides. Under pathologic conditions, food allergies can be caused by several factors,

Pharmacology of Natural Medicines 21. Andre C, Lambert R, Bazin H, Heremans JF.Interference of oral immunization with the intestinal absorption of heterologous albumin. EUI J Imm~n011974;4701-704. 22.Dannae1.1~A, Inganas M, Johansson SG, Foucard T. Intestinal uptake of ovalbumin in malabsorption and food allergy in relation to serum IgG antibody and orally administered sodium cromoglycate. Clin Allergy 1979;9:263-270, 23. Wolf JL, Rubin DH, Fmberg R, et al. Intestinal M cells a pathway for entry of retrovirus into the host. Science 1981;212:471-472. 24. McLean E, Ash R. The time-course of appearance and net accumulation of horseradish peroxidase ( H R P )presented orally to juvenile carp, Cyprinus curpio. Comp Biochem Physiol A 1986;84:687-690. 25. Ormiston BJ. Clinical effects of TRH and TSH after i.v. and oral administration in normal volunteers and patients with thyroid disease. In R Hal et al, eds. Thyrotropin releasing hormone (Frontiers of hormone research,vol. I). Basel: Karger, 197245-52. 26. boss M, Rivier J, Guillemin R. Release of gonadotrophins by oral administration of synthetic LRF or tripeptide fragment of LRF. J Clin Endocrinol Metab 197235175177. 27. Siefert J, et al. Mucosal permeation of macromolecules and particles. Science 1975;127505-513. 28. Laskowski M Jr, Haessler HA, Miech RP, et al. Effect of trypsin inhibitor on passage of insulin across the intestinal bamer. Science 1958;1271115-1116. 29. Bergkvist R, Svaed PO. Studies on the thrombolytic activity of a protease from Aspergillus o r y m . Acta Physiol Scand 1964;60:363-371. 30. Verstraefe M, Verhaege R, Schetz J, et al. Clinical trial of Brinase and anticoagulents as a method of treatment for advanced limb ischemia. Eur J Clin Pharmacol1979;16165-170. 31. Kiessling H, Svensson R. Influence of an enzyme from Aspergillus oryzae, protease I, on some components of the fibrinolytic system. Acta Chem Scand 1970;24569-579. 32. Larsson LJ, Frisch EP, Tomeke K, et al. Properties of the complex between alpha-2-macroglobulin and brinase, a proteinase from Aspergillus oyzae with thrombolytic effect. Thromb Res 1988; 4955-68. 33. Vanhove P, Donati MB, Claeys H, et al. Action of brinase on human fibrinogen and plasminogen. Thromb Haemost 1979;42571-581. 34.Kiessling H. Some properties of a complex between alpha2-macroglobulin and brinase. Protides Biol Fluid Proc Colloq 1975;2347-52. 35.Bergkvist R The proteolytic enzymes of Aspergillus o r y m II: properties of the proteolytic enzymes. Acta Chem Scand 1963;17 1541-1551. 36.Fitzgerald DE, Frisch EP, Milliken JC. Relief of chronic arterial obstruction using intravenous brinase: a control study. Sand J Thorac Cardiovasc Surg 1979;13327-332. 37. Verhaeghe R, Verstraete M, Schetz J, et al. Clinical trial of brinase and anticoagulants as a method of treatment for advanced limb ischemia. Eur J Clin Pharmacol1979;16165-170. 38. Keljo DJ, Hamilton JR. Quantitative determination of macromolecular transport rate across intestinal Peyer's patches. Am J Physiol 1983;244:G637-G644. 39. Wolf JL, Bye WA. The membranous epithelial (M) cell and the mucosal immune system. Annu Rev Med 1984;35:95-112. 40.Bjamason I, Peters J. Helping the mucosa make sense of macromolecules.Gut 1987;281057-1061. 41. Ambrus JL, Lassman HB, DeMarchi JJ.Absorption of exogenous and endogenous proteolytic enzymes. Clin Pharmacol Ther 1967;8:362-368. 42.Kabacoff BL, Wohlman A, Umhey M, Avakian S. Absorption of chymotrypsin from the intestinal tract. Nature 1963;199:815. 43.Martin GJ, et al. Further in vivo observations with radioactive trypsin. Am J Pharm 1964;129386-392. 44.Avakian S. Further studies on the absorption of chymotrypsin. Clin Pharmacol Ther 1964;66:712-715.

45. Miller JM, Wfiard RF, Polachek AA. An investigation of trypsin 1-131 in patients. Exp Med Surg 1960;18352-370. 46.Leibow C, Rothman SS. Enteropancreatic circulation of digestive enzymes. Science 1975;189472-474. 47. Guyton AC, ed. Textbook of medical physiology, ed 4, Philadelphia: WB Saunders, 1971:761. 48. Bore1 P, Armand M, senft M, et al. Gastric lipase: evidence of an adaptive response to dietary fat in the rabbit. Gastroenterology 1991;100:1582-1589. 49. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973;288.813-815. 50. Heizer WD,Cleaveland CR, Iber F'L. Gastric inactivation of pancreatic supplements. Bull Johns Hopkins Hosp 1965;116261-270. 51.Go VL, Poley JR, Hofmann AF, Summerskill WH. Disturbances in fat digestion induced by acidic jejunal pH due to gastric hypersecretion in man. Gastroenterology 197058638-646. 52.Griffin SM, Alderson D, Famdon JR. Acid resistant lipase as replacement therapy in chronic pancreatic exocrine insufficiency: a study in dogs. Gut 1989;301012-1015. 53. DiMagno EP. Controversies in the treatment of exocrine pancreatic insufficiency. Dig Dis Sci 1982;27481-484. 54.Stapleton FB, Kennedy J, Nousia-Arvanitakis S, Linshaw MA. Hyperuricosuria due to high dose pancreatic extract therapy in cystic fibrosis. N Engl J Med 1976;295246-248. 55.Gow R, Bradbear R, Francis P, Shepherd R. Comparative study of varying regimens to improve steatorrhea and creatorrhea in cystic fibrosis: effectiveness of an enteric-coated preparation with and without antacids and cimetidine. Lancet 1981;2:1071-1074. 56.Graham DY. Pancreatic enzyme replacement: the effect of antacids or cimetidine. Dig Dis Sci 1982;27485-490. 57. Staub JL, Sarles H, Soule JC, et al. No effects of cimetidine on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med 1981304:1364-1365. 58. Regan FT,Malagelada JR, Dih4agno EP, et al. Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med 1977;297854-858. 59. htler-Munro PL, Fitzpatrick WJ, Batten JC, Northfield TC. Effect of intrajejunal acidity and aqueous bile acid and lipid concentrations in pancreatic steatorrhea due to cystic fibrosis. Gut 1984;25:500-507. 60.Schneider Mu, Knoll-Ruzicka ML, Domschke S, et al. Pancreatic enzyme replacement therapy: comparative effects of conventional and enteric-coated microspheric pancreatin and acid-stable fungal enzyme preparations on steatorrhea in chronic pancreatitis. Hepatogastroenterology1985;3297-102. 61. Ladas SD, Giorgiotis K, Raptis SA. Complex carbohydrate malabsorption in exocrine pancreatic insufficiency. Gut 1993;34:984-987. 62.Nakamura T, Takeuchi T, Tando Y. Pancreatic dysfunction and treatment options. Pancreas 1998;16:329-336. 63.Roberts IM.Enzyme therapy for malabsorption in exocrine pancreatic insufficiency. Pancreas 1989;4:496-503. 64.Zom J. [Experienceswith substitution therapy using a new pancreatic enzyme of plant origin.] Fortschr Med 1978;96:1941-1943. 65.Pointner H, Flegel U. [Treatment of exocrine pancreatic insufficiency with fungal lipase.] Arzneimittelforschung 1975;25: 1833-1835. 66. Medow MS, Thek KD, Newman LJ, et al. Beta-galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am J Dis Child 1990;144:1261-1264. 67. Barillas C, Solomons NW. Effective reduction of lactose maldigestion in presd-1001children by direct addition of beta-galactosidases to milk at mealtime. Pediatrics 1987;79:766-772. 68. Rosado JL, Solomons NW, Lisker R, Bourges H. Enzyme replacement therapy for primary adult lactase deficiency: effective

Microbial Enzyme Th ~

reduction of lactose malabsorption and milk intolerance by direct addition of beta-galactosidases to milk at mealtime. Gastmenterology 1984;871072-1082. 69. Rosado JL, Deodhar AD, Bourges H, Solomons NW. The effect of the digestion products of lactose (glucose and galactose) on its intraintestinal, in vivo hydrolysis by exogenous microbial betaD-galactosidase. J Am Coll Nutr 1986;5:281-290. 70.Corazza GR, Benati G, Sorge M, et al. Beta-galadosidase from Aspergillus niger in adult lactose malabsoxption: a double-blind crossover study. Aliment Pharmacol "her 1992;661-66. 71. OKeefe S. The use of lactase enzyme in feeding malnourished lactose intolerant patients. XIII International Congress of Nutrition. Brighton, England, 1985190. 72. Rand AG Jr. Enzyme technology and the development of lactosehydrolyzed milk. In Paige DM, Bayless TM, eds. Lactose digestion: clinical and nutritional implications. Baltimore: Johns Hopkins University Press, 1981:219-230. 73. Lactose intolerance [editorial].Lancet 1991938:1280. 74. Frisch El', Fitzgerald DE. Relief of chronic peripheral artery obstruction by intravenous brinase. J Ir Med Assoc 1973;66: 313-318. treatment 75. Lund F, Ekestrom S, Frisch EP,Magaard F. Thrombolyt~c with i.v. brinase of advanced arterial obliterative disease of the limbs. Angiology 1975;26534-556. 76. Frisch EP, Blomback M, Ekestrom S, et al. Dosage of i.v. brinase in man based on brinase inhibitor capacity and coagulation studies. hgi010gy 1975;26:557-563.

77. Roschlau WH, Fisher AM. Thrombolytic therapy with local perfusions of CA-7 (fibrinolytic enzyme from Aspergillus myme) in the dog. Angiology 1966;17670-682. 78.Frisch EP, Blomback M. Blood coagulation studies in patients treated with brinase. In Davidson JF, ed. Progress in chemical fibrinolysis and thrombolysis, vol Iv.Edinburgh, Churchdl Livingstone, 1979184187. Weijers HA, Dicke WK. Coeliac disease. Iv.An 79. Van De Kamer JH, investigation into the injurious constituents of wheat in connection with their action on patients with coeliac disease. Acta Paediatr 1953;&223-231. 80. Van De Kamer JH,Weijers HA. Coeliac disease. V. Some experiments on the cause of the harmful effect of the gliadin. Acta Paediatr 1955;44:465-469. 81. Phelan JJ,Stevens FM, McNicholl B, et al. Coelic disease: the abolition of gliadin toxicity by enzymes from Aspergillus niger. Clin Sci Mol Med 1977;5335-43. 82. McCarthy CF. Nutritional defects in patients with malabsorption. Proc Nutr Soc 197635:37-40. 83. Phelan JJ. The nature of gliadin toxicity in coeliac disease. Biochem Soc Trans 1974;2:136&1370. 84. Hekkens WTJM. Antibodies to gliadin in serum of normals, coeliac patients and schizophrenics. Nature 1963;199:259-261. 85. Hekkens WTJM, et al. Antibodies to wheat proteins in schizophrenia: relationship or coincidence? In Hemmings G, ed. The biochemistry of schizophrenia and addiction. Lancaster, PA: MTP Press, 1980125-133.

Naturally Occurring Antioxidants Robert A. Ronzio. PhD CHAPTER CONTENTS Introduction 1085 Free Radicals and Reactive Oxygen Species 1085 Free Radicals 1085 Reactive Oxygen Species 1086 Formation of Free Radicals and Reactive Oxygen Species 1086 Functions of Free Radicals and Reactive Oxygen Species 1087 Inflammation 1087 Antioxidants 1088 Enzyme Antioxidants 1088 Nutrient Antioxidants 1090 Antioxidants Produced by the Body 1093

INTRODUCTION Mitochondria use oxygen to maximize production of adenosine triphosphate (ATP) in oxidizing fuel molecules to carbon dioxide. Paradoxically, oxygen is such a powerful reactant that it can disrupt cellular function and impair homeostatic mechanisms primarily through oxygen radicals. Research suggests that free radical attack and cumulative oxidative damage are associated with many diseases and chronic conditions, including cancer,'r2 cardiovascular disease,3r4cataracts? inflammation and autoimmune disease,6v7lung disease? neurologic disorders?JO aging,11J2 he pa ti ti^,'^ and cell death.I4 Box 109-1 summarizes prominent examples of the more than 100 conditions that reflect oxidative damage. Free radicals may be a consequence of the disease process, or they may be a cause. The following discussion focuses on the formation and physiologic effects of free radicals and oxygen-based reactants, and then addresses cellular antioxidant mechanisms and the use of antioxidant supplements.

Nonnutritive Antioxidants 1096 Botanical Extracts 1096

Comparison of Antioxidants 1098 Antioxidants and Regulation of Cell Function 1099 The Adequacy of Antioxidant Defenses 1100 Guidelines for Use of Antioxidants 1101 Precautions in Using Antioxidant Supplementation 1101 Selecting Antioxidants

1102

FREE RADICALS AND REACTIVE OXYGEN SPECIES Free Radicals Free radicals are highly reactive molecules. Unlike most molecules, which contain pairs of electrons, free radicals possess at least one unpaired electron, an unstable condition. Consequently, free radicals remove electrons from bystander molecules indiscriminately to make up for their own deficiency. Lipid peroxidation remains the best-studied example of molecular modifications induced by reactive oxygen species (see later) and free radicals. An initial event generates free radicals, and propagation steps repeated many times perpetuate their formation. Thus, free radical reactions tend to "snowball'' unless held in check by antioxidant defenses.15 Nitric oxide (NO.) and superoxide (O,.-), are examples of physiologically important radicals. When present at low levels, these species play regulatory roles, but excessive concentrations lead to cell damage. The hydroxyl radical (*OH)is one of the most reactive radicals occurring in the body. Its high degree of chemical reactivity precludes any useful physiologic role. 1085

ROS sources

Alcohol-induced damage Atherosclerosis Autoimmune diseases (rheumatoid arthritis and others) Cancer Contact dermatitis Coronary artery bypass Diabetic cataracts Drug toxicity Emphysema Hypertensivecerebrovascular injury immune deficiency of aging Inflammatory bowel disease Iron overload disease Liver cirrhosis Myocardial infarction Nephrotoxicity Nutrient deficiencies Obstructive lung disease Parkinson's disease Prematureaging Premature retinopathy Senile dementia and neurologic degeneration Stroke Systemic lupus erythematosus Thermal injury Viral infections, including acquired immunodeficiencysyndrome

I

Of+ H202

ROS targets Protein

DNA

Lipiddmembranes

-OH I

I

@= Chain breakers @ = Preventive antioxidants

1

I

'ROOH

Flgure 1041 Sources, targets, and sites of antioxidant neutralization for reactive oxygen species (ROS).

Reactive Oxygen Species In addition to these free radicals, the body generates an array of oxidizing agents, including hydrogen peroxide (H202),lipid peroxide (ROOH),and hypochlorite (OC-). Although 02.-and H202are not very reactive chemically, they can yield hydroxyl radical in the presence of transition metal ions. Reduced iron catalyzes the conversion of superoxide to singlet oxygen, an activated oxygen molecule with an unstable electron configuration. Furthermore, nitric oxide and superoxide, in excess, form peroxynitrite ( O N W ) , an extremely powerful oxidizing agent and radical generator. It is useful to regard these metabolites collectively as reactive oxygen species (ROS) to include the various forms of more or less reactive oxidizing agents, whether or not they are free radicals.15 Likely targets of free radicals and ROS include polyunsaturated fatty acids in membrane lipids, serum lipoproteins, proteins, and even DNA (Figure 109-1). The oxidation products include lipid peroxides and hydroperoxides, protein carbonyls, and altered purines such as &oxo-2-deoxyguanosine."J6 The consequences of attack by free radicals and ROS are often subtle: Increased membrane fluidity and damage to (1)membrane receptor proteins may alter cellular regulatory mechanisms such as signal transduction, (2) inactivation of proteins required for All' production, leading to an energy deficit, and (3)inactivation of calcium ATPase, changing

calcium homeostasi~.'~ Mitochondria as principal radical generators represent especially important targets of free radical attack. ROS damage could trigger apoptosis by altering mitochondria1 membrane permeability, leading to the release of apoptogenic substances such as cytochrome c. There is strong circumstantial evidence that ROS and free radicals also play a role in cancer initiation and promotion. Although ROS often damage DNA and induce malignant transformation, the development of cancer depends on many factors, including the rates of damage and repair, the status of defenses, and alternative pathways for initiation and promotion.

Formation of Free Radicals and Reactive Oxygen Species Although not plentiful, free radicals are surprisingly common in the body. Free radicals and ROS arise through a variety of mechanisms. Some sources are spontaneous chemical accidents: Free radicals are generated by air pollutants such as ozone, by nitric oxides in air pollutants such as cigarette smoke, and by cosmic rays and radiation. On the other hand, oxygen may react with heme proteins such as myoglobin, hemoglobin, and cytochrome c as well as with iron (F$+) to generate superoxide, which yields H202. The extremely reactive hydroxyl radical can be formed from H202in the

Naturally Occurring Antioxidants

presence of Fe2+or copper (Cu’).Therefore, the release of these ions from storage sites during inflammation and injury may promote the spontaneous production of free radicals. In addition, normal metabolism yields free radicals and ROS in the following ways: As noted previously, mitochondria mishandle oxygen. Approximately 1%to 3% of oxygen molecules passing through mitochondria end up as superoxide owing to the leakage of electrons from the electron transport chain during damage, generating about 10 g/day of superoxide.18 The aging process may be related to cumulative mitochondria1 deterioration. Cells contain peroxisomes, organelles that oxidize fatty acids while producing H202 Drugs that cause peroxisome proliferation, such as clofibrate, may act as promoters by stimulating the production of hydrogen peroxide. The oxidation of purines from DNA, RNA, and ATP relies on xanthine oxidase, an enzyme that produces superoxide. Various cytoplasmic oxidases generate ROS, including dopamine oxidase, beta hydroxylase, and urate oxidase. The detoxication of metabolites and xenobiotics by microsomal mixed function oxidases (cytochromeP450) can generate ROS (1 mole of free radical is generated for each mole of toxin metabolized). Furthermore, drugs such as penicillamine and phenylbutazone can be metabolized to free radicals. Also, several xenobiotics, such as paraquat and alloxan, catalyze the formation of superoxide through cyclic reactions (“redox recycling”),promoting autooxidation. A number of pesticides and drugs are hepatotoxins for these rea~0ns.l~ It is worth noting that certain phenolic compounds in plant-derived foods, such as chlorogenic acid and caffeic acid, can also generate oxidants through redox cycling.

Functions of Free Radicals and Reactive Oxygen Species It is important to emphasize that ROS serve many useful functions. NO* functions as a neurotransmitter, a hormone, and a paracrine molecule as well as a messenger and may regulate processes as diverse as vasodilation and memory?O Furthermore, hydrogen peroxide and superoxide may regulate cellular redox balance and levels of key cellular antioxidants such as glutathione, thereby functioning as second messengers to alter signal transduction and gene expre~sion.’~ The mechanisms entail activation of transcription factors, regulated in turn by stimulating calcium (Caz+)signaling and protein phosphorylation via the activation of protein kinases and inhibition of phosphatases. Thus ROS may be second messengers for apoptosis, cell growth, and chemotaxis.21”

Superoxide,hydrogen peroxide, and nitric oxide serve as defensive compounds. Phagocytic cells, including macrophages, monocytes, neutrophils, and eosinophils, create ROS as part of their defensive mechanism. The binding of immune complexes, bacterial endotoxins, or other inflammatory agents to cell surface receptors triggers a respiratory burst in phagocytic cells. This localized production of highly reactive chemicals species oxidizes viruses, bacteria, and other foreign substances. Production of ROS follows a definite sequence: Initially, plasma membrane nicotinamide adenine dinucleotide phosphate (NADPH) oxidase releases superoxide, which undergoes dismutation to H2O2.Myeloperoxidase in lysosomes then transforms H202and chloride ion to hypochlorite, the same powerful oxidizer found in commercial bleach. Hypochlorite spontaneously reacts with amines and ammonia to produce very reactive chloramines. Furthermore, nitric oxide is produced, which reacts with molecular oxygen to yield nitrogen oxides NOz and N203,which are potent oxidizing agents. Note that the respiratory burst can activate xenobiotics.=

Inflammation Inflammation represents a major source of oxidants. Infection, toxic exposure, ischemia, and trauma activate phagocytic cells? Inappropriate activation of ROS production is potentially dangerous. Inflammation activates the arachidonic acid cascade, which converts polyunsaturated fatty acids to eicosanoids, lipid peroxides such as prostaglandjn (PG) G2and PGH, leukotrienes, and hydroxyeicosatetraenoic acid (HETE) via cyclooxygenase and lipoxygenase. The autooxidation of polyunsaturated fatty acids with three or more double bonds in membranes yields proinflammatory PGG2-likeisomers called F2 isoprostanes.” Isoprostanes represent important markers of radical-induced lipid peroxidation. The more or less continuous production of ROS by activated phagocytes during chronic, possibly low-level, inflammation may eventually deplete antioxidant Ensuing defenses, thus allowing ROS to attack ~ells.2~ tissue injury often impairs function in a downward spiral from health to disease. For example, free radicals and ROS are present at high levels in the colons of patients with ulcerative colitis.26

Oxidative Stress In an attempt to help develop theoretical models, certain global terms have been formulated. The term oxidative stress refers to a shift in the ratio of prooxidant/antioxidant balance and its consequence^.^^ Although cell damage may be implied, tissue changes that favor prooxidants are not necessarily detrimental. A redox imbalance can be due to excessive ROS production and/or to limited antioxidant defenses. Furthermore, endogenous defenses may be consumed or impaired by

ROS attack. Inadequate antioxidants could also be the result of inadequatedietary intake of antioxidant nutrients or chronic conditions such as malabsorption syndromes.

ANTIOXIDANTS Antioxidants are substances that inhibit the oxidation of a target molecule, often induced by free radical attackF8 Thus oxidative damage due to exposure to environmental pollutants such as ozone can be ameliorated with antioxidant^.^^ Antioxidants are both lipid-soluble and water-soluble. In addition, there is a "pecking order" among antioxidants; some are more readily oxidized than others and will be consumed rapidly unless replenished or recycled.30 Box 109-2 lists the primary and secondary antioxidant defenses, including enzymes,

Detoxication Enzymes Superoxide dismutases (copper, zinc, manganese) Catalases (iron) Glutathione peroxidases (selenium) Glutathione transferase (glutathione)

Auxiliary Proteins Glutathione reductase (niacin, glutathione) Glucose-6-phosphate dehydrogenase (niacin) Albumin Transferrin (iron) Ferritin (iron) Ceruloplasmin (copper) Metallothionein (cysteine)

Vitamin Antioxidants Betacarotene (provitamin A) Vitamin C Vitamin E (tocopherols)

Plant Antioxidants (Nonvitamins)

nutrients, and metabolites, that protect against free radicals and ROS. Certain antioxidants are preventive inhibitors, which block the initiation of free radical attack (Figure 109-2). Preventive inhibitors include defensive enzymes such as catalase, superoxide dismutase (SOD), and peroxidases as well as the tripeptide glutathione. Beta-carotene, chelating agents such as organic acids, and plant polyphenols also represent preventive antioxidants when they quench singlet oxygen or sequester metal catalysts. Other antioxidants function us chain breakers, which convert free radicals to stable products and thus block free radical chain reactions. Vitamin E and ascorbic acid are essential chain-breaking antioxidants (Figure 109-3).

Enzyme Antioxidants Antioxidant enzymes either neutralize a free radical, superoxide, or they catalyze the breakdown of peroxides which can generate free radicals. Furthermore, viable antioxidant enzyme production decreases with age?* The following three types of enzymes detoxify ROS are recognized:

SOD Catalase Glutathione peroxidase These enzymes occur throughout the body in cells, tissues and fluids.

Superoxide Dismutase SOD very rapidly converts superoxide to H2OPBecause H202may yield dangerous hydroxyl radicals if allowed to accumulate, SOD cooperates with catalase to break down H202to water and with glutathione peroxidases to inactivate both H202and lipid peroxides. By "dismutating" superoxide to H20> SOD intervenes before ROS causes damage. The mitochondria1

Carotenoids and xanthophylls Phenolic acids and polyphenols Diketones Tocotrienols

ROH + 0 2

'ROOH

02-*uperoxide

Metabolites Coenzyme Qlo Uric acid Cysteine Glutathione Polyfunctional organic acids (citric acid, malic acid) Bilirubin, biliverdin Alpha-lipoic acid Histidine Melatonin Peptides (carnosine, anserine)

GSH p e r o x i d a s e h H2O + 0 2

H202-(6atalase,

dismutas*

H202 + 0,

Figure 1042 Preventive antioxidants.

RO HQ

0,

-[ (

Beta-carotene Tocopherol \->H20+ROH Coenzyme Q , ~)

Figure 109-3 Chain-breaking antioxidants.

enzyme requires manganese, whereas the cytoplasmic form requires copper and zinc. These trace mineral nutrients are often classified as antioxidants, although it is their enzyme host that more accurately deserves this classification. Evidence for the role of SOD in preventing damage comes from a variety of sources. Aorta from copper-deficient rats contains less Cu-SOD activity and more lipid peroxidation than nondeficient ExtracellularSOD found in vessel walls may have a major role in regulating the vascular level of superoxide.33 Manganese (Mn) SOD is induced during acute inflammation.34Patients with a familial dominant form of amyotrophic lateral sclerosis (ALS) possess a defective gene that decreases cytoplasmic SOD by 40Y0.~Although mutations in the SOD gene account for only 1%of ALS cases, this area has been key in understanding the pathology of the disease. The level of SOD in the cerebral cortex of patients with Alzheimer's disease is 25% to 35%lower than in the brains of healthy people.%Further evidence for the involvement of SOD in neurologic abnormalities comes from studies with transgenic animals that overexpress SOD or knockout animals that are enzyme-deficient as well as from SOD mutations in some cases of familial ALS, although the precise mechanism is Administering SOD bound to polyethylene glycol together with catalase reduces reperfusion injury in heart and kidney and induces lung injury in animals.% The SOD gene has been cloned and is being studied. As an example, premature infants have been treated with prophylactic recombinant human SOD in pilot studies.39Oral supplementation with coated plant or liver Cu/Zn SOD has anecdotally been noted to ameliorate symptoms in some patients with inflammatory conditions and sunburn. Unlike mammalian enzymes, a coated, non-soy legume-derived SOD resists the action of pancreatic enzymes, and a small double-blind, placebo-controlled study suggested that oral ingestion of this material can increase the activity of erythrocyte SOD within 4 hours.40

Catalase An iron-dependent enzyme, catalase occurs widely in

cells and is a component of peroxisomes, which generate H202 through oxidative metabolism. Catalase seems specifically designed to prevent a buildup of H20p Animal studies with catalase, usually in conjunction with SOD, suggest protection against ischemic injury to the retina;' intestinal ROS damagela and radiation.& The transcytosis of catalase and SOD across capillaries has also been observed.MExamination of human atherosclerotic coronary arteries revealed that vascular antioxidant enzymes including catalase were selectively elevated in smooth muscle cells and macrophages in atheroscleroticlesi0ns.4~

Glutathione Peroxidases A family of enzymes known as glutathione peroxidases functions with catalase. They require reduced glutathione to reduce cytoplasmic H202 as well as lipid peroxides. Unlike catalase and SOD, glutathione peroxidases use the trace mineral nutrient selenium in the form of selenocysteine. For this reason, selenium is sometimes referred to as an antioxidant nutrient. Glutathione peroxidases exist as several isofonns. Phospholipid hydroperoxide glutathione peroxidase can reduce membrane lipid peroxides to readily metabolized, nontoxic fatty acid alcohols.46In the lung, antioxidant enzymes, including extracellular glutathione peroxidase, are induced by exogenous oxidative stress, such as associated with lung diseases." Lipoxygenase and phospholipid glutathione peroxidase constitute a "yin-yang" regulatory mechanism controlling the oxygenation of polyunsaturated lipids and regulation of cell function.& Selenium plays a role in the induction of glutathionerequiring enzymes, including five peroxidases. Thioredoxin reductase is a selenocysteine-containingenzyme that catalyzes the reduction of thioredoxin. Nearly 60% of plasma selenium is represented by selenoprotein P, which seems to function in protecting endothelial cells of the liver and glomerular capillaries from oxidative damage independent of peroxidases." In vitro, selenoprotein P protects against peroxynitrite-induced damage and reduces phospholipid hydroperoxides.5" More than 30 mammalian selenoproteins have been detected, but the functions of most of them remain unkn0wn.5~ Defensive enzymes are often inducible. For example, in animal models, exhaustive exercise causing oxidative stress was found to raise levels of SOD, glutathione peroxidase, and glutathione transferase; however prior supplementation with vitamin E and selenium reduced ROS production, and lesser amounts of detoxification enzymes were induced.52 In human atherosclerotic coronary arteries, catalase, glutathione peroxidase, and SOD were upregulated in atherosclerotic lesions, possibly as the result of oxidative stress.45Deprenyl, a monoamine oxidase B inhibitor, has been shown to increase the lifespans of several animal species. This drug upregulates SOD and catalase in the brain as well as the heart, kidneys, adrenals, and spleen, leading to the proposal that deprenyl may protect the neuroimmunoendocrine system against oxidative stress in the aging pr0cess.5~ Results of studies of the effects of training on antioxidant capacity have been mixed. As examples, a study of a cohort of Canadian men and women found no significant correlation between erythrocyte glutathione peroxidase and exercise level.% In marathon runners and sprint-trained athletes, SOD activity was significantly higher than in controls at rest. In marathon runners SOD rose immediately after strenuous exercise, but lipid

peroxidation increased early in the postexercise period. SOD was not altered by sprints in sprint-athletes, and lipid peroxidation also increased early after exercise, suggesting that both strenuous exercise and exhaustive exercise may temporarily overwhelm antioxidant defenses in trained athletes.55When male volunteers were subjected to a 10-week endurance training program, selenium supplementation with 180 kg selenomethionine daily had no effect on exercise-induced adaptations, nor did muscle glutathione peroxidase activity respond to exercise or to selenium supplementation.56

Other Defensive Enzymes Glutathione transferase adds glutathione to potentially toxic substances and is considered a component of phase II detoxificationenzymes. Non-selenium-dependent glutathione peroxidase reduces aldehydes produced by radical-induced fragmentation of polyunsaturated fatty acids, and epoxides produced during detoxification, in addition to peroxides. Like glutathione peroxidase, glutathione transferase requires a ready supply of reduced glutathione, produced by the action of glutathione reductase from oxidized glutathione. In turn, glutathione reductase requires NADPH, dependent on a robust glucose metabolism. NADPH and glutathione serve other reductases that help regenerate tocopherol and ascorbate, demonstrating the principle that overall metabolic balance is a prerequisite for adequate antioxidant defense.15Our knowledge of innate antioxidant defenses continues to expand. For example, recent research indicates that antibodies are able to catalyze the conversion of singlet oxygen, a reactive form, to hydrogen peroxide, which can be neutralized by ~ a t a l a s e . ~ ~

Nutrient Antioxidants Vitamin E (Tocopherols) Vitamin E refers to eight fat-soluble compounds, of which alpha-tocopherol is the most active in the usual biologic test systems (although some human models, such as the red blood cell [RBC] membrane stabilization test, suggest that other forms may be more active). Vitamin E is acknowledged as the primary chain-breaking antioxidant of lipids, lipoproteins, and membranes. In addition, vitamin E contributes to membrane r e p a p ; it blocks the formation of nitro~oamines,5~ helps protect low-density lipoprotein (LDL) against oxidative damage,60,61 reduces symptoms of tardive dyskinesiaperhaps by reducing nerve damage62-and decreases platelet aggregation and blood clot formation.63Vitamin E also acts as an antiinflammatory agent and can promote beta cell activity. Supplementation of patients with type 2 diabetes with 800 IU vitamin E/day for 1month significantly reduced serum lipid peroxidation and

improved beta cell function in comparison with control subjects." Although several studies have indicated that supplementation with vitamin E can improve various aspects of the immune resp0nse,6~supplementation of apparently well-nourished elderly individuals with 200 mg vitamin E daily did not reduce the incidence of upper respiratory tract infections.& Patients with rheumatoid arthritis treated daily with 1200 mg vitamin E in addition to standard drug treatment experienced improvement in symptoms, decreased lipid peroxidation, and increased glutathione peroxidase activity.67 Vitamin E has been implicated in the reduction of cardiovascular disease. Observational studies of women and men suggest that increasing dietary vitamin E intake to more than 20 times the usual intake in a Western-type diet can reduce the risk of heart disease and its manifestations, such as myocardial infarction, among low-risk

population^.^,^^ Nevertheless, most randomized trials with patients at risk for congestive heart disease (CHD) have found that even high-dose vitamin E supplementation did not differ from placebo in terms of cardiovascular disease mortality in subjects monitored for several years.70Thus supplementation with 400 IUvitamin E/day in high-risk patients did not improve outcomes after a mean followup of 4.5 years.7I Similar results were reported by the Collaborative Group of the Primary Prevention Project." In the Alpha Tocopherol Beta Carotene trial, there was no marked association between supplementation with 50 mg vitamin E/day and coronary heart disease or angina in male smoker^.^*^^ The Cambridge Heart Antioxidant Study demonstrated a large, sigruficant reduction in nonfatal myocardial infarction among patients with atherosclerosis who had been supplemented with vitamin E (400 or 800 IU) compared with those receiving a placebo for a median of 1.4 years.75However, there was no reduction in cardiovascular mortality. On the other hand, when a large population at high risk of dying from coronary disease was treated with a combination of 600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene daily for 5 years, there was no sigruficant reduction in 5-year mortality according to a recent Large-scale randomized primary trials currently under way may help resolve remaining issues. The Heart Outcome Prevention Evaluation trial was extended (median follow-up of 7 years). In this randomized trial, 3994 patients with either diabetes or heart disease received placebo or 400 IU/day natural vitamin E. In these patients with advanced disease, vitamin E did not reduce the incidence of cancer or major cardiovascular events. The authors reported a somewhat increased risk of heart failure in the vitamin E group."

Naturally Occurring Antioxidants

How might antioxidants reduce the risk of heart disease?According to the ”oxidation hypothesis’’ of cardiovascular disease, the oxidation of LDL and other lipoproteins helps initiate atherosclerosis. Each molecule of LDL possesses an average of seven molecules of alpha-tocopherol, but less than one molecule of betacarotene. On the other hand, vitamin E accounts for only 30%of total antioxidants present in LDL in some people. Supplementation with 800 IU of alpha-tocopherol daily for 3 months increased the tocopherol level in isolated LDL and decreased the rate of LDL lipid peroxidation by 40y0.~~ Vitamin E may reduce the risk of neurodegenerative disease. A high intake of vitamin E and vitamin C was associated with a reduced risk of Alzheimer’s disease according to the Rotterdam studyn In a controlled trial, alpha-tocopherol was administered at a daily level of 2000 IU to patients with moderately severe Alzheimer’s disease.s0With vitamin E supplementation, there was a 230-day delay in the onset of severe dementia or death in comparison with controls, although there was no improvement in cognition with supplementation. These data lend support to the possible involvement of oxidative stress in neurodegenerative disease and a role for antioxidant supplementation in therapeutic programs. A protective role of vitamin E in cancer is less clear: The Nurses’ Health Study failed to confirm a reduced risk of breast cancer in patients with high intakes of vitamins E and C.81In the Alpha Tocopherol Beta Carotene trial, treatment with 50 mg vitamin E/day decreased the incidence of prostate cancer as well as mortality due to this disease in heavy male smokers.n Other studies suggest an inverse association between vitamin E intake8* and supplemental vitamin E on the risk of prostate cancer, especially sm0kers.8~ Whole foods provide mixtures of tocopherols, including alpha, beta, and gamma isomers, and the typical U.S. diet supplies twice as much gamma-tocopherol as the alpha form. Alpha-tocopherol predominates in the body, probably owing to selection by tocopherol-binding protein in the liver. Gamma-tocopherol,not the alpha form, selectively blocks peroxynitrite, although it is a weaker antioxidant than alpha-tocopherol. Gamma-tocopherol seems to complement the actions of alpha-tocopherol in blocking ”electron-loving” mutagens and acting as an antioxidant.84 Supplementing with alpha-tocopherol, a form common in commercial supplements, may not be as effective as using natural mixed tocopherols. One study found no correlation between body stores of gamma-tocopherol and the risk of heart attack, suggesting that this isomer may not offer protection against heart disease.% Tocotrienols are a form of vitamin E having an unsaturated side chain. The antioxidant literature on these

compounds is meager compared with vitamin E. They appear to complement tocopherols. Tissue distribution of tocotrienols, coenzyme Qlo (CoQlo),and vitamin E differ, suggesting that selective mechanisms maintain the lipid antioxidants in various tissues.86 In vitro tocotrienols are potent antioxidants. In addition, they can inhibit human breast cancer cell line, possibly by mechanisms independent of their antioxidant properties. They can also inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductase and thus potentially could inhibit cholesterol synthesis.87However, treatment of hypercholesterolemic patients with 250 mg mixed tocotrienyl acetatedday for 8 weeks did not reduce cholesterol levels, although this treatment lowered the rate of LDL oxidation and improved resistance to lipid peroxidation by 22%.88 Tocopherol and other chain-breaker antioxidants become radicals as they deactivate potentially toxic substances. The tocopheryl radical (chromanoxyl radical) does not readily attack lipids and proteins and will decompose unless converted back to tocopherol by ascorbic acid, glutathione, and CoQlo, illustrating the theme that antioxidant defenses complement one The dietary reference intake (RDI) for vitamin E is 15mg. This intake is believed adequate to prevent myopathy and neuropathy. An earlier study found that healthy people consuming balanced diets supplying the daily requirement of vitamin E experienced less oxidative damage when supplemented with 100 mg vitamin E dailyg1The daily vitamin E requirement can vary dramatically according to factors that increase oxidative stress, including an increased consumption of polyunsaturated fatty acids, even with as little as 2.5 g of fish oil daily.92 The best sources of vitamin E-such as unrefined vegetable oils, wheat germ, liver and eggs-represent high-fat foods, and it is difficult to provide high levels of vitamin E in the usual diet without supplementation. Synthetic alpha-tocopherol contains a mixture of D and L isomers; only the D form (actuallyRRR-alpha-tocopherol) is active in the body. Esterified alpha-tocopherol is considerably more stable than unesterified tocopherol, and supplemental forms incorporate acetate, succinate, or palmitate, which are readily hydrolyzed and absorbed during digestion. As with other fat-soluble vitamins, absorption of vitamin E depends on fat digestion and absorption. Therefore conditions that impair fat digestion and assimilation reduce tocopherol uptake, and supplementation is prudent in patients with malabsorption syndromes.

Ascorbic Acid (Vitamin C) A prominent, water-soluble antioxidant, ascorbic acid (vitamin C) occurs in body fluids and the cytoplasm.

Pharmacology of Natural Medicines

Ascorbic acid is one of the most efficient chain-breaking antioxidants in human plasmag0;it can react with a wide range of ROS and other oxidants, including superoxide, singlet oxygen, hypochlorite, and sulfur radicals.91 Ascorbic acid protects lipids and membrane from oxidative damage by scavenging peroxyl and hydroxyl radicals.% It is also reported to reduce the risk of cataracts and retinal increase immune function and detoxi~ation,9~ and decrease heavy metal Ingested ascorbic acid reduces the gastrointestinal production of nitrosamines and fecal mutagens." These factors help explain why higher ascorbic acid intake is linked to a reduced risk of cancers of the oral cavity and esophagus," stomach,* colon, and lung.'O0 Observational studies suggest that ascorbic acid has at most only a modest effect on the risk of coronary heart disease. Ascorbate supplementation can reduce plasma LDL oxidation.'O' A combination of ascorbate with vitamin E is possibly more effective than ascorbate alone for older adults.'02 In other research, patients who had recently undergone heart transplant surgery were supplemented with 1000 mg vitamin C and 800 IU vitamin E or placebo daily. After 1 year, arteries had narrowed by 8% in controls, compared with no arterial narrowing in supplemented patients.lo3Serum ascorbic acid is depleted in patients with inflammation in peripheral arterial disease and reduced lower limb blood flow.'04 There is some evidence that supplementation with ascorbic acid may lower blood pressure in hypertension. However, the effect of 500 mg vitamin C/day was sigruficant only during the first month of treatment, suggesting only a short-term benefit.lo5Current randomized trials may clanfy the role of ascorbic acid supplementation on cardiovascular disease risk. Data from the Rotterdam Study suggest that a high intake of ascorbic acid and vitamin E is associated with a reduced risk of Alzheimer's disease, especially among cigarette smokersn Plasma ascorbic acid is a biomarker of oxidative stress. For example, cigarette smoking depletes the ascorbic acid pool and decreases the body's capacity to maintain plasma ascorbic acid in the reduced (bioactive) form.lMLike the tocopheryl radical, the ascorbyl radical is relatively stable and has little tendency to attack cells. Dehydroascorbate can be reduced back to ascorbate by glutathione and NADPH by redox recycling. In animal models, high levels of ascorbate can compensate for low glutathione production, and vice versa. Ascorbic acid functions with glutathione and lipoic acid to regenerate alpha-tocopherol. Possibly during inflammation or injury, released iron or copper and ascorbate play a prooxidant role. Note that supplemental antioxidants may transiently increase oxidative stress after strenuous exertion. In a study of acute muscle injury due to eccentric exercise in volunteers,

supplementation immediately after injury with vitamin C, 12.5 mg/kg, and N-acetylcysteine, 10 mg/kg, transiently induced oxidative stress compared with p1aceb0.l~' Excessive dietary iron or iron accumulation could also promote ascorbate-induced oxidation. The DRI for vitamin C is 90 mg for men and 75 mg for women. However, convincing evidence that the recommended dietary allowance for (healthy young) men should be at least 200 mg is based on careful tissue saturation studies.lo8 Similar studies found that young healthy women may require 90 mg ascorbic acid/day.lW Lifestyle choices such as cigarette smoking increase the need for vitamin C.

Carotenoids and Vitamin A Carotenoids represent more than 500 different (red, orange, yellow) plant pigments and are conveniently divided into carotenes and xanthophylls (oxygenated carotenes). The best-known carotenoid is beta-carotene. Although it is the most abundant in nature, betacarotene does not stand alone: In green leafy vegetables xanthophylls make up 90% of the carotenoids. Betacarotene represents only one quarter to one third of the carotenoids in plasma.'1° Carotenoids exhibit tissue specificity. Thus, betacarotene is the major carotenoid in liver, adrenal gland, kidney, ovary, and adipose tissue, and lycopene, a red carotene from tomatoes, is prevalent in testes and human plasma."' Lycopene effectively quenches free radicals, although it does not form vitamin A.112 Lutein and zeaxanthin are xanthophylls that accumulate in the body: They are the only carotenoids found in the retina and macula of primates. Lutein and lycopene are plentiful in blood. Levels of these carotenoids in blood are not affected by vitamin A status. Plasma alpha-carotene,beta-carotene, and lutein are useful biomarkers of carotenoid-rich food consumption, and lutein may serve as an intake biomarker for the Cruciferae (cabbage) farnily.Il3There is a preferential uptake of lutein and zeaxanthin from the intestine into chylomicrons, a general carrier of lipid nutrients.'14 In general, carotenoids are versatile antioxidants; lycopene, lutein, zeaxanthin, and others complement the antioxidant activity of beta-carotene. Beta-carotene absorbs energy from singlet oxygen and releases it as heat. This carotenoid is especially effective at low oxygen tension, as found in tissues, where it can scavenge peroxyl radicals and alkoxyl radicals.l15 Carotenoids also enhance immune function, regardless of their provitamin activity. They quench ROS due to inflammation, help maintain membrane receptors, and modulate the release of prostaglandins and leukotrienes.116,117 Increased carotenoid levels have been associated with decreased LDL oxidation.118The greater consumption of carotenoids, especially lutein and zeaxanthin, correlates with a lower

Naturally Occurring Antioxidants

risk of advanced, age-related macular degenerati~n."~ In one study, supplementing with beta-carotene in combination with vitamin E, vitamin C, zinc, and copper slowed the progression of advanced, age-related macular degeneration. Several epidemiologic studies suggested an inverse correlation between carotenoid consumption and several forms of cancer, including lung cancer.121,122 Later cohort studies found an inverse association between lycopene and alpha-carotene intake, but not betasarotene intake, and the risk of lung cancer. Lung cancer risk was reduced by a diet that provided a variety of carotenoids.lZ Increased serum levels of beta-carotene, lycopene, and lutein/zeaxanthin were shown to be inversely related to mortality from all causes and to cancer mortality in Japanese subjects.l" The beneficial effects of carotenoids in chemoprevention of cancer are thought to occur through protection against oxidative stress and immune enhancement.lZ Nonetheless, the results of intervention studies with beta-carotene supplementation in cancer have been mixed. A study of Finnish men who had a decade-long history of heavy cigarette smoking and alcohol use found an increased risk of lung cancer with betacarotene supplementation, but not in subjects administered both vitamin E and beta-carotene.lZ6Subjects who had the highest level of serum beta-carotene at the beginning of the study-indicative of a greater intake of fruits and vegetables-had the lowest risk for development of lung cancer. Another intervention trial suggested that beta-carotene raised the risk of cancer in high-risk groups (smokers or persons exposed to asbest~s).'~' In contrast, the Linxian, China, study, which involved administering beta-carotene, vitamin E, and selenium to marginally malnourished people, lowered the risk of cancer mortality.lZ8The Physicians' Health Study did not detect any positive or negative effects on the incidence of cancer or heart disease after 12 years of supplementation with beta-carotene.IB Overall, intervention studies have not demonstrated that supplemental vitamin E and beta-carotene can prevent or treat coronary disease." The failure to find a reduced risk of lung cancer with beta-carotene supplements is consistent with the generally accepted view of the chemopreventive properties of antioxidants: They can block cancer initiation and early promotion but are less effective during very late stages of carcinogenesis. Increased serum/plasma levels of carotenoids have been associated with a reduced risk of coronary heart disease.131 Although the antioxidant properties of carotenoids were hypothesized to prevent coronary heart disease, five primary prevention trials with betacarotene found no reduction in the risk of this disease with beta-carotene supplementation, such as 50 mg/day. As examples, men and women enrolled in a study to

prevent nonmelanoma skin cancer experienced no reduction in mortality from all causes or from cardiovascular disease when supplemented with 50 mg beta-carotene daily for a mean of 4.3 years and &year follow-up.132 The Physician's Health Study I did not detect any significant effect on the incidence of cancer or heart disease after more than 12 years of treatment with 50 mg betacarotene (alternate days) and follow-up.133The second study of this series, PHS II, examines the effects of betacarotene as well as vitamin E, vitamin C, and multivitamins on the incidence of prostate cancer and age-related eye diseases, in addition to cardiovascular disease.133 The synthetic form of beta-carotene represents the all trans isomer, whereas fruits, vegetables and algae provide varying amounts of the 9-cis isomer together with minor carotenoids. The 9 4 s isomer appears to be a somewhat more efficient antioxidant.lMNatural mixed carotenoids containing alpha- and beta-carotenes as well as xanthophylls were better absorbed, and they functioned as more effective antioxidants in vivo than synthetic (all trans) beta-~arotene.'~~ (For additional discussion of the broad impact of carotenoids on health, see Chapter 71.) Vitamin A can act as a free radical trap and lipid peroxyl radical scavenger; it contributes to the antioxidant status of LDL, for e ~ a m p 1 e .Cutaneous l~~ vitamin A and vitamin E may be complementary antioxidants to reduce ultraviolet light-induced damage.13' Vitamin A analogues, such as 1 3 4 s retinoic acid and trans retinoic acid, can also reduce lipid peroxidation in vitro. However, the major role of vitamin A and its derivative in most tissues remains the regulation of transcription and translation in differentiation.

Antioxidants Produced by the Body Glutathione A sulfhydryl-reducing agent, glutathione is a tripeptide that contains cysteine. Glutathione occurs in high (millimolar) concentrations in most cells and plays many roles. It serves as a detoxifying agent, assists amino acid transport, quenches free radicals, and helps regulate the internal redox environment of cells. As a substrate for glutathione peroxidases, glutathione plays a key role in antioxidant defenses. In addition, glutathione reacts directly with singlet oxygen, hydroxyl radicals, and superoxide radicals to form oxidized glutathione (GSSG).l%Glutathione reductases regenerate reduced glutathione (GSH) and the ratio of GSH to GSSG is normally more than 100:1.138 Together with ascorbate, GSH participates in the regeneration of vitamin E, which emphasizes the cooperation of antioxidants. Oxidative stress reduces this ratio, activates transcription factors, and increases production of interleukin-1 and tumor necrosis f a ~ t 0 r .Depletion l~~ of intracellular glutathione is associated with immunodeficiency.

Pharmacology of Natural Medicines

Patients with acquired immunodeficiency syndrome

(AIDS)appear to have low levels of reduced glutathione, which could activate transcription factor NF (nuclear factor) kappaB to increase transcription of the human immunodeficiency virus (HN) genome." A clinical study demonstrated that low GSH levels in CD4 T cells from HIV-infected subjects is associated with a decreased survival of 2 to 3 years.14' Low glutathione levels are also associated with a variety of chronic conditions, such as diabetes, age-related macular degeneration, gastrointestinal disorders, and neurodegenerative disease, although cause and effect remain to be established in this disease state. N-Acetylcysteine is an effective precursor for glutathione, and oral supplementation with this substance can raise intracellular GSH'" in model systems and in healthy individuals,'43 but not necessarily in patients with AIDS.14 Indeed, HIV in clinically stable patients may not be specifically associated with oxidative stress.145

Higher blood levels of glutathione correlate with higher levels of health in elderly subjects.'& Whether glutathione concentrations predict aging and whether low glutathione is a cause of aging remain to be determined. Initial research suggested that oral glutathione can increase plasma glutathione concentrations in animals.147However, it now seems unlikely that orally administered reduced glutathione can raise tissue glutathione levels in humans, on the basis of the observation that a 3-g bolus did not increase plasma glutathione or cysteine.l& Certain cancer chemotherapiesas well as radiotherapy rely on induced apoptosis and other free radical actions, and debate regarding the safety of providing antioxidants during chemotherapy continues. Intravenous glutathione has been used prior to cisplatin administration in order to reduce the severity of cisplatin-induced nephrotoxicity in patients with ovarian cancer,'49 and before oxaliplatin administration to reduce the druginduced nephrotoxicity. Significantly, GSH did not diminish the effects of chemotherapy on the colonic tumors.lm Further clinical studies are needed to clarify the safety and efficacy of antioxidant treatment with chemotherapy. The use of doxorubicin (Adriamycin), an effective chemotherapeutic agent, is limited by cardiotoxicity, and antioxidants may be effective in reducing the drug-induced oxidative stress.'51 Intramuscular glutathione injection, 600 mg on alternate days for 2 months, has been used for ir~ferti1ity.l~~

Coenzyme Qlo (Ubiquinone) Ubiquinones are a family of fat-soluble antioxidants containing 1 to 12 isoprene units. The predominant form in humans is ubiquinone 10, or CoQlo. Long recognized

as a lipophilic electron carrier in mitochondria1ATP production, CoQloalso stabilizes membranes and functions as an important antioxidant that can recycle tocopher01.I~~ CoQlois also involved in the regulation of gene expression, possibly via superoxide as a second messenger.'% CoQlocan enhance the immune system,155and it has been used to improve the health statusin patients with angina,'56 hypertension and insulinre~istance,l~~ and various cardiornyopathies.lMCoQlois generally recognized as an adjuvant therapy for chronic heart failure.'59J60In addition, CoQlosupplementation before cardiac surgery can improve cardiac function and reduce postoperative stress.'61 CoQlo may also improve immune function in patients with HIV infection."j2Ubiquinol, the reduced form of CoQlo, protects LDL against lipid peroxidation.'@ Patients with cancer are often low in CoQlo, and preliminary studies suggest that treatment with CoQlo may be helpful in treating patients with advanced breast cancer.164 The largest benefits of CoQlosupplementation apparently occur in those who are the most deficient in this coenzyme.'65 CoQlo synthesis requires vitamins B2, B6, B12 and folate, and synthesis may not be optimal in people with a low intake of these important vitamins. The normal value for CoQloin plasma is approximately 0.4lmol/L, mostly in the reduced form. Ubiquinol is readily oxidized, and dietary forms are ubiquinones, which are readily reduced after absorption. A decline in lipid peroxidation in plasma after supplementation with CoQlo supports an antioxidative role for CoQ10.166 Certain drugs also lower serum levels of C O Q ~ OThey .~~~ include beta blockers and HMG-CoA reductase inhibitors. However, the necessity of CoQlo supplementation in these situations has not yet been established.

Alpha-Lipoic Acid Alpha-lipoic acid (ALA) was initially classified as a vitamin. However, later research demonstrated that ALA is synthesized in humans and animals. As a coenzyme of pyruvate dehydrogenase and alpha-ketoglurate dehydrogenase, ALA is required in the catabolism of carbohydrate and fatty acids. Isolated ALA exists in the oxidized or disulfide form. This is reduced to the sulfhydryl form, dihydrolipoic acid, by many tissues indicating its antioxidant potential. Exogenous ALA is both watersoluble and fat soluble. In tissues, ALA is able to regenerate endogenous antioxidants, including ascorbic acid and glutathione, which in turn recycle vitamin E. Furthermore, ALA scavenges hydroxyl radicals, peroxynitrite, superoxide, and peroxyl radicals-all strong oxidizing agents.la Pharmacologic doses of ALA have been used to treat a number of disease states. The derived benefits probably reflect the antioxidant potential of this compound.

Naturally Occurring Antioxidants

The antioxidant capacity of plasma increases after tea Intravenous ALA has been used to treat diabetic peripheral neuropathy. In one study doses of 600 mg IV or consumption, and most of this increase is due to higher 1800 mg orally daily for 3 weeks led to sigruficant uric acid concentrations.l@ improvement in Total Symptom S ~ 0 r e s .ALA l ~ ~ was also found to improve glucose tolerance and insulin sensitiv- Polyfunctional Organic Acids Citrate, fumarate, succinate, malate, and tartrate can ity in patients with type 2 diabetes when administered either 1200 mg/day orally for 4 weeks or 500 mg/day IV bind (chelate) transition metal ions and block ROS production, thus acting as preventive antioxidants. These for 10 ~ e e k s . ' ~ ~ Although J'~ placebo-controlled studies showed that neuronal conduction improved in diabetic acids require the presence of chain-breaking antioxidants for maximum effectiveness. Not all chelates confer patients with neuropathy following oral ALA treatment, properties; for example, iron-ascorbate and there was no sigruficantimprovement in ~ y m p t o m s . l ~ ~ antioxidant J~ iron EDTA complexes catalyze oxidation. Tartaric acid High-dose ALA is approved in Germany for the treatcan enhance the bioavailability of wine polyphenols.184 ment of diabetic neuropathy. ALA has also been used to treat radiation poisoning Melatonin and HIV infection. Children exposed to radiation during In addition to helping set the body biorhythms, endocrine the Chemobyl disaster who were treated with ALA secretion, and sleep patterns, the hormone melatonin alone or with vitamin E experienced better organ funcalso acts as an antioxidant in vitro and in vivo.185The cention and less oxidative stress.In A small open trial with HIV-positive patients suggested that ALA supplementatral nervous system consumes 20% of the oxygen used daily and thus is likely to generate ROS at a high rate. tion might reduce lipid peroxidation, improve antioxidant status, and increase ratios of helper-to-suppressor Hypothetically, conditions involving damage by free radicals to DNA could be aggravated by light suppresT cells.174Whether ALA can reverse age-related organ sion of melatonin.ls6 Melatonin production and sleep decline in humans remains unknown. Resultsof animal studies are provocative. Mitochondria may play a pivotal part in preventing oxidative damage decay with age, due to oxidation of their constituent of nerves.IE7In senescence-accelerated mice, long-term administration of physiologic levels of melatonin cormacromolecules, including catabolic enzymes. Feeding rected hepatic mitochondria1 dysfunction, suggesting rats very high doses of acetylcamitine and ALA (0.5%in chow) partially reversed this decay as indicated by that melatonin may reduce oxidative damage associated with aging.Iss In addition, pretreatment with melatonin reduced oxidative stress, partial reversal of the decline in sigruficantly reduced cardiac damage resulting from activities of key enzymes, as well as increases in hepatic cellular respiration and ambulatory activity.175Feeding ischemia-reperfusion injury in rats.189Whether melatonin is effective in treating or preventing neurodegenerhigh-dose ALA to aged rats for 2 weeks reduced myocardial oxidant production to levels observed in healthy ative disease such as Alzheimer's disease remains to be established. Although melatonin is sometimes sold as a young rats.176Aging is also associated with neurodegeneration, and animal studies suggest that high-dose ALA food supplement, it is actually a potent hormone. and/or acetyl-L-camitine can improve brain function, Storage and Transport Proteins: increase the activity of key catabolic enzymes,ln Ferritin, Transfernn, Ceruloplasmin, decrease brain lipid peroxidation, and increase brain Metallothionein antioxidant enzyme activities.178 Free iron and copper ions catalyze the conversion of Uric Acid (Urate) H202to hydroxyl radicals; therefore proteins that bind Uric acid is a waste product of a purine metabolism these ions help protect tissues against ROS. Under that occurs in high levels in plasma. Urate is a broadnormal circumstances, it is questionable whether unbound iron is normally present in cells. However, spectrum antioxidant capable of scavengingfree radicals and of chelating transition metals.179Uric acid is responwith chronic inflammation, iron may be released from ferritin, and potentially this unbound iron may pose a sible for 21% to 34% of the total plasma antioxidant hazard. Iron storage disease is linked to oxidative activity, in which it appears to protect alpha-tocopherol damage. Transferrin (which has a high affinity for iron) from peroxyl radicals." Also, assays of total antioxidant and ceruloplasmin (which binds copper) can be considcapacity (TAC) based on crocin bleaching indicated ered part of the antioxidant defenses." Iron stored in that 49% of the TAC activity in human plasma is due to ferritin does not participate in generation of free radiuric acid.181 In patients with acute ischemic stroke, cals. Another intracellular cysteine-rich protein, metalserum TAC strongly correlated with uric acid levels. lothionein, binds many metals, including copper. It is Levels of both vitamin C and uric acid were lower in patients who had experienced stroke than in controls.182 induced by cytokines, toxic metals, and oxidative stress.

Pharmacology of Natural Medicines Mitochondrial-specific ROS generators can increase the production of metallothioneinin liver by 3.7- to 11.8-fold in mice, far more than SOD or glutathione peroxidase.lg1 Similarly, acute ethanol-induced hepatotoxicity and associated oxidative stress were curtailed in mice that had been genetically manipulated to overexpress metallothionein, compared with wild-type mice.192

Whether higher consumption of flavonoids can reduce the risk of cancer and cardiovascular disease is not clear from currently available studies.202Among Finnish men and women, individuals with increased quercetin intake had lower mortality due to heart disease, and the risk of cerebrovascular disease was inversely related to intake of kaempferol, naringenin, and hesperidin. Men with the highest intake of quercetin Nonnutritive Antioxidants had a lower incidence of lung cancer, and those with the Flavonoids highest intake of myricetin had a reduced risk of The typical diet provides a wide range of substances of prostate cancer. In addition, the incidence of asthma was plant origin that play important roles in maintaining lower with greater intakes of quercetin, naringenin and health. Many act as antioxidants. One of the largest he~peridin.2~~ classes is the flavonoids, found mainly in fruits, leaves, On the other hand, there was no strong relationship stems, and roots of vegetables, legumes, and tea. between flavonoid intake and total coronary heart Flavonoids potentiate the effects of vitamin C and prodisease among American male health professionals?04 tect other easily oxidizable substances. More than 40oO Among elderly Dutchmen dietary catechins were not flavonoids have been reported; undoubtedly more associated with a reduced risk of lung cancer or epithelial cancers.2o5In a cohort of postmenopausal American remain to be discovered. Natural phenolics include flavonoids (anthocyanidins, catechins, flavanones, women, dietary catechins were inversely proportional only with the incidence of rectal cancer.2o6Quercetin can flavones, flavonols, and isoflavones); tannins (ellagic Ascorbic acid enhances the inhibit melanoma ~ells.2~' acid, gallic acid); phenyl isopropenoids (caffeic acid, inhibition of cancer cells by fisetin and quercetin in vitro, coumaric acids, ferulic acid); lignans; and other substances, including catechol, resveratrol (grape skins), suggesting that ascorbate potentiates the action of flavonoids as chemoprotective agents?08 Case-control and rosmarinic acid (rosemary). Substantial amounts of ingested quercetin, a common flavone, are absorbed studies suggest a protective effect of apple and red wine by the gastrointestinal tract in humans.'" Quercetin consumption on asthma severity in adults; this associaand kaempferol, another flavone, are among the most tion may reflect their flavonoid content.209 abundant flavonoids in the diet. Previous estimates of daily consumption of total Antioxidant properties are the best-documented charflavonoids ranged from 200 to 1000 mg daily. However, acteristic of flavonoids. Antioxidant properties, physioaccurate food consumption data and refined analytical logic activities, bioavailability, and other properties are methods based on high-performance liquid chromatogfunctions of the chemical structure of flavonoids." The raphy indicate that for northern European elderly men, total phenolic content of common plant foods and beverthe mean daily intake of the putative anticancer ages has been found to correlate with total antioxidant flavonoids was only about 23 mg daily, with quercetin activity in ~ i t r 0 . l ~ ~ being the predominant flavonoid?10 Though quercetin Various flavonoids inhibit peroxidation in vitro by consumption was low, this flavonoid level represents scavenging ROS, superoxide, hydroxyl radical, and sinsubstantially more antioxidant activity than the typical glet oxygen. For example, rutin, myricetin, and quercetin daily consumption of vitamin E or beta-carotene.Furtherscavenge s ~ p e r o x i d e 'and ~ ~ block LDL 0xidati0n.l~~ more, this level of flavonoid consumption correlated Flavonoids from bilberries and grapes were able to with a decreased risk of cardiovascular disease2I0but not protect collagen from superoxide-induced damage.19* of cancer?ll Flavonoids can also bind transition metals, limiting Botanical Extracts their ability to catalyze free radical formation.199Some flavonoids also inhibit the induction of nitric oxide Botanical extracts have been used for centuries by natusynthase, for example during ischemia-reperfusion ral health care practitioners. Research has now demoninjury.2ooExcessive nitric oxide poses a potential probstrated that much of their clinical efficacy is due to their lem because it reacts with radicals to form peroxynitrite, flavonoid constituents, which are often organ specific. which can severely damage cells. Xanthine oxidase Silybum marianum and Other releases superoxide, and this activity can be inhibited Hepatoprotective Botanicals by quercetin, among others.2ooSeveral flavonoids possess antiinflammatory properties. They may inhibit Milk thistle extracts containing silymarin,212extracts of both the cyclooxygenase and 5-lipoxygenase pathways, Indian herbs such as Picrorhiza kurroa,213 Eclipta a1ba,2l4 thus limiting the production of proinflammatory and Tinosporu c0rd@fOlia,2~~ and combinations of these eicosanoids.201 extracts concentrate flavonoids in the liver, where they

Naturally Occurring Antioxidants

exert hepatoprotectiveeffects. Oxidative stress is a prime feature of liver disease, and antioxidantsmay potentially play important therapeutic roles.216Because liver detoxication promotes autoxidation due to ROS produced by cytochrome Pqm,217 the antioxidant properties of these botanical flavonoids largely explains the beneficial effects of these plant extracts in normalizing liver function. In addition to scavenging ROS and inhibiting the 5-lipoxygenase pathway, silymarin has other properties, such as modification of gene expression. The preponderance of evidence suggests that silymarin is a useful adjunct in the treatment of alcoholic liver Tinospora cordifolia extract has been found to reduce lipid peroxidation and increase glutathione, catalase, and superoxide dismutase levels in diabetic rats.219 Pretreatment with extracts of Picrorhiza kurroa can protect against experimentalhepatic ischemia-reperfusion injury in part through its antioxidantproperties.220 In vitro studies with human cells found these extracts to reduce oxidant-induced DNA damage and cytotoxicity.221

Proanthocyanidins and Anthocyanidins A variety of plant sources yield a family of flavonoids called proanthocyanidins. Often they are chained together (oligomers); hence the name oligomeric proanthocyanidins (OPCs).Pine bark and grape seeds are typical commercial sources. Animal experiments indicate that grape seed extracts can limit lipid peroxidation in the brain, suggesting that constituents or their colonic fermentation products are absorbed and cross the blood-brain barrier.w Short- and long-term exposure studies have not indicated appreciable toxicity or side effects for grape seed O P C S . ~ Laboratory animals fed OPCs from grape seeds demonstrated cardioprotection against ischemia-reperfusion compared with control animals.224Furthermore, pretreatment with grape seed OPCs protected against experimentally induced hepatotoxicity, pulmonary toxicity, doxorubicin-induced cardiotoxicity, and drug-induced immunotoxicity in mice.225 Preparations of European pine bark (Pycnogenol) have been used as supplements for capillary dysfunction in patients with diabetes and for other venous abnormalities, including retinal hemorrhage.226Pycnogenol protects against ROS and raises levels of antioxidant enzymes in vitro. It can also help regenerate vitamin E and attenuate vitamin C.226Pycnogenol can inhibit the production of ROS in cultured macrophages as well as the activation of nuclear transcription factors involved in the expression of proinflammatory cytokines, such as interleukin-l-beta.=' These observations suggest that OPCs may be useful in reducing inflammation, and a pilot study reported that Pycnogenol si&cantly reduced inflammation associated with systemic

lupus erythematosus.22sFurthermore, cell culture experiments demonstrated that Pycnogenol may prevent neurons from amyloid-beta-induced apoptosis by suppressing ROS and reducing DNA f r a g m e n t a t i ~ n . ~ ~ O K s are also major constituents of legume-derived polyphenols, which inhibit peroxynitrite-induced apoptosis in human colonic cells, a model system for gut inflammation.m French men consume a high-fat diet yet appear to have a lower mortality due to heart disease. Several explanations have been proposed for the so-called French paradox. Of particular interest is the correlation of heart protection with red wine consumption, although the mechanism is u n k n ~ w n . ~ ' The cholesterol-lowering effect of spirits is not unique to wine. However, red wine contains abundant tannins and other polyphenols, including caffeic acid and anthocyanidins, and drinking red wine increases the antioxidant capacity of serum.232,233 In animal models, grape polyphenols protect against ethanolinduced neuronal damage.= Such experiments suggest the absorption of polyphenols and related derivatives. Red wine has a higher phenol antioxidant index as measured against isolated LDL than white wine.235 Red wine polyphenols can inhibit vascular smooth muscle cells but not endothelial cells in vitro. The mechanism may involve downregulation of expression of cyclin A gene, a cell cycle regulator.% Grape skins and red wine contain resveratrol, a polyphenolic compound, and phytoalexin, a compound produced by plants in response to environmental stressors. Exposure to resveratrol correlates with a decrease in myocardial damage associated with ischemiareperfusion and inhibition of LDL oxidation.237This substance apparently inhibits platelet aggregation and eicosanoid syntheses and blocks cellular events linked to tumor initiation, promotion, and progression.238 These effects seem to be independent of its antioxidant properties.

Catechins Tea is a rich source of polyphenols that are highly substituted with hydroxyl groups. Catechin and gallic acid derivative-including epigdocatechin, epigdocatechin3 gallate, and epicatechin-3 gallatefunction as radical quenchers in vitr0.239,240 Tea consumption has been linked to a lower risk of cancer, and antiproliferative effects seem to be a function of polyphenol content."' There is also in vitro evidence that green tea catechins may block signal transduction pathways and induce apoptosis in tumor cells?@Green tea polyphenols may also block nitric oxide production implicated in inflammation243 and reduce DNA oxidation, lipid peroxidation, and free radical production in smokers?44The relationship between catechins and cancer incidence

Pharmacology of Natural Medicines is conflicting. For example, cat& intake was found to be inversely associated only with redal cancer risk among postmenopausal women in the United Urokinase, a proteolytic enzyme overexpressed in many cancers, can be inhibited by green tea flavonoids. In addition, green tea prevented loss of liver superoxide dismutase, glutathione peroxidase, and catalase activities, which were due to chronic alcohol consumption in laboratory animals, while protecting membrane lipids from peroxidation.246Thus, green tea polyphenols probably have multiple effects in the body, including quenching of radicals. Green tea extracts free of caffeine are now commercially available (see Chapters 74 and 77).

Infusion of amyloid beta protein has been used in a rat model of neurotoxicity. Dietary curcumin suppressed both microgliosis oxidative damage and neuropathology and prevented Abeta-induced spatial memory deficits, which are relevant to Alzheimer’s disease.= Rabbits fed an atherogenic diet with curcuminoids exhibited lower levels of plasma lipid peroxides and had higher levels of CoQlo and alpha-tocopherol than controls lacking curcuminoids. The supplemented animals also had fewer aortic fatty streak lesions.257 Curcuminoids are diketones, not flavonoids, emphasizing the point that many other plant ingredients besides polyphenols may function as antioxidants and as anticarcinogens. Garlic serves as a second example of this class of Other Botanicals botanicals. Garlic contains a wide range of organosulfur Extracts of Ginkgo biloba have long been known to supcompoundswith multiple physiologicactivities, including port vascular function and cerebral insufficiency. It antioxidant properties. Allicin inhibited nitric oxide proseems probable that active constituents, gdgolides, duction in stimulated cardiac myocytes by inhibition and related flavonoids reduce oxidative ~ t r e s s . 2 ~ As~ 2 ~of nitric oxide synthase, while Sally1 cysteine inhibited oxidant-induced damage to cultured endothelial cells examples of this research, pretreatment with the extract and inhibited the formation of hydrogen peroxide EGb 761 reduced skin damage induced by ultraviolet B light in laboratory Mice supplemented with induced by oxidized LDL.258z9Rabbits fed an atherogenic diet and garlic extract had sigruficantly better EGb 761 also had less ROSinduced apoptosis in lymphocytes than untreated mice; this result was larger in antioxidant status and reduced plaque area compared old mice than in young animals.25o with animals not fed garlic.260In addition, aged garlic Cell culture studies suggest that EGb 761 can generacts as an antioxidant in vivo. A pilot study of smokers ally raise glutathione levels and induce gammaand nonsmokers found that supplementation daily glutamylcysteinyl synthetase, the rate-limiting enzyme with aged garlic extract for 2 weeks lowered levels of 8-iso-prostaglandin FZ, a rather specific marker of in glutathione synthesis.251Rats treated with EGb 761 radical-induced lipid oxidation.261 had increased catalase and superoxide dismutase activity and reduced lipid peroxidation in the hippocampus, striatum, and substantia nigra than controls.252 COMPARISON OF ANTIOXIDANTS Culinary herbs contain potent antioxidants. A comparison of culinary and medicinal herbs found that There are several points to consider in comparing antioxthe phenolic content and radical-quenching properties idants. Studies of the quenching activity of antioxidants of ahnary herbs were appreciably higher. The most frequently employ single time points measured at a potent culinary herbs were dill, oregano, marjoram, and single concentration of antioxidant (end-point assay). sweet bay Among medicinal herbs, thyme, peppermint, This practice can lead to erroneous conclusions in comand St. John’s wort were notable. The total radical parisons of the effectiveness of antioxidants. A far more absorbance capacity was directly proportional to the reliable approach evaluates the IC%,the concentration of total phenolic content of both types of herbs.253Turmeric antioxidant yielding 50% inhibition of a given oxidant has a long history of use in Eastern traditions as a or radical. The smaller the ICw, the more efficient the seasoning and as a medicinal herb. Curcuminoids antioxidant. Using DPPH (diphenyl picrylhydrazyl are the bright yellow pigments isolated from this radical), one of the test systems used for measuring free source. These lipids limit the metabolism of environradical quenchingF6*pine bark OPCs, a study found that mental mutagens and they possess antioxidant and grape seed OPCs and polyphenols from lentil effectively antiinflammatory activities. Consumption of 200 mg quench organic free radicals.230It is important to comof curcuma daily by healthy subjects decreased serum pare antioxidant activity in several systems, such as lipid peroxide levels and in HDL and LDL lipid superoxide, lipid peroxidation in LDL or microsomes, peroxidation.254Animal studies suggest that consump- and chemiluminescenceto detect the formation of reaction of curcumin can limit lipid peroxide-induced tive oxygen species. The order of decreasing effectivecataracts and that curcumin may suppress colon ness of these superoxide quenchers is as follows: ~ancer.25~ lentil-derived polyphenols > ascorbic acid > quercethB1

Naturally Occurrin On the basis of ICs0 values calculated from radical

quenching with spin-labeled substrate, epicatechin gallate was shown to be the most effective catechin in human blood plasma. It was also the most effective in protecting alpha-to~opherol.~~~ Using inhibition of NADPH-dependent lipid peroxidation of rat liver microsomes, one study found that catechins have IC5,, values between 10 and 51 pM, and galloyl catechins were more effective than simple catechins. In this membrane system, antioxidant activity was a function of lipophilicity as well as ease of

Antioxidants and Regulation of Cell Function After the in vitro effectivenessof an antioxidant has been demonstrated, the following question arises: “Does this antioxidant improve cellular function?” Antioxidants possess multiple actions that may or may not be directly related to their free radical scavenging activity and the curtailment of oxidative damage. Current interest focuses especially on molecular mechanisms affecting the redox status of the cell and the regulation of redoxdependent gene expression. The transcription factor IW-kappaB regulates the production of multiple inflammatory cytokines and adhesion molecules. This factor is upregulated during aging and may contribute to age-related chronic diseases such as rheumatoid arthritis. In human monocytes alphalipoic acid can prevent tumor necrosis factorstimulated production of intracellular adhesion molecule (ICAh4-1 expression). It does so by inhibiting the binding of NF-kappaB to DNA?6 Apoptosis (programmed cell death) is also regulated by a complex pathway involving activation of transcription factors, and relies on the cellular redox balance. Oxidative stress induced by ROS triggers apoptosis in several model systems, and apoptosis may be regulated by antioxidant^.^^^,^^^ Indeed, conditions ranging from diabetes mellitus and heart failure to HIV infection may entail altered apoptosis.267 Thioredoxin and thioredoxin reductase represent a widespread endogenous redox-regulating system with multiple roles in intracellular signaling and resistance to oxidative stress. Thioredoxin is a small sulfhydryl protein capable of recycling antioxidants by reducing oxidized forms of ascorbic acid, alpha-lipoic acid, CoQlo, as well as selenocysteine-dependentenzymes and regulatory proteins. Thioredoxin also promotes the activation of several transcription Antioxidant vitamins can have far-reaching effects on tissues. Thus vitamin E supplementation can reduce the induction of the protein kinase C pathway in hyperglycemic aortas. This pathway regulates endothelial cell permeability and cell proliferation, and in this case,

vitamin E inhibits the migration and proliferation of vascular smooth muscle cells, opening the possibility of reducing the risk of vascular disease associated with type 2 It is of interest that alpha-tocotrienol inhibited monocyte adhesion by endothelial cells more than alpha-tocopherol. The mechanism of inhibition of expression of adhesion molecule-1 and E-selectin was found to be NF-kappaB dependent.270It is worthwhile to note that ascorbic acid plays critical roles in hormone synthesis and wound healing in serving as a cofactor for hydroxylation reactions. Phytochemicals have multiple effects, ranging from enzyme inhibition to enzyme induction via alteration of signal transduction. Certain carotenoids enhance immune function, regardless of their provitamin activity. For example, supplementation of healthy male nonsmokers with 15 mg of beta-carotene daily for 26 days increased the function of isolated blood monocytes, suggesting that higher beta-carotene consumption may enhance cell-mediated immunity.lE Flavonoids, in particular, often have multiple effects, so they are often regarded as “biologic response modifiers.” Furthermore, there are indications that certain polyphenols can alter several enzyme activities, and interactions with cell receptors as well as enzymes remain an important arena of flavonoid research. There is a growing awareness of the necessity of understanding the impact of flavonoids on the oxidative stress that contributes to mutagenesis and apoptosis. Consumption of green tea and red wine flavonoids as well as of oligomeric proanthocyanidins can lower various indices of oxidative stress, such as plasma malondialdehyde and F2-isoprostanes (from fatty acid peroxidation), tissue inflammation, and urinary output of oxidized DNA bases. Effectiveness of an antioxidant in vivo relies on adequate absorption and assimilation. Water solubility of polyphenols would likely favor intestinal uptake; however, quercetin is readily absorbed despite its minimal water solubility.193The effects of bioactive ingredient or ingredients in botanical extracts are seldom completely understood. An additional complication is the fact that intestinal bacteria degrade complex polyphenols to simple phenolic acids, which may be more bioactive than the starting material. For example, red wine polyphenols are absorbed and metabolized to glucuronide conjugates, which possess antioxidant activity in pla~ma.2’~ Gastric cleavage of higher procyanidin oligomers to monomers and dimers increases their bioavailability. Flavonol monomers including epicatechin are extensively 0-methylated, sulfated, or conjugated as glucuronides during absorption into the circulation. However, studies of the in vivo properties of these derivatives is in its infancy2”

Pharmacology of Natural Medicines

The Adequacy of Antioxidant Defenses Protection by free radical scavengers is limited, and free radical damage is not completely prevented even in healthy people. All cells lack an enzyme defense against hydroxyl radicals, the most damaging species. Therefore when free radical production exceeds the scavenging systems, hydroxyl radicals can be released, causing severe cellular damage. The body's ability to respond to oxidative stress is a function of age, inheritance, medical history, level of exposure to pollutants and other environmental stressors, and diet.

Age Because repair mechanisms decline with age, the body gradually loses functional resiliency, especially to oxidative stress. According to the free radical theory of aging, aging represents progressive oxidative damage." Ames et all1 have estimated that the average human cell sustains 10,000 DNA "hits" per day. Although most of this damage is repaired, unrepaired damage accumulates with age. Subtle structural alterations occur first, leading to decreased repair of damaged membranes and DNA, ultimately limiting the function of the nervous, endocrine, and immune systems." The rate of free radical formation by mitochondria in nondividing tissues is negatively related to animal longevity. Thus long-lived animals have less oxidation of mitochondria1 DNA, but not of nuclear DNA, than short-lived animals.274The production of superoxide anions and expression of SOD are common denominators of various degenerative processes. Studies with genetically engineered laboratory animals (both transgenic and knockout) as well as human SOD mutations provide a direct link between free radical scavenger enzymes and aging.275Evidence suggests that cumulative ROS damage to mitochondria leads to the decrease in ATP production associated with aging. Supplemental antioxidants result in the sign& cant extension of the mean lifespan in laboratory animals. Potentially antioxidants could block ROS at their sites of production, the mitochondria.276

Inheritance Owing to heredity, the levels of protective enzymes can vary among individuals.People who possess low levels of these enzymes face greater risks of free radical-induced disease. This distinction is blurred somewhat because these enzymes are often inducible, and greater enzyme synthesis occurs in many organs, such as liver and lung, as they adapt to increased oxidative burden (upregulation of antioxidant defense enzymes)."

Medical History and Environmental Exposure Processes such as trauma, inflammation, and infection generally increase ROS production. Oxidative stress

sometimes accompanies drug treatment. Cigarette smoke, ozone, oxides of nitrogen, solvents, and pesticides can cause toxicity when radicals are created during their detoxification. The gut epithelium does not appear to adapt to long-term oxidative stress and, because of low initial levels of defensive enzymes, may be especially susceptible to oxidative damage with even moderate inflammation.278 Strenuous physical exercise increases ROS production, and supplementing with antioxidant vitamins such as E, C and CoQlo may decrease associated oxidative damage, especially in older people?79 and increase LDL antioxidant capacity in endurance However, the conflict between exercise-induced oxidative stress and the obvious benefits of exercise has not been entirely resolved. Indeed, certain benefits of exercise may be oxidant-mediated. Whether supplemental antioxidants are needed to counteract the increase in oxidative stress has not yet been established, but athletes who exercise strenuously are likely to benefit from higher antioxidant intake.281In addition, antioxidants may attenuate muscle cell damage following strenuous exercise. Thus supplementation with 1200 IU alpha-tocopherol daily for 4 weeks before 6 days of endurance running reduced the leakage of creatine b a s e and lactate dehydrogenase compared with placebo.282

Nutritional Status Americans do not consume enough antioxidants, and the trend seems unlikely to change in the foreseeable future. Perhaps only 10% to 20% of adults eat a minimum of five daily servings (3 to 5 cups) of fruits and vegetables.283a World Health Organization recornmendations for fruits and vegetables entail a minimum combined intake of about 400 g/day/person, as 250 g vegetables and 150 gfruit per person. Median intakes of key antioxidants indicate that the consumption of vitamins C and E, betacarotene, zinc, selenium, copper, and manganese are low for specific segments of the population, and far below the recommended daily allowances (RDAs) for some. Furthermore, the RDAs do not address contributing factors related to chronic diseases, lifestyle choices, or medical history, nor do they address the issue of the mutually supportive roles of antioxidants. Europeans may not consume enough antioxidants. On the basis of the 1998 German Nutrition Survey, substantial numbers of healthy women and men do not consume recommended intakes for several vitamins, including antioxidants such as vitamin E.285The immune system, in particular, requires ample antioxidant nutrients.286The health of the immune system represents a key predictor of longevity. Antioxidants protect immune cells against oxidative damage and limit the production of noninflammatory eicosanoids. For example, supplementing apparently healthy, elderly people

Naturally Occurring Antioxidants

(who were consuming an otherwise typical diet) with 60 to 800 mg vitamin E improved several aspects of cellSeveral mediated immunity within 6 to 12 studies also suggest that consumption of 200 mg/day vitamin E may be more effective than 800 mg/day. In other research, ingestion of 268 mg natural vitmin E per day for 8 months sigxuficantly reduced serum immunoglobulin E with apparently normalization of most lesions in patients with atopic d e r m a t i t i ~If. ~one ~ extrapolates from such data, antioxidant supplements may profoundly affect healthy aging. Overall the studies suggest that the RDAs for this nutrient and other antioxidants are inadequate for optimal immune function for certain groups.

GUIDELINES FOR USE OF ANTIOXIDANTS Antioxidants represent powerful additions to the health care practitioner’s armamentarium. However, their application in treatment protocols requires an understanding of their strengths and limitations. No single supplement, nutrient, or food can maintain the body’s antioxidant defenses: There are simply too many oxidants to be neutralized and too many layers of antioxidant defenses to be sustained, and the range of reactivities of water- and lipid-soluble ROS is far too great. Thus it is unrealistic to expect that one or more antioxidants will be completely effective in disease prevention or treatment. Indeed, the often negative or conflicting results reported from clinical trials may reflect wide variations in the nutritional status and heterogeneity of antioxidant intake in the study populations. Clearly, multiple nutrients, including vitamins, minerals, and other food factors, are essential to ensure normal function of organ systems such as the cardiovascular system. A basic strategy is to gear supplementation to correct any imbalances in an individual’s nutritional status. Multiple, complementary antioxidants are far more effective than large amounts of a single antioxidant. Often antioxidants work synergistically. An additional consideration is that antioxidant requirements should be balanced against oxidant burden. Thus, exposure to pollutants such as cigarette smoke, nitric oxides, and ozone as well as chronic inflammation raises oxidative stress. High intake of fish oil and polyunsaturated fatty acids increases the need for vitamin E. The goal is to support the body’s defense system rather than to quench all free radicals in the body, which would be counterproductive. Superoxide and nitric oxide play essential roles in maintaining the body’s defenses and homoeostatic mechanisms, for example. Greater consumption of antioxidant-rich foods-especially colored fruits, vegetables and legumes, and beverages such as green tea-may

generally be the most effect way to increase intake of a broad spectrum of defined and undefined antioxidants. Analysis of vegetable and fruit intake from a cohort of American male nonsmokers supports the contention that vitamin C is an especially critical antioxidant for health-promoting effects of fruits and vegetables.2N

PRECAUTIONS IN USING ANTIOXIDANT SUPPLEMENTATION The clinician should take the following precautions when using antioxidant supplementation in patients: 1. The uptake, assimilation and disposal, dosage, duration of treatment, effects of mixtures, and longterm safety of polyphenols are generally not well studied.291 2. Flavonoids are metabolized and detoxified by liver enzymes, and pharmacologic doses may increase toxin burden. Some flavonoids can induce phase I detoxification enzymes, increasing the ability to transform toxins. The tradeoff lies in the possible greater sensitivity to mutagens. In this context, quercetin at typical dietary levels appears to be a possible anticarcinogen in V ~ V O . ~ ~ ~ 3. Vitamin E can exacerbate hypertension in susceptible people. High levels may antagonize other fat-soluble vitamins, thus decreasing bone mineralization. This vitamin may be contraindicated in patients receiving anticoagulants or in those with a vitamin K def i~iency.2~~ 4.Large doses of vitamin C rarely increase oxalate production; the effects seems to be counterbalanced by increased vitamin B6h1take.2~~ 5. Excessive iron and iron overload may cause hydroxyl radical production in viv0.2~~ 6. Beta-carotene could act as a prooxidant, unless protected by other antioxidants such as vitamin E, when there is excessive oxidative stress (smoking, alcohol consumption) and when diets are inadequate. Beta-carotene may raise the risk of lung cancer in high-risk populations unless protected by antioxidants like vitamin E.296In addition, betacarotene may exacerbate liver abnormalities in patients with alcoholic liver disease. In one study, the rate of fatal coronary heart disease rose in patients receiving 20 mg/day beta-carotene (with or without alpha-to~opherol).~~ High levels of betacarotene may be contraindicated in smokers with myocardial infarctions. 7 . h antioxidant in one system is not necessarily an antioxidant in all systems. For example, vitamin C and vitamin E exhibit prooxidant activity in vitro under certain conditions. When exposed to catalytic levels of

iron or copper ions, ascorbate promotes the formation of H202 and hydroxyl radicals."JMIn vitro studies suggest that ascorbic acid can decompose lipid peroxides to gen0toxins.2~~ In vivo, these effects would likely require high ascorbate concentrations coupled with the depletion of tocophero1.l" 8. Prooxidant effects of carotenoids are poorly understood, and consumption of large amounts could be hazardous themselves in susceptible individuals. Carotenoids generally lose their effectiveness at high concentrations and at high partial pressures of oxygen. This feature may account for the possible benefits of consumption of carotenoid-rich foods even though therapeutic doses of isolated carotenoids may be deleterious.298Depending on the concentration of supporting antioxidants, even flavonoids can become prooxidants. Prooxidant activity of polyphenolic radicals is well documented.299 9. Vitamin A is a teratogen when the intake is 25,000 IU or more per day for several months. The general advice to women who are or who might become pregnant is to limit both their daily intake of vit& A from supplements to no more than 5000 IU/day (1500 pg) and their consumption of liver and liver products.300The current tolerable upper intake level for vitamin A is 3000 pg (10,000 IU).301 10. Nutrient-drug interactions and phytochemical-drug interactions are additional important considerations. The literature in this area, although steadily growing, remains incomplete. A number of reviews have been published.302mThe following examples are illustrative of such interactions: Taking vitamin C with flavonoids can stabilize the vitamin and increase its uptake.= Lycopene reacts synergisticallywith either vitamin E, rosmarinic acid (from rosemary), glabridin (from licorice), or garlic to block LDL oxidation.N5 Studies with transformed cell lines suggest that flavonoids such as myricetin and quercetin can inhibit the uptake of dehydroascorbate and ascorbic acid, potentially reducing intracellular ascorbic acid.% Silybin can potentiate the activity of the chemotherapeutic agent cisplatin in animal models.N7 Certain flavonoids can decrease cyclosporin uptake in laboratory animals.308 Quercetin inhibits the sulphation of certain drugs (dopamine, salbutamol, paracetamol, minoxidil) in the duodenum and liver of rats.Molecular modeling studies suggest that flavones can interact with benzodiazepine-binding sites and thus may compete with this class of drugs.310 Oral tangeretin seems to inhibit the tumor inhibition actions of tamoxifen in animal models.3lI

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SELECTING ANTIOXIDANTS The traditional definition of an essential nutrient (e.g., mineral or vitamin) is too restrictive from the perspective of lifelong protection against chronic disease. The presence of vast numbers of nonvitamin antioxidantsin addition to established nutrients in vegetables, legumes, fruits, and grains-poses the question whether those antioxidants are in fact essential in the diet for optimal health and disease prevention. The consumption of vegetables and fruits by well-nourished individuals reduces the risk of radical-induced DNA damage. Because short-term interventions with vitamin C or E, beta-carotene, or flavonoids have not demonstrated this benefit, the data suggest that other plant food factors account for such protection.312 Consequently, antioxidant supplementation cannot substitute for a prudent diet, cessation of smoking, and regular exercise. Supplementation may be most effective for those individuals with the lowest baseline antioxidant levels whether from genetic or environmental causes. Foods supply a rich assortment of substances that can function as antioxidants. As an example, the total oxygen radical capacity of certain fruits has been determined.313 Strawberry, plum, orange, red grapes, kiwi fruit, and grapefruit possess high radical-quenching activity. Blackberry, blueberry, raspberry, strawberry, plums, red wine, and red grapes contain large amounts of anthocyanidins with strong antioxidant ~roperties.3~~ Further research will undoubtedly uncover many more phytochemical interactions. Though the picture is far from complete, antioxidants apparently operate ~ynergistically.~~~ Thus, animal studies indicate that consumption of a greater diversity of antioxidants provides more antioxidant protection than Even members of the vitamin B single complex, such as pantothenic acid, may indirectly stimulate antioxidant prod~ction.3'~ A number of studies recognize the importance of supplementation with complementary antioxidants.For example, daily supplementation with vitamin C (500 mg), vitamin E (400 IU), beta-carotene (15 mg), zinc (80mg), and copper (2 mg) sigruficantly slowed the progression of advanced agerelated macular degeneration. In one study, however, this regimen did not affect the risk of cataracts or loss of visual acuity.121In other research CoQlo,vitamin E, and alpha-lipoic acid synergistically protect LDL against lipid peroxidation in vitro?l8 It should be emphasized that many ingredients in foods play important physiologic roles in addition to their properties as antioxidants. Furthermore, their effects may be indirect; antioxidants and response elements help the cell adapt to ROS exposure and correct ROS-induced damage.319Exploration of the role of

Naturally Occurring Antioxidants

I

Recommended safe upper intake levels for antioxidant nutrients

Vitamin E

1000 mg'

Vitamin C

2000 mg'

Vitamin A

3000 pg*

Beta carotene

None established (Five or more servings of fruits and vegetables would provide an estimated 3-6 mg beta carotene daily.)

Copper

10 mg*

Magnesium

250 mg+

Selenium

300 pg*

Zinc

40 mg'

From Flynn A, Moreiras 0.Stehle I? et al. Eur J Nutr 2003;42:118-130. "US. Food and Nutrition Board, Institute of Medicine Tolerable Upper intake Levels. +EuropeanCommission SCF, Tolerable Upper Intake Level.

1.Kovacic P, Jacinth0 JD.Mechanisms of carcinogenesis: focus on oxidative stress and electron transfer. Curr Med Chem 2001;8: 773-796. 2. Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82:47-95. 3.Ross JS, Stagliano NE, Donovan MJ, et al. Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann N Y Acad sci 2001;947271-292. 4. Iuliano L. The oxidant stress hypothesis of atherogenesis. Lipids 2001;36S41-S44. 5. Ottonello S, Foroni C, Carta A, et al. Oxidative stress and agerelated cataract. Ophthalmologica 2000;2147&85. 6. DOdorico A, Bortolan S, Cardin R, et al. Reduced plasma antioxidant concentrations and increased oxidative DNA damage in inflammatory bowel disease. Scand J Gastroenterol 2001;36: 1289-1294. 7. Tak PP,Zvaifler NJ, Green DR, Firestein GS. Rheumatoid arthritis and p53 how oxidative stress might alter the course of inflammatory diseases. Immunol Today 2000;21:7&82. 8.Rahman I. Oxidative stress, transcription factors and chromatin remodeling in lung inflammation. Biochem Pharmacol 2002;64: 935-942. 9. Esposito E, Rotilio D, Di Matteo V,et al. A review of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerativeprocesses. Neurobiol Aging 2002;23:719. 10. Moosmann B, Behl C. Antioxidantsas treatment for neurodegenerative disorders. Expert Opin Investig Drugs 2002;11:1407-1435. 11. Ames BN, Shigenaga h4K, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci U S A 1993;90:7915-7922. 12. Wei YH, Lee HC. Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med 2002;227671-682.

a major oxidant, peroxynitrite, and nitrogen oxides as NRS ("nitrogen reactive species") in chronic degenerative diseases is still in its infancy3" Consequently, the antioxidants that best defuse these reactive compounds have not yet been established. Table 109-1 provides a s u m m a r y of a recommended intake of antioxidants for maintenanceas compiled by the European Federation of Health Product Manufacturers.301 The levels often prescribed in treatment protocols may be considerably higher than those listed in the table. Thus, the consumption of a broad spectrum of antioxidants in amounts geared to meet an individual's oxidant burden and nutritional status appears to be essential to promote optimal health and to minimize the effects of genetic predisposition that compromise defenses against aging, degenerative disease, and toxic chemical exposure. Future health claims for antioxidants must await additional studies, including intervention clinical trials demonstrating better function with supplementation and prospective studies exploring risk reduction for degenerative diseases.321

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Pharmacology of Natural Medicines 271. Yamashita S, sakane T, Harada M, et al. Absorption and metabolism of antioxidative polyphenolic compounds in red wine. Ann N Y Acad Sci 2002;957325-328. 272. Spencer JP,Schroeter H, Rechner AR, Rice-Evans C. Bioavailability of flavan-Sols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo. Antioxid Redox Signal 20013:1023-1039. 273. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol1956;11:298-300. 274.Baja G. Endogenous oxidative stress: relationship to aging, longevity and caloric restriction. Ageing Res Rev 2002;1:397-411. 275. Levin ED, Christopher NC, Lateef S, et al. Extracellular superoxide dismutase overexpression protects against aging-induced cognitive impairment in mice. Behav Genet 200292:119-125. 276. Miquel J. Can antioxidant supplementation protect against a g e related mitochondrial damage? Ann N Y Acad Sci 2002;959:508-516. 277.Visner GA, hugall WC, Wilson JM, et al. Regulation of manganese superoxide dismutase by lipopolysaccharide, interleukin-1 and tumor necrosis factor. J Biol Chem 1990;265:2856-2864. 278. Grisham MB, MacDermott RP,Deitch EA. Oxidant defense mechanisms in the human colon. Inflammation 1990;14669-680. 279. Goldfarb AH. Antioxidants: role of supplementation to prevent exercise induced oxidative stress. Med Sci Sports Exerc 1993; 25232-236. 280. Vasankari TJ, Kujala UM,Vasankari TM, et al. Increased serum and low density lipoprotein antioxidant potential after antioxidant supplementation in endurance athletes. Am J Clin Nutr 1W7;65:1052-1056. 281. Sen CK. Antioxidants in exercise nutrition. Sports Med 2001;31: 891-908. 282. Itoh H, Ohkuwa T, Yamazaki Y, et al. Vitamin E supplementation attenuates leakage of enzymes following 6 successive days of running training. Int J Sports Med 2000;21:369-374. 283.Block G. Antioxidant intake in the US. Toxicol Ind Health 1993;9:295-301. 284. Patterson BH, Block G, Rosenberger WF, et al. Fruit and vegetables in the American diet: data from the NHANES II Survey. Am J Public Health 1990;801443-1449. 285.Beitz R, Mensink GB, Fischer B, Thamm M. Vitamins-dietary intake and intake from dietary supplements in Germany. Eur J Clin Nutr 200256539-545. 286.Meydani SN, Santos MS, Wu D, Hayek MG. Antioxidant modulation of cytokines and their biologic function in the aged. Z Emahrungswiss 1998;3735-42. 287. Bogden JD, Bendich A, Kemp FW,et al. Daily micronutrient supplements enhance delayed hypersensitivity skin test responses in older people. Am J Clin Nutr 1994;60:437-447. 288. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. JAh4A 1997;277:1380-1386. 289. Tsoureli-Nikita E, Hercogova J, Lotti T, Menchini G. Evaluation of dietary intake of vitamin E in the treatment of atopic dermatitis. a study of the clinical course and evaluation of the immunoglobulin E serum levels. Int J Dermatol2002;41:146-150. 290. Block G, Norkus E, Hudes M, et al. Which plasma antioxidants are most related to fruit and vegetable consumption? Am J Epidemiol 2001;154:1113-1118. 291. Canada AT, Watkins WD, Nguyen TD. The toxicity of flavonoids to guinea pig enterocytes. Toxicol Appl Pharmacol 1989;99: 357-361. 292. Stavric B. Quercetin with our diet: from potent mutagen to probable anticarcinogen. Clin Biochem 1994;27245-248. 293. Meydani M. Vitamin E. Lancet 1995;345:170-175. 294.Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol 1999;10:840-845.

295. Toyokuni S. Iron-induced carcinogenesis: the role of redox regulation. Free Radic Biol Med 1996;20:553-566. 296. Paiva SA, Russell RM. Beta carotene and other carotenoids as antioxidants. J Am Coll Nutr 1999;18426-433. 297. Lee SH, Oe T, Blair IA. Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science 2001;292 2083-2086. 298. Young AJ, Lowe GM. Antioxidant and prooxidant properties of carotenoids. Arch Biochem Biophys 2001;385:20-27. 299. Galati G, Sabzevari 0, Wilson JX, OBrien PJ. Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics. Toxicology 2002;177:91-104. 300. Rothman KJ, Moore LL, Singer MR, et al. Teratogenicity of high vitamin A intake. N Eng J Med 19953331369-1373. 301. Flynn A, Moreiras 0, Stehle P, et al. Vitamins and minerals: a model for safe addition to foods. Eur J Nutr 2003;42:118-130. 302. Evans AM. Influence of dietary components on the gastrointestinal metabolism and transport of drugs. Ther Drug Monit 2000;22:131-136. 303. Brinker F. Herb contraindications and drug interactions. Sandy, OR Eclectic Medical Publications, 1998. 3 0 4 , V i i n JA, Bose P. Comparative bioavailability to humans of ascorbic acid alone or in a citrus extract. Am J Clin Nutr 1988;

48601-604. 305. Fuhrman B, Volkova N, Rosenblat M, A&am M. Lycopene synergistically inhibits LDL oxidation in combination with vitamin E, glabridin, rosmarinic acid, camosic acid or garlic. Antioxid Redox Signal 2OOO;2491-506. 306. Park JB, Levine M. Intracellular accumulation of ascorbic acid is inhibited by flavonoids via blocking of dehydroascorbic acid and ascorbic acid uptakes in HL-60, U937 and Jurkat cells. J Nutr 2000;130.1297-1302. 307. Giacomelli S, Gallo D, Appollonio P, et al. Silybin and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro and in vivo the activity of cisplatin. Life Sci 2002;701447-1459. 308. Chen HY, Wu TS, Su SF, et al. Marked decrease of cyclosporin absorption caused by phellamurin in rats. Planta Med 2002;68:' 138-141. 309. Marchetti F, De Santi C, Vietri M, et al. Differential inhibition of human liver and duodenum sulphotransferase activities by quercetin, a flavonoid present in vegetables, fruit and wine. Xenobiotica 2001;31:841-847. 310. Marder M, Estiu G, Blanch LB, et al. Molecular modeling and QSAR analysis of the interaction of flavone derivatives with the benzodiazepine binding site of GABA(A) receptor complex. Bioorg Med Chem 2001;9:323-335. 311. Bracke ME, Depypere HT, Boterberg T, et al. Influence of tangeretin on tamoxifen's therapeutic benefit in mammary cancer. J Natl Cancer Inst 1999;91:354-359. 312. Halliwell B. Effect of diet on cancer development: is oxidative DNA damage a biomarker? Free Radic Biol Med 2002;32: 968-974. 313. Wang H, Cao G, Prior RL. Total antioxidant capacity of fruits. J Agric Food Chem 1996;44:701-705. 314. Wang H, Cao G, Prior RL. Oxygen radical absorbing capacity of anthocyanidins. J Agr Food Chem 1997;45:304309. 315. May JM, Qu ZC, Whitesell RR, Cobb CE. Ascorbate recycling in human erythrocytes: role GSH in reducing dehydroascorbate. Free Radic Biol Med 1996;20:543-551. 316. Chen H, Tappel AL. Protection by vitamin E, selenium, Trolox C, ascorbic acid palmitate, acetylcysteine, coenzyme Q, betacarotene, canthaxanthin, and (+,-) catechin against oxidative damage to liver slices measured by oxidized heme proteins. Free Radic Biol Med 1994;16437-444. 317. Slyshenkov VS, Moiseenok AG, Wojtczak L. Noxious effects of oxygen reactive species on energy-coupling processes in Ehrlich

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320. Yermilov V, Rubio J, Ohshima H. Formation of 8-nitroguanine in DNA treated with peroxynitrite in vitro and its rapib removal from DNA by depurination. FEBS Lett 1995;376:207-210. 321 Van’t Veer P, Kok FJ. Human studies to substantiate health effects of antioxidants: what is needed? Free Radic Res 2000;33: S109-115.

Opuntia Species (Prickly Pear) Kathy Abascal, BS, JD, KH(AHG) Eric L. Yarnell, NI), RH(AHG) CHAPTER C O N T E N T S General Description 1113 Chemical Composition 1113 History and Folk Use 1113 Pharmacology 1114 Analgesic Effect 1114 Antiinflammatory Effect 1114 Antiviral Effect 1114 Cicatrizant Effect 1114 Diuretic and Other Renal Effects 1114 Hypoglycemic Effect 1114 Hypocholesteremic Effects 1115

Opuntia spp. (family: Cactaceae) Common names: prickly pear, nopal

GENERAL DESCRIPTION There are about 260 species of Opuntia.' These cacti are shrubs with many stems branching at their bases. The flat, pear-shaped pads are stems or branches, not leaves as many suppose. The true leaves are small and scalelike, and they wither away quickly. Some prickly pear varieties form thickets many feet tall and many feet across. Prickly pear's thorns are simple spines-they do not have radial or central spines. Their flowers range from yellow through orange and red to rose. Their fruits also come in shades of yellow through red to purple. Most species have glochids, sometimes referred to as tiny spines although they are actually leaf hairs with tiny retrorsed barbs.2 The stems, fruits, and flowers are all used as medicines.

CHEMICAL COMPOSITION Data comparing the constituents of the many prickly pear species are sparse to nonexistent, and there is no indication that any particular species is a better medicinal plant. The pad is high in mucilage, consisting of carbohydrate-containing polymers that typically have

Clinical Applications 1115 Diabetes (Adult-Onset Non-lnsulin-Dependent) 1115 Hyperlipidemia 1115 Prostatic Hyperplasia 1115 Weight Loss 1115 Dosage 1116 Toxicology

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Drug Interactions 1116

an alternating galacturonic acid-rhamnose backbone, although the polysaccharide structure of the mucilage varies in different species? The pads also contain a mixture of saturated and unsaturated long-chain aliphatic esters, malonyl daidzen, genistein, beta-sitosterol, and vanillic, ferulic, myristic, palmitic, and stearic acid^.^-^ Prickly pearfruits are high in carbohydrates and contain the pigments indicaxanthin, betanin, three varieties of methyl citrate, and l-methyl malate.7 The flowers contain flavonoids (quercitin and isorhamnetin-3 glucosides and 3-rutinosides, isorhamnetin 3-rhamnosylgalactoside, and kaempferol 3-galactoside) in varying amounts.8

HISTORY AND FOLK USE Prickly pear has a long history of medicinal use. The Aztecs used prickly pear root with Geranium spp. (cranesbill) as a febrifuge, to alleviate hernias, and to soothe irritated livers? The fruit and seeds were used to prevent diarrhea. Indigenous peoples along the Yaqui River used the fluid from roasted prickly pear pads to relieve pain.*O In New Mexico, prickly pear pads were used as poultices for painful, inflamed skin conditions, for swollen glands in the neck, and for congested, purplish breasts in lactating women. The pads were also used as emollients for tumors, warts, and calluses. The Tarahumara used 1113

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the pads for the pain of bites and burns, and the Paipai used them to heal festering wounds. The Yaqui and the Hispanics in New Mexico soak diced pads in water and drink the liquid for thirst and diabetes; they also use the roasted pad to treat diabetic infections. Prickly pear was brought from the Americas to Africa and Europe, and its medicinal uses followed." Today, the Moors apply the heated pads to swellings on the body, the South African Bantu use prickly pear for a variety of tumors, and Zimbabweans use prickly pear internally as a treatment for pain in gouty arthritis.12J3In the Canary Islands, prickly pearfruits are used topically for a variety of inflamed wounds and internally for gastrointestinal and bronchial problems. In the Mediterranean region, prickly pear pads are used to treat gastric ulcers, and in Sicilian folk medicine, a flower infusion is used for its diuretic and relaxant action on the kidneys.I4

PHARMACOLOGY Analgesic Effect Prickly pear fruits and pads had sigruficant analgesic effects in mice in the hot plate and writhing tests.15 Prickly pear fruit injected intraperitoneally (400 mg/kg) had an analgesic effect comparable to that of aspirin (70 mg/kg) in mice in the writhing test.

Antiinflammatory Effect Prickly pear sigruficantly reduced carrageenan-induced edema in rat paws and showed an antiinflammatory effect in the adjuvant-induced chronic inflammation model in mice.16 The active constituent was isolated and identified as beta-sitosterol. Another study showed that prickly pear (Opuntiu dillenii) fruit extract injected intraperitoneally (100 to 400 mg/kg) had an antiinflammatory action in mice.17 Pretreatment with prickly pear significantly reduced edema in a dose-dependent manner, and its maximal effect was similar to that of indomethacin. However, the fruit extract induced a much more transient effect than the reference drug.

Antiviral Effect Preliminary pharmacologic studies show prickly pear pad to have antiviral effects.18These effects were investigated after a patient with mild diabetes who suffered frequent recurrences of herpes genitalis reported that taking 2 g prickly pear a day stopped the herpes outbreaks. In vitro studies indicate that prickly pear displays some antiviral activity: In hamster kidney cells, prickly pear sigruficantly and specifically reduced herpes simplex virus type 2 (HSV-2) replication at 3.5 mg/ml and completely inhibited replication at 15 mg/ml. Also, prickly pear sigruficantly inhibited other herpes viruses (pseudorabies virus, bovine mammillitis virus, equine

herpes virus type 1 as well as the more cell-associated human herpes virus, cytomegalovirus, and varicella zoster virus). Prickly pear inhibited replication by HSV-2 in infected human cervix tissue at 15 mg/ml, and inhibited RNA virus replication, although inhibition was greater aftei pre-infection incubation in prickly pear medium." Testing involved a laboratory strain of influenza A virus, an isolate of respiratory syncytial virus, and strains oj encephalomyocarditis (EMC) virus and human immm odeficiency virus type 1 (HN-1). The only virus thai prickly pear failed to inhibit was the picomavirus EMC The researchers concluded that fresh prickly pear extraci showed significant inhibition of virus replication and that the inhibitory activity resided in the wall of thc plant. They found prickly pear to be a promising antiviral agent deserving of more study, because it combines a breadth of in vitro reactivity with a high index of clinical safety. However, prickly pear pads combined with freslCapsicumfrutescms (cayenne) fruit and fresh Citrus Iimon (lemon) did not protect chickens from Newcastle virus.'!

Cicatrizant Effect When administered by mouth, dried prickly pear pac (Opuntiuficus indicu) signhcantly inhibited hydrochloride induced, aspirin-induced, and ethanol-induced gastric lesions in rats.20,21 Prickly pear did not affect gastric juice secretion, acid output, or stomach pH in the rats Extracts of 0. ficus indicu showed significant wound healing activity in rats.=

Diuretic and Other Renal Effects Fruit and flower infusions of 0.ficus indicu significantlq increase diuresis in rats, and the fruit infusion had ar antiuric effect.= Infusions of the pad, fruit, and flowei have each showed a modest but statisticallyinsigruficani increase in natriuresis and kaluresis. Prickly pear pad: (20 mg per 100 g body weight daily for 5 weeks) sigrufi cantly decreased uric acid levels and increased watei intake while only slightly raising urine output in rats? Although the rise in urine flow was slight, the investiga tors suggest that it could account for the greater excretion of uric acid. Opuntia megacantha pads (20 mg/kg daily for 5 weeks) significantly increased urinarj sodium output in diabetic rats and normal rats compared with controls.25Prickly pear did not alter plasma aldosterone concentrations. In earlier studies by the samc researchers, prickly pear extract administered orallj (20 mg per 100 g body weight) increased creatinine clear. ance in diabetic rats and raised plasma creatinine anc urea levels in all rat^.^*,^^

Hypoglycemic Effect Animal studies show prickly pear pad to have a hype glycemic effect in streptozotocin-induced diabetes ir

Opuntia Species (Prickly Pear)

rats and rabbits, although one study showed no effect if the rabbits’ pancreatic beta cells were completely ~ b l i t e r a t e d . ~In~ -one ~ ~ rabbit study, prickly pear’s hypoglycemic effect was comparable to that of tolbutamide.27Prickly pear and insulin equivalently reduced, but did not normalize, glucose and insulin levels in diabetic rats. Interestingly, prickly pear combined with insulin had a synergistic effect. Diabetic rats being given the combination rapidly achieved normal glucose levels and at 7 weeks became hypoglycemic. At that point, prickly pear alone was sufficient to maintain normal glucose levels.28

Hypocholesterolemic Effects Prickly pear pectin had a hypocholesterolemic effect in guinea pigs in several studies conducted by the same research g r o ~ p .In~ each , ~ ~study, prickly pear reduced blood cholesterol levels, reduced low-density lipoprotein (LDL) cholesterol and increased its density. Highdensity lipoprotein (HDL) cholesterol levels were not affected significantly. Isotope studies indicated that prickly pear’s effect on blood fats was due to decreases in hepatic cholesterol concentrations and homeostasis rather than a change in cholesterol absorption.

CLINICAL APPLICATIONS Diabetes (Adult-Onset Non-Insulin-Dependent) There are a number of clinical trials on the effect of prickly pear pad in non-insulin-dependent diabetes A preliminary metaanalysis of mellitus (NIDDM).32-38 the clinical trials on prickly pear’s benefit in NIDDM concluded that the intervention data showed it to lower blood glucose levels by 10 to 30 mg/dl in patients with NIDDM and supported claims that prickly pear has a However, the control true metabolic effect in data were insufficient for a full metaanalysis. Most of these studies are very small, and many lacked valid placebo controls. Nonetheless, a statistically significant reduction of blood glucose and, when tracked, insulin levels was seen consistently when broiled prickly pear was administered to volunteers with NIDDM. Glucose levels dropped in the first hour after ingestion but typically reached sigruficance 2 to 3 hours later in one study, indicating an action that was measurable over a span of 6 hours. The magnitude of the hypoglycemic effect varied from mild to moderate depending on dose. For example, a 300-g dose of broiled pad acutely lowered blood glucose levels by 30 mg/dl in 8 subjects, whereas 500 g lowered levels by an average of 45 mg/dl in the same subjects. Most studies used broiled pads. One that used homogenized prickly pear pad preparation did not find a hypoglycemic effect.% However, when the pad was

ground in a regular blender rather than ultrahomogenized, it had an effect equivalent to that of broiled Capsules of dried prickly pear did poorly in a small, crossover, single-blind study in which a single dose of 30 capsules had no hypoglycemic effect.40Only a mild effect was seen in volunteers taking 30 capsules per day for 10 days-an impractical dose for most people. In contrast, prickly pear has been shown to affect glucose levels mildly or not at all in normal individuals.3335f” In two studies, prickly pear pad did not reduce glucose or insulin levels in healthy volunteers. In a third study, nondiabetic individuals who ate broiled prickly pear pads before meals for 10 days showed a mild but significant reduction in fasting glucose levels, but prickly pear pad had a significant hypoglycemic effect in volunteers in an induced hyperglycemic state.w In three studies using oral glucose loading, glucose levels dropped signhcantly, but in one test in which the glucose was administered intravenously, prickly pear had no effect.

Hyperlipidemia Prickly pear pads lowered cholesterol levels, improved ratios of cholesterol, and reduced triglyceride levels in a small, non-placebo-controlled clinical trial?5 Eight healthy patients, fourteen obese patients (18% to 70% overweight), and seven patients with NIDDM ate 100 g of broiled prickly pear pads before meals three times a day for 10 days. Each group experienced a sigruficant reduction in total cholesterol levels compared with their entry values. Levels of beta-cholesterol diminished significantly in the obese and diabetic patients, and the ratio of beta to alpha cholesterol showed a mild but significant drop. Triglyceride levels also diminished significantly in obese and diabetic patients (23%0-27%)but remained unchanged in healthy patients.

Prostatic Hyperplasia Dried prickly pear flowers improved subjective symptomology of prostatic hyperplasia in a preliminary open study.@ Eighty-eight patients at two centers took two 250-mg capsules of flower three times daily for 2 to 6 months. Many patients reported decreases in urgency, emergency urinations, and the sensation of fullness in the bladder, but not all patients experienced relief.

Weight Loss In a small, open-label study, prickly pear pads significantly reduced body weight of obese and diabetic subjects and showed a trend toward weight loss in normal ~ubjects.3~ Fourteen obese patients, seven patients with NIDDM, and eight healthy patients ate 100 g of broiled prickly pear pad before meals three times a day for 10 days. Each group showed a mean reduction in weight of 1.5 kg while maintaining their usual diets.

DOSAGE Studies of the use of this plant have used a variety of forms of prickly pear pad. Most have used broiled or grilled pads, whereas some studies have used juiced slurries. These studies used 100 to 500 g (3-170 2 ) of pads three times a day, taken before meals. There is little information on dried preparations, but as mentioned previously, such preparations did not achieve results in some small trials.

TOXICOLOGY Prickly pear showed a high degree of safety in studies of mice, horses, and humansB It has a long history of use as a food, a factor that also indicates a high level of safety. Most adverse events involving the plant are the result of its glochids (tiny,nearly invisible spines),which can become embedded in the skin.45Sabra dermatitis is an occupational disease among prickly pear fruit handlers, in which the glochids cause a widespread skin eruption resembling scabies that in chronic cases involves granuloma formation. However, in two animal

1.Thomber JJ, Bonker F. The fantastic clan: the cactus family. New York Maanillan, 1932. 2. Moore M. Medicinal plants of the desert and canyon west. Santa Fe: Museum of New Mexico Press, 1989. 3.Smestad PB, Steinar W.Watersoluble polysaccharides of Opuntia fius-indicn cv “Burbank‘sspineless.”Phytochemishy 1%’9;18:569-571. 4. Munoz EC, Millan AL, Braverman V, et al. Isoflavones in Mexican foods and soy products. FASEB J 2001;15:A286. 5.Abramovitd-1 RA, Coutts RT, Knaus EE. Identification of constituents of Opuntiafragilis. Planta Med 1968;16147-157. 6.McGarvie D, Parolis H. The mucilage of Opuntia aurantiaca. Carbohydrate Res 19819467-71. 7. Femandez-Lopez JA, Almela L. Application of high-performance liquid chromatography to the characterization of the betalain pigments in prickly pear fruits. J Chromatog A 2001;913415-420. 8. Clark DW, Parfitt BD. Flower flavonoids of Opuntia series Opuntiae. Phytochemistry 1980;191856-1857. ’ WW, liemey GD. Wild plants of the Pueblo province. 9. Dunrmre Santa Fe: Museum of New Mexico Press, 199531-34. 10. Curtin LSM, Moore M, eds. Healing herbs of the upper Rio Grande: traditional medicine of the Southwest. Santa Fe: Western Edge Press, 1997116-120. 11. Kay MA. Healing with plants in the American and Mexican west. Tucson: University of Arizona Press, 1996, pp 201-202. 12. Dimmitt MA. Genus Opuntia (incl. Cylindropuntia, Grusonia, and Corynopuntia). In Phillips SJ, Comus PW, e d s A natural history of the Sonoran desert. Tucson: Arizona-Sonoran Desert Museum Press, 2000:209-218. 13.Hartwell JL. Plants used against cancer. Lawrence, MA: Quarterman Publications, 198286. 14.Galati EM, Tripodo MM, Trovato A, et al. Biological effect of Opuntia ficus indica (L.) Mill. (Cactaceae) waste matter. Note 1: D i w t i c activity. J Ethnopharmacol2002;7917-21.

studies, prickly pear sigmfmntly raised blood urea and creatinine levels in rats, and increased urinary creatinine clearance rates in diabetic rats ~ n l ~The . ~researchers ~p expressed concern that prickly pear perhaps caused an early stage of kidney dysfunction in rats. However, the same researchers did not report similar results in a subsequent study, and no other studies have reported such eff ectsZ6

DRUG INTERACTIONS No human data on drug interaction are available for prickly pear. All herbs rich in complex carbohydrates may affect transit time and thus may alter absorption of practically any medication. Many of the diabetes trials of this plant included patients who were taking oral hypoglycemic agents (tolbutamide, glyburide, chlorpropamide), and no adverse interactions were rep~rted.=~~J’,% Prickly pear and insulin had a synergistic effect in rats, first normalizing blood sugar levels and then inducing hypoglycemiaF8 The effect of combining prickly pear and insulin in human subjects has not been studied.

15. Choi J, Chung KL, Young CL, et al. [Screening on biological activities of the extracts from fruit and stem of prickly pear (Opuntiaficus indica var. saboten).] Korean J Pharmacogn 2001;32;330-337. 16.Park EH, Kahng JH, Lee SH, Shin KH. An anti-inflammatory principle from cactus. Fitoterapia 2001:72:288-290. 17. Lon, JF,del Rio I, Perez-Santana L. Preliminary studies of analgesic and anti-inflammatory properties of Opuntia dillenii aqueous extract. J Ethnopharmacol1999;67213-218. 18. Ahmad A, Davies J, Randall S, Skinner GR. Antiviral properties of extract of Opuntia strepfacantha.Antiviral Res 1996;3075-80. 19. Mtambo MM, Mushi El,Kinabo LD, et al. Evaluation of the efficacy of the crude extracts of Capsicumfrutescens, Citrus Zimon and Opuntia vulgaris against Newcastle disease in domestic fowl in Tanzania.

J Ethnopharmacol1999;68:55-61. 20. Lee EB, Hyun JE,Li da W, Moon M.Effects of Opuntiaficus-indica var. Saboten on gastric damage in rats. Arch Pharmacal Res 2002;25:67-70. 21.Galati EM, Monforte MT, Tripodo MM, et al. Antiulcer activity of Opuntia ficus indica (L.) Mill. (Cactaceae): Ultrastructural study. J Ethnopharmacol2001;761-9. 22. Park EH, Chun MJ. Wound healing activity of Opuntiaficus indica. Fitoterapia 2001;72:165-167. 23. Galate EM, Tripod MM, Trovata A, et al. Biological effect of Opuntia ficers indica (L.) Mill. (Cactaceae waste matter: Note I: diuretic activity). J Ethnopharmacol2002;79:17-21. 24.Bwititi P, Zamurawo M, Mabhachi G, Mashanga N. Toxic and hypericaemic effects of Opuntia megacantha extract in rats. Phytother Res 1997;11:389-391. 25. Bwititi PT, Machakairr T, Nhachi CB, Musabayane CT. Effects of Opuntia megacantha leaves extract on renal electrolyte and fluid handling in stmptozotocin (STZ)-diabetic rats. Renal Fail 2001;23:149-158. 26. Bwititi,’l Musabayane CT, Nhachi CF. Effects of Opuntia megacantha on blood glucose and kidney function in streptozotocin diabetic rats. J EthnopharmacolZO00;69:247-252.

Opuntia Species (Prickly Pear) 27. Trejo-GonzalezA, Gabriel-Ortiz G, Puebla-Perez AM, et al. A purified extract from prickly pear (Opuntia fuliginosa) controls experimentally induced diabetes in rats. J Ethnopharmacol 1996;55:27-33. 28. Ibanez-Camacho R, Roman-Ramos R. Hypoglycemic effect of Opuntia cactus. Arch Invest Med (Mex) 1979;10223-230. 29. Ibanez-Camacho R, Meckes-Lozoya M, MelladoCampos V. The hypoglucemic effect of Opuntia streptacantha studied in different animal experimental models. J Ethnopharmacol1983;7175-181. 30. Femandez ML, Trejo A, McNamara DJ. Pectin isolated from Prickly Pear (Opuntia sp.) modifies low density lipoprotein metabolism in cholesterol-fed guinea pigs. J Nutr 1990;1201283-1290. 31.Femandez ML, Lin EC, Trejo A, McNamara DJ. Prickly pear (Opuntia sp.) pectin reverses low density lipoprotein receptor suppression induced by a hypercholesterolemic diet in guinea pigs. J Nutr 1992;1222330-2340. 32. Frati AC, Jimenez E, Ariza CR. Hypoglycemic effect of Opuntia ficus-indica in non insulin-dependent diabetes mellitus patients. Phytotherapy Res 1990;4195-197. 33. Frati AC, Gordillo BE, Altamirano P, et al.. Acute hypoglycemic effect of Opuntia streptacantha Lemaire in NIDDM. Diabetes Care 1990;13:455-456. 34. Frati-Munari AC, Gordillo BE, Altamirano P, Ariza CR. Hypoglycemic effect of Opuntiu streptucantha Lemaire in NIDDM. Diabetes Care 1988;11:63-66. 35. Frati-Munari AC, Femandez-Harp JA, De La Riva H, et al. [Effects of nopal (Opuntia sp.) on serum lipids, glycemia and body weight.] Arch Invest Med (Mex) 1983;14117-125. 36. Frati-Munari AC, Del Valle-Martinez LM, Ariza-Andraca CR, et al. [Hypoglycemic effect of different doses of nopal (Opuntia streptacantha Lemaire) in patients with type ll diabetes.] Arch Invest Med (Mex) 1989;20197-201.

37. Frati-Munari AC, Gil UR, Ariza-Andraca CR, et al. [Duration of hypoglucemic action of Opuntia strepfacantha Lem.] Arch Invest Med (Mex) 1989;20297-300. 38. Frati-Munari AC, Altamirano-BustamanteE, Rodriguez-BarcenasN, et al. [Hypoglycemic action of Opuntia streptacantha Lemaire: study using raw extracts.] Arch Invest Med (Mex) 1989;20321-325. 39. Aguilar C, Ramirez C, Castadeda-Andrade I, et al. Opuntia (prickly pear cactus) and metabolic control among patients with diabetes mellitus. Annu Meet Int Soc Techno1Assess Health Care 1996;1214. 40. Frati-Mumari AC, Vera-Lastra 0, Ariza-Andraca CR. [Evaluation of nopal capsules in diabetes mellitus.] Gac Med Mex 1992;128 431-436. 41. Frati-Munari AC, Yever-Garces A, Islas-Andrade S, et al. [Studies on the mechanism of ‘hypoglycemic’ effect of nopal (Opuntia sp.,.] Arch Invest Med (Mex) 1987;187-12. 42. Frati-Munari AC, Quuoz-Lazar0 JL, Altamirano-Bustamante P, et al. [The effect of various doses of nopal (Opuntia streptacantha Lemaire) on the glucose tolerance test in healthy individuals.] Arch Invest Med (Mex) 1988;19143-148. 43.Frati-Munari AC, Licona-Quesada R, Araiza-Andraca C, et al. [Activity of Opuntia streptucantha in healthy individuals with induced hyperglycemia]. Arch Invest Med (Mex) 1990;21:99-102. 44. Palevitch D, Earon G, Levin I. Treatment of benign prostatic hypertrophy with Opuntia ficus-indicu (L.) Miller. Journal of Herbs, Spices 81 Medicinal Plants 1993;24549. 45. Whiting DA, Bristow JH. Dermatitis and keratoconjunctivitis caused by a prickly pear (Opuntia rnicrodasys). S Afr Med J 1975; 49~1445-1448. 46. Meckes-Lozyoa M, Roman-Ramos R. Opuntia streptacantha:a coadjutor in the treatment of diabetes mellitus. Am J Chin Med 1986;14116-118.

Panax ginseng (Korean Ginseng) hlichael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1119 Chemical Composition 1119 History and Folk Use

1120

Pharmacology and Clinical Indications 1120 Adaptogenic Activity 1121 Cognitive Performance 1122 Antistress Activity 1122 As an Ergogenic Aid 1123 Diabetes 1123 Reproductive Effects 1124 Menopause 1124

Panax ginseng C.A. Meyer (family: Araliaceae) Synonym: Panax schinseng Nees Common names: Korean ginseng, Chinese ginseng, Asiatic ginseng, Oriental ginseng

GENERAL DESCRIPTION Korean or Chinese ginseng is a small perennial plant that originally grew wild in the damp woodlands of northern China, Manchuria, and Korea. Wild ginseng is now extremely rare. However, ginseng is a widely cultivated plant, especially in Korea but also in Russia, China, and Japan. In addition to Panax ginseng C.A. Meyer, the following four other, closely related species are often used:

Panax quinquefolius (American ginseng) Panax juponicum C.A. Meyer (Japanese ginseng) Panax pseudoginseng (Himalayan ginseng) Panax trifoliurn

I? ginseng C.A. Meyer is the most widely used and most extensively studied species.l” Its pharmacology is the major focus of this chapter. Fully mature, Korean ginseng is an herbaceous plant with a taproot, five-lobed palmate leaves, and greenishwhite flowers in an umbel. In the first year, ginseng bears only a single leaf with three leaflets. In the second

Cell-Proliferating, Antioxidant, and Antiaging Effects 1124 lmmunomodulating Effects 1125 Anticancer Properties 1125 Cardiovascular Effects 1125 Hepatic Effects 1126 Radiation-ProtectingEffects 1126

Toxicology Dosage

1126

1126

Drug Interactions 1127

year it bears a single leaf with five leaflets, and in its third year it bears two leaves with five leaflets. It usually starts flowering in its fourth year, while bearing three leaves. The roots of the cultivated plant are 3 to 4 mm in diameter and 10 cm long, and the roots of wild plants may attain 10 cm in diameter and a length of 50 to 60 cm. Ginseng is often processed in two forms, white and red. White ginseng is the dried root whose peripheral skin is frequently peeled off. Red ginseng is the steamed root, which has a caramel-like color.2 There are many types and grades of ginseng and ginseng extracts, which vary according to the source, age, and parts of the root used, where it was grown, the time of harvesting, and the methods of preparation.’” Old, wild, well-formed roots are the most valued, whereas rootlets of cultivated plants are considered the lowest grade. High-quality preparations are usually in the form of extracts of the main root of plants between 4 and 6 years old that have been standardized for ginsenoside content (see later) and ratio to ensure optimum pharmacologic effect.

CHEMICAL COMPOSITION Ginseng contains at least 13 different triterpenoid saponins, collectively known as ginsenosides, which are 1119

believed to be the most important active constituents. The usual concentration of ginsenosides is between 2% and 3%.The ginsenosides have been designated &, hI, h~krR, R+ %I Rtl 2O-glucO-Rf,$1, and $2. The ginsenosides originate from the following three fundamental aglycones: Oleanolic acid (ginsenoside &) 20-S-protopanaxadiol (ginsenosides to &) 20-Sprotopanaxatriol(ginsenosides& to $2)

As can be seen from Figure 111-1, the ginsenosides differ primarily in their sugar groups. Ginsenosides h1, F&2r R,%, and are present in sigruficantconcentrations in Korean ginseng. In contrast, American ginseng (Punax quinqu#oliurn) contains primarily ginsenosidesb1and F& and does not contain ginsenosides Rf, hBor, in some instances, These features allows for easy detection of species with high-pressure liquid chromatography (HPLC). Other components of ginseng are as follows'2:

s1.4

Panacene, a volatile oil Free and glucoside-bound sterols (e.g., beta-sitosterol and its beta-glucoside) Polyacetylene derivatives beta-elemene and panaxynol 8% to 32% starch Low-molecular-weight polysaccharides Pectin Vitamins (e.g., thiamine, riboflavin, B12,nicotinic acid, pantothenic acid, biotin)

R"

Ginsenoside

R

R'

R"

R,,

CIC-~GIC CIC-~GIC Cb2Glc CIC-~GIC CIC-~GIC CIC-~GIC Cb2Glc H H H H H H

H H H H

Xyl-4Ara(p)-6Glc Xyl-4Ara(f)-6Glc GIC-~GIC Am( )-6Glc Xyl- GIC Ara(f)-6Glc Glc Glc H Glc

Rbl Rb2

Rb3

Rc R,

Re Rf 3 1 x~GI~CO-R, Rhl

H H H Rha-2Glc-0 GIc-~GIc-O Glc-0 Rha-2Glc-0 GIc-~GIc-O Glc-0

Although it had been reported that ginseng contains large amounts of germanium (i.e., 300 parts per million), a follow-up study using highly sensitive (detection limit of 1 part per billion [ppb]), flameless atomic absorption spectrometry combined with solvent extraction demonstrated that the highest concentration of germanium measured in samples of ginseng purchased in the Osaka market was only 6 ~ p bMore . ~ research is needed to accurately determine the germanium content of botanical medicines, as the reported concentrations vary widely. Such low levels suggest that a connectionbetween the pharmacology of ginseng and its germanium content is unlikely,

HISTORY AND FOLK USE Perhaps the most famous medicinal plant of China, ginseng has been generally used alone or in combination with other herbs to restore the "Yang" quality. It has also been used as a tonic for its revitalizing properties, especially after a long illness. Conditions for which ginseng is used in folk medicine are shown in Box 111-1. It has been used as an alterative, anodyne, aperitif, aphrodisiac, cardiotonic, carminative, emetic, estrogenic, expectorant, gonadotrophic, nervine, sedative, sialogogue, stimulant, stomachic, and tranquilizer.l.2As can be seen from this list, ginseng has been used for most conditions, reflecting a broad range of nutritional and medicinal properties.

PHARMACOLOGY AND CLINICAL INDICATIONS

R

Ra2

0.1% to 0.2% choline Minerals (including germani~m)~ Simple sugars (glucose, fructose, sucrose, maltose, trisaccharides, etc.) Unique proteins (e.g., panaxagin, a protein that possesses antifungal, antiviral, translation-inhibiting, and ribonuclease activities)6 Various flavonoids

f

H Glc H

Am, Arabinose; Glc, glucose; Rha, rhabinose; Xy/, xylose. Figure 111-1 Ginsenosides of Panax ginseng.

Since the 1950s, a great amount of research has been conducted worldwide to determine whether the therapeutic properties attributed to ginseng belong in the realm of legend or fact. Unfortunately, inconsistent results (due mostly to different procedures in the preparation of extracts, use of nonofficial parts of the plant, use of adulterants, and lack of quality control in the ginseng used) have made determination of ginseng's true properties difficult. Nonetheless, enough good research does exist to indicate that ginseng possesses pharmacologic activity consistent with its near-legendary status, especially when high-quality extracts, standardized for active constituents, are used.

Panax ginseng (Korean Ginseng

Amnesia Anemia Anorexia Asthma Atherosclerosis Boils Bruises Cachexia Cancer Convulsions Cough Debility Diabetes Diuretic Divination Dysentery Dysmenorrhea Dyspepsia Enterorrhagia Epilepsy Epistaxis Fatigue Fear Fever Forgetfulness Gastritis Hangover Headache

Heart Hematoptysis Hemorrhage Hyperglycemia Hypertension Hypotension Impotence Insomnia Intestinalcomplaints Longevity promotion Malaria Menorrhagia Nausea Neurasthenia Palpitations Polyuria Pregnancy Puerperium Rectocele Rheumatism Rhinitis Shortness of breath Sores Spermatorrhea Splenitis Swelling Vertigo

Over the years, ginseng has been reported to have numerous pharmacologic effects in humans and laboratory animals, including the f~llowing'J*~: General stimulatory effects during stress Decrease in sensitivity to stress Increase in mental and physical capacity for work Improved endocrine system function Amelioration of radiation sickness, experimental neurosis, and cancer Enhanced protein synthesis and cell reproduction Improved glucose control in diabetes Modulation of various immune system parameters Lowering of serum cholesterol Protection of the liver from hepatotoxins Some of these actions are discussed in greater detail here.

Adaptogenic Activity Ginseng was originally investigated for its adaptogenic qualities.An aduptogen was defined in 1957by the Russian pharmacologist 1.1. B r e w 2 as a substance with the following properties: It must be innocuous and cause minimal disorders in the physiologic functions of an organism. It must have a nonspecific action (i.e., it should increase resistance to adverse influences through a

wide range of physical, chemical, and biochemical factors). It usually has a normalizing action irrespective of the direction of the pathologic state. According to tradition and scientific evidence, ginseng possesses thiskind of equilibrating, tonic, antistress action, and so the term adaptogen is quite appropriate to describe its general effects?r73 From a clinical perspective, ginseng can be used as a general tonic, especially in debilitated and feeble individuals. Use in this manner is consistent with its historic application.

Antifatigue (Mental and Physical) Activity Some of the first studies of ginseng's adaptogenic activities were performed during the late 1950s and early 1960s by Brekhman and Dardymov7fiin the USSR, and by Petkov9-" in Bulgaria. In one of Brekhman's experiments, Soviet soldiers given an extract of ginseng ran faster in a 3-km race than those given a placebo. In another, radio operators tested after administration of ginseng extract transmitted text significantly faster and with fewer mistakes than those given placebo. These and similar results found reported by European researchers, who demonstrated improvement in human physical and mental performance after the administration of ginseng extracts, prompted researchers to confirm the results in experimental models using m i ~ e ? , ~ - ~ In perhaps the best known of these experiments, mice were subjected to swimming in cold water or runningup an apparently endless rope to determine whether ginseng could lengthen the time to exhaustion. The results indicated that ginseng possessed sigruficant antifatigue activity, because a clearly dose-dependent increase in time to exhaustion was noted in mice receiving ginse~~g?fi,'~-~~ In one study, the time to exhaustion was lengthened by up to 183%in the mice given ginseng 30 minutes before exercising compared with controls? Experimental animal studies indicated that much of the antifatigue action of ginseng was due to the stimulant effect of ginseng on the central nervous system (CNS). Stress coupled with ginseng ingestion induced alterations in energy metabolism during prolonged exercise.'@15 Ginseng has been shown to improve locomotor activity>6 mod+ electroencephalography (EEG) tracing~,'~ improve metabolic activity in the CNS,'7 and affect the hypothalamic-pituitary-adrenal axis (discussed later), all of which could be largely responsible for ginseng's antifatigue activity in mental and physical performance. The CNS activity of ginseng is essentially different from that of the usual stimulants. Although stimulants are active under most situations, ginseng reveals its stimulatory action only with the challenge of ~tress.'~

On the physical level, ginseng's antifatigue properties appear to be closely related to its ability to spare glycogen utilization in exercising mu~cle.'~ Exercise physiologists have clearly established that during prolonged exercise, the development of fatigue is closely related to the depletion of glycogen stores and the buildup of lactic acid, both in skeletal muscle and in the liver. If an adequate supply of oxygen is available to the working muscle, nonesterified fatty acids are the preferential energy substrate, thus sparing utilization of muscle glycogen, blood glucose, and, consequently, liver glycogen. The greater the ability to conserve body carbohydrate stores through mobilization and oxidizing of fatty acids, the greater the amount of time to exhaustion. Ginseng enhances fatty acid oxidation during prolonged exercise, thereby sparing muscle glycogen stores.14 Mental and physical antifatigue activity effects have been demonstrated in both animal studies and doubleblind, clinical trials in humans. In one double-blind clinical study, nurses who had switched from day to night duty rated themselves for competence, mood, and general well-being, and were evaluated with an objective test of psychophysical performance, blood cell counts, and blood chemistry analysis. The group administered ginseng demonstrated higher scores in competence, mood parameters, and objective psychophysical performance than those receiving a placebo.18 From a clinical standpoint, ginseng's antifatigue properties may be useful whenever fatigue or lack of vigilance is apparent. Athletes in particular may derive some benefit from ginseng use (see later). Another important clinical indication appears to be chronic obstructive pulmonary disease (COPD). In one doubleblind study, 92 adults with COPD were randomly assigned to receive either ginseng or pla~ebo.'~ Pulmonary function tests (PFTs), maximum voluntary ventilation 0, maximum inspiratory pressure (MIP) and maximal oxygen consumption (Vqmax) were studied before treatment and every 2 weeks for the %month study period. In the ginseng group, but not in the control group, all parameters were significantly higher than baseline and than parameters in the placebo group. Maximum increases, in comparison with baseline, were FVC 32.5'/0, FEVl,o 27.0%, M w 40.4%, MIP 47.0% and Vozmax 37.5%. No side effects were observed.

Cognitive Performance Standardized extracts of P. ginseng alone or in combination with Ginkgo biloba (a formula called Gincosan) have been shown to improve cognitive performance in animal and clinical s t u d i e ~ . ~In@one ~ ~ of the earlier studies (a double-blind, crossover design) in university students in Italy, ginseng extract alone was compared with placebo in various tests of psychomotor performance. A favorable effect of ginseng relative to baseline performance was observed in attention (cancellation test), mental

arithmetic, logical deduction, integrated sensorimotor function (choice reaction time), and auditory reaction time. However, statistically significant superiority of the ginseng group over the placebo group was noted only for mental arithmetic. It is interesting to note that during the course of the trial, the students taking ginseng reported a greater sensation of well-being." Later studies in college-aged students showed similar results with a clear dose d e p e n d e n ~ y .However, ~ ~ - ~ unlike for studies in older subjects, no positive effect on mood or quality of life has yet been demonstrated with ginseng administered to healthy young adults. The benefits of ginseng on cognitive performance, mood, and quality of life assessment are considerably greater in middle-aged adults than in younger adults. In several studies of the administration of ginseng alone or in combination with G. biloba extract, significant improvements have been noted not only in tests of cognition and memory but also in social functioningand mental health?&%In one study however, the results attenuated after 4 weeks of use,indicating that cotherapy with G. biloba may be more efficacious or that cycling of the ginseng dosage may be necessary to produce a prolonged effect.% Both G. biloba and P. ginseng have been shown to modulate aspects of cognitive performance, including effects on EEG recordings. One double-blind, placebocontrolled, balanced crossover experiment assessed, in 15 healthy volunteers, the effects of single doses of G. biloba extract (360 mg), P. ginseng extract (200 mg G115), and an identical placebo on auditory-evoked potentials, contingent negative variation (CNV), and resting power within the delta, theta, alpha, and beta wavebandsz9The results showed that ginseng led to a significant shortening of the latency of the P300 component of the evoked potential. Both ginseng and @go also led to significant reductions in frontal "eyes closed" theta and beta activity, with additional reduction for ginseng in the alpha waveband. These findings demonstrated for the first time that P. ginseng can directly modulate EEG activity and that these effects are more pronounced than those that follow ingestion of G. biloba.

Antistress Activity Ginseng has been shown to enhance the ability to cope with various stressors, both physical and mental. Presumably, as has been demonstrated in several animal studies, this is a result of delaying the alarm phase response in Selye's classic model of stress. These studies found that adrenal cholesterol levels are many times higher in animals given ginseng than in their matched controls, indicating greater tolerance of stress and delayed alarm phase re~ponse.~~3O,~~ Italian researchers have studied the effect of a standardized ginseng extract, the ginsenoside composition of which was accurately determined, on the adrenal functions of rats exposed to cold.30The ginseng extract

significantly counteracted body temperature decline without affecting blood glucose or cortisone levels. In a group of adrenalectomized rats, the ginseng extract had no significant effects. Administration of hydrocortisone to the adrenalectomized rats did, however, cause body temperature to be maintained when the rats were exposed to cold. Histologic findings in this study were as follows: Evidence of hyperfunctioning in the supraoptic and paraventricular nuclei of the hypothalamus in rats fed the ginseng extract Remarkable increase in corticotropic basophilic cells (adrenocorticotropic hormone [ACTHI-producing) in the pars distalis of the pituitary gland Hyperplasia of the adrenal zona fasciculata, indicating that hyperfunctioning of the adrenal was promoted by the administration of the ginseng extract Other researchers have demonstrated that ginseng saponins significantly increase plasma ACTH and corticosteroids (in a parallel kinetic pattern).3z,33 Because this effect could be blocked by dexamethasone (which acts on the hypothalamus and pituitary to prevent ACTH release), it was concluded that ginsenosides act predominantly on the hypothalamus or pituitary to promote secretion of ACTH. This conclusion has been further confirmed by indirect studies. ACTH first stimulates an increase in cyclic adenosine monophosphate (CAMP)in the adrenal and then promotes corticosteroid synthesis. Ginseng administration has been shown to increase adrenal CAMP in normal rats, but not in hypophysedomized rats. These investigations make quite clear that ginseng’s antistress action is mediated by the hypothalamicpituitary-adrenal axis, as follows: The antistress action of ginseng is greatly reduced by adrenalectomy. Ginseng continues to exert its antistress action after hypophysectomy only if ACTH is administered. Histologic and chemical evidence demonstrates a strong link between ginseng and the hypothalamicpituitary-adrenal axis. Dexamethasone blocks the effects of ginseng. This release of ACTH and associated pituitary substances (e.g., beta-lipoprotein, endorphins, enkephalins) coupled with their end-organ effects is probably responsible for many of the antifatigue and antistress actions of ginseng, because ACTH and corticosteroids have been shown to bind directly to brain tissue to increase mental activities during stress. From a clinical perspective, it is apparent that ginseng has a balancing effect or alterative action on the hypothalamic-pituitary-adrenalaxisthrough adjustment of metabolic and functional systems governing hormonal control of homeostasis. This effect assists the body’s response to the challenge of stress and therefore is indicated when disruption of this axis is apparent.

Ginseng may prove especially effective in restoration of normal adrenal function and prevention of adrenal atrophy associated with corticosteroid administration. In rats, ginseng has been found to inhibit cortisone-induced adrenal and thymic atrophy?

As an Ergogenic Aid The benefits of ginseng on athletic performance are not clear. Results of later double-blind studies have been negative. For example, one study, in which 36 healthy young men received a standardized ginseng extract (Ginsana)at a dosage level of 400 mg/day, showed that ginseng had no effect on any exercise-related parameter (e.g., blood lactic acid concentration, heart rate, and perceived exert i ~ n ) Similar ?~ results were seen in a study in women and an even more comprehensive laboratory evaluation in 38 health adults also showed no improvement in any ~arameter.~J’ The totality of results at this time do not offer support for claims that ginseng improves athletic performance. However, other benefits have been noted, such as an ability to protect against muscle injury and inflammation in athletes as well as improve psychomotor performance at rest during a graded exercise te~t.%3~

Diabetes Ginseng, used either alone or in combination with other botanicals, has a long folk use in the treatment of diabetes. This hypoglycemic activity has been confirmed in both experimental and clinical trials. In one double-blind study in type 2 diabetes, ginseng therapy reduced fasting blood glucose levels, elevated mood, improved psychophysical performance, and lowered body weight and glycosylated hemoglobin.4o The chief constituents responsible for this effect are as follow^^*^^: Five glycans (polysaccharides designated panaxans A to E) Adenosine A carboxylic acid A peptide A fraction designated DPG-3-2 The ratio of ginsenosides also appears to be an important factor. In one human study, the ratio of protopanaxadiol to protopanaxatriol was the sole predictor of whether or not a ginseng preparation would exert hypoglycemic effects.&It appears that it is important to utilize crude, standardized extracts having a higher protopanaxadiol-protopanaxatriol ratio, such as those from American ginseng extract, in order to produce the desired benefit. Powdered American ginseng root (P.quinquefoliurn)at a dosage of about 3 g before each meal has been shown to reduce postprandial blood sugar signrficantly in patients with type 2 diabetes. It has been determined that American ginseng works through the stimulation of pancreatic beta cells with a subsequent increase in

Pharmacology of Natural Medicines insulin secretion. This substance also has sigruficant antioxidantproperties and improves cognitive function. In addition, American ginseng has been shown to possess nerve protection and regeneration properties. This could prove to be valuable in diabetes, in which peripheral and autonomic nerve damage so often occurs.4749 It is interesting to note that ginseng raises serum cortisol levels in nondiabetic individuals but reduces serum cortisol levels in patients with diabetesw Because cortisol antagonizes insulin,this is presumably a beneficial effect. This action again demonstrates ginseng’s nonspecific balancing effect, which is baffling to researchers accustomed to investigating compounds with consistent pharmacologic effects. Ginseng is indicated as an adjunctive therapy in the treatment of diabetes, both for its hypoglycemic effect and for its ability to decrease the atherogenic index (see later). Although the root has received the most attention, animal studies indicate that extracts from ginseng berry may even be more beneficial owing to a higher concentration of ginsenoside %.sosl

or hypofunction, other organic causes of male infertility, ovarian atrophy or hypofunction, amenorrhea, and other organic causes of female infertility. It should be noted that several reports of mastalgia have been reported in women taking ginse11g.5~3’ Most of the later clinical studies involving reproductive effects have focused on ginseng’s effect on erectile dysfunction. A plausible mechanism involves evidence that ginsenosides can facilitate penile erection by directly inducing the vasodilatation and relaxation of penile corpus cavernosum mediated by the release and/or modification of the release of nitric oxide from endothelial cells and perivascular In one double-blind, crossover study a total of 45 patients with clinically diagnosed erectile dysfunction showed significantly higher Mean International Index of Erectile Function scores with Korean red ginseng than those who received placebo. In response to the global efficacy question 60% of the patients answered that Korean red ginseng improved erection.b0

Reproductive Effects

Ginseng has also been a popular treatment for menopausal symptoms. One double-blind study in 384 menopausal women was performed to compare the effects of a standardized ginseng extract with those of a placebo on quality of life, menopausal symptoms, and physiologic markers of menopause (follicle-stimulating hormone and estradiol levels, endometrial thickness, maturity index, and vaginal pH). Although the ginseng extract showed only a tendency for a slightly better overall symptomatic relief, it was associated with statistically sigrulicant improvements in mood and well-being. No statistically significant effects were seen for the physiologic parameters, including vasomotor symptoms (hot flushes). The results of this study suggest that the beneficial effects of ginseng in menopause are most likely not mediated by phytoestrogen or hormone replacementlike effects.6I

Although it is claimed to be a ”sexual rejuvenator” and aphrodisiac, human studies supporting this belief are scanty. In animal studies, however, ginseng has been shown to have the following a f f e c t ~ ~ ~ s ~ : Promotes the growth of the testes and increase spermatogenesis in rabbits Accelerates the growth of the ovary and enhance ovulation in frogs Stimulates egg-laying in hens Facilitates lordotic response in female rats Increases gonadal weight in both male and female rats Raises testicular nucleic acid content in rats Increases sexual activity and mating behavior in male rats These animal study results seem to support ginseng‘s

use as a fertility and virility aid. In other experimental animal studies, ginseng has been shown to increase testosterone levels while reducing prostate weight.%This finding suggests that ginseng should have favorable effects in the treatment of benign prostatic hyperplasia; however, no clinical trials have yet been reported. Ginsenosides have also been shown to bind to human myometrial receptor proteins, and they apparently exert estrogen-like action on the vaginal epithelium. These activities are sigruficant enough to prevent the atrophic vaginal changes associated with postmenopause and other menopausal symptoms.55 Other clinical indications involving the reproductive system (based on historical use and experimental evidence) are decreased sperm counts, testicular atrophy

Menopause

Cell-Proliferating, Antioxidant, and Antiaging Effects Ginseng has a dual effect on cell growth: It stimulates cell division in an adequate nutritional environment but acts cytostatically under adverse conditions (as described previously).61Furthermore, ginseng has yielded impressive results in lengthening the lifespan of cells in culture.6* This enhancement of cellular proliferation and function has been shown in a variety of cell types (epithelial, hepatic, lymphocyte, fibroblast, thymic, etc.), but especially nerve cells, which appears to be a result of potentiation of nerve growth factor (NGF) by ginsenosides?rM Clinically, these results indicate a potential use of ginseng in healing damage to virtually all tissue types, but especially the brain. In animal studies, ginseng has been

Panax ginseng (Korean Ginseng) shown to reduce oxidative stress, scavenge free radicals directly, protect endothelial cells from damage, and increase cellular antioxidant enzymes like superoxide dismutase Again these effects demonstrate ginseng’s nonspecific action.

in vitro, this has not been the observed effect in vivo, in which lymphocyte proliferation has been enhanced.74

These effects may be related to a dose-dependent ginseng-induced elevation of interferon (which inhibits lymphocyte proliferation).

lmmunomodulating Effects

Anticancer Properties

That ginseng possesses immunomodulating activity is evidenced by its ability to enhance the following immune function^^-^^:

Regular ginseng consumption may protect against cancer. In two large population studies, the risk for development of cancer was sigruficantly lower among people who consumed ginseng on a regular basis. Ginseng extract and powder were shown to be more effective than fresh sliced ginseng, ginseng juice, or ginseng tea in reducing the cancer risk. A statistically highly significant dose-response relationship between ginseng intake and cancer risk was observed. These results support the preventive and anticancer effects of ginseng demonstrated in animal and in vitro studies.8749 Long-term oral administration of ginseng to newborn mice has been shown to reduce the incidence and also to inhibit the proliferation of tumors induced by various chemical carcinogens, including DMBA (7,12-dimethylbenz[a]anthracene), urethane, and aflatoxin B1.39 The anticancer effects of ginseng in other experimental models can be summarized as follow^^-^^:

Antibody plaque-forming cell response Circulatory antibody titer against sheep erythrocytes Cell-mediated immunity Natural killer (NK) cell activity The production of interferon Lymphocyte mitogenesis Reticuloendothelial system proliferativeand phagocytic functions

In addition to these immunostimulatory aspects, ginseng components have been shown to exert antiallergy and antijnflammatory effects in experimental models.sOsl From a clinical perspective, the long-term ingestion of ginseng by individuals with mild immunodeficiency may reduce the risk of viral infection. It use in this manner is consistent with the historical use of ginseng by debilitated individuals. There is clinical evidence of benefit in these applications. Extracts of l? ginseng were found to stimulate NK function in normal individuals and patients with either chronic fatigue syndrome or acquired immunodeficiencysyndrome (AIDS)F2Ginseng has been shown to prevent respiratory viral infections in a nursing home environment (89% relative risk reduction) and potentiate influenza vaccinations.mB It should be noted that large dosages of ginseng may be contraindicated in acute infections. The reason may be its in vitro inhibition of lymphocyte transformation (similarto cortisone) at high (i.e., >1 mg/ml), but not low concentrations.85,s6 In fact, in vitro, ginseng at 1.6 pg/ml has been shown to inhibit phytohemagglutinin-induced transformation of peripheral blood lymphocytes to a greater degree than cortisone at 500 pg/mLS The greatest level of inhibition, however, was observed when ginseng was used in combination with cortisone. These results suggest that ginseng at high doses may be effective against T cell-mediated inflammatory diseases without producing glucocorticoid-like side effects. It also suggests that a lower dose of cortisone could be used if ginseng were given simultaneously. When using ginseng, the clinician must remember (1)that ginseng’s in vim effect on lymphocyte proliferation is biphasicthat is, it exerts a strong inhibition at high concentrations and a moderate stimulation at low concentrations-and (2) that although ginseng has demonstrated significant inhibition of lymphocyte proliferation

Ginseng promotes apoptosis. The effect is observed only in slow-growing tumors, such as Ehrlich and sarcoma 180 ascites tumor. The effect is not observed in rapidly growing tumors, such as 11210 and p388, and Walker carcinoma. There is no dose-response relationship or cumulative effect. The lack of a dose-response relationship suggests that ginseng’s anticancer effects are indirect and subject to a threshold mechanism. Thus, ginseng once again appears to demonstrate nonspecific effects. In addition to a possible role in cancer prevention, some researchers are investigating P. ginseng extracts as a possible adjunct in cancer t~eatment.9~ Exerting some direct and indirect anticancer actions, ginseng may also offer protection against chemotherapy-induced damage to normal cells. In one animal study, l? ginseng extract was shown to protect against cisplatin nephrot~xicity.~~

Cardiovascular Effects From a clinical perspective, ginseng may offer some protection against atherosclerotic disease, further supporting its use as a general tonic. It may also possess a blood pressureregulating effect via improvement in the endothelial dysfunction underlying many cases of hypertension.% Ginseng administered to human subjects with hyperlipidemia has been shown to reduce total serum Cholesterol, triglyceride, and nonesterified fatty acid levels

Pharmacology of Natural Medicines while raising serum high-density lipoprotein (HDL) cholesterol levels. Platelet adhesiveness was also decreased.97 These results in humans confirmed earlier studies on rats fed high-cholesterol The mechanism of action appears to be through accelerated degradation, conversion, and excretion of cholesterol and triglyceride despite increased lipogenesis and cholesterogenesis. Ginseng has also been shown to be effective in lnhibiting platelet aggregation and the conversion of fibrinogen to fibrin@ .' '

Hepatic Effects

the Journal of the American Medical Association (JAMA) titled "Ginseng Abuse Syndrome."107 In this article, a number of side effects of commercial preparations of ginseng are reported, including the following: Hypertension Euphoria Nervousness Insomnia Skin eruptions Morning diarrhea

Given the extreme variation in quality of ginseng in the American marketplace and the use of both nonofficial Obviously, any adaptogenic substance must affect the parts of the plant and adulterants, it is not surprising that liver because of this organ's central role in metabolic and detoxification reactions. Ginseng affects the liver in sevside effects were noted. None of the commercial preparaeral ways. Perhaps the most important is its ability to tions used in the trial had been subjected to controlled produce a marked hyperplasia of the Kupffer cells of the analysis. Furthermore, the species of ginseng used liver and of the folliculi in the spleen and lymph nodesN included P. ginseng, Panax quinquefolius, Eleutherococcus The hyperplastic folliculi show an increase in the senticosus, and Rumex hymenosepalus in a variety of differnumber and volume of light centers, thus demonstrating ent forms-roots, capsules, tablets, teas, extracts, cigamorphologic evidence of increased host defense capacity rettes,chewing gum, and candies. It is virtually impossible against a wide variety of external assaults. Because these to derive any firm conclusions from the data presented cells are responsible for filtering out much of the toxins in the J A M A article. The author's final words do, and debris from the portal circulation, increasing their however, seem sensible and appropriate: number and activity could have profound effects. An important caveat is that these GAS [ginseng abuse synGinseng has also been shown to increase nuclear drome] effects are neither uniformly negative nor uniformly RNA biosynthesis, indicating greater protein synthepredictable. Nevertheless, long-term ingestion of large sis.3*101 In fact, ginseng has been shown to increase not amounts of ginseng should be avoided, as even a panacea can only nuclear RNA synthesis, but also ribosomal and cause problems if abused. messenger RNA, the amount of rough endoplasmic reticulum, and the activity of RNA p o l y m e r a ~ e . ~ J ~ ' - ~Studies ~~ performed on standardized extracts of These results indicate that ginseng activates virtually ginseng demonstrate the absence of side effects and every step in protein biosynthesis. As protein synthesis mutagenic or teratogenic effects.'08110These studies differ is often reduced in the elderly, the significance of the markedly from the trial reported in JAMA in that highquality extracts were used. An extensive review of the described effects on enhancement of hepatic protein synthesis would be extremely high. However, these results safety of P. ginseng concluded, "Data from clinical trials have yet to be confirmed by clinical studies. suggest that the incidence of adverse events with ginseng Ginseng has also been shown to reverse diet-induced monopreparations is similar to that with pla~ebo."'~' fatty liver in animals and to possess significant antihepatotoxic action.Io4 The clinical indications of these DOSAGE hepatic actions of ginseng are quite broad and support its general tonic/adaptogen properties. The dosage of ginseng is inversely proportional to the ginsenoside content; that is, if an extract or ginseng Radiation-Protecting Effects preparation contains high concentrations of ginsenoGinseng has been shown to offer some protection sides (and presumably other active components), a lower dose suffices. The standard dose for ginseng is in against harmful radiation, both in vivo and in vitro, and to hasten recovery from radiation s i c k n e ~ s . In ~ ~the ~ J ~ the range of 4.5 to 6 g daily. presence of ever-increasing environmental radiation Currently, there is almost a total lack of quality control contamination, ginseng may be an appropriate prophyin ginseng products marketed in the United States. lactic against radiation exposure. Independent research and published studies have clearly documented a tremendous variation in the ginsenoside content of commercial preparations. In fact, TOXICOLOGY many products on the market contain only trace amounts of p e n o s i d e s , and some formulations contain no ginThe problem of quality control makes toxicology difficult to address. This is exemplified by a 1979 article in seng at all. This situation has led to several problems,

Panax ginseng (Korea lower dose and increase it gradually. The Russian approach for long-term administration is to use ginseng cyclically for a period of 15 to 20 days followed by a 2-week interval without any ginseng.

ranging from toxicity reactions (discussed later) to lack of medicinal effect. The widespread disregard for quality control in the health food industry has done much to tarnish the reputation of ginseng as well as other important botanicals. We recommend the use of standardized ginseng preparations to ensure sufficient ginsenoside content, consistent therapeutic results, and reduced risk of toxicity. Products should be standardized in their ginsenoside content. The typical dose (taken one to three times daily) for general tonic effects should contain a saponin content of at least 5 mg of ginsenosides with an &,-$,ratio of 2:l. For example, for a high-quality ginseng root powder containing 5% ginsenosides, the dose would be 100 rng.”O Because each individual’s response to ginseng is unique, the patient should be monitored for signs of possible ginseng toxicity (see later). It is best to begin at a

glyburide (Diabeta, Micronase). It is important to discuss proper monitoring of blood sugar levels with patients who have diabetes before prescribing ginseng. Ginseng may interferewith the anticoagulant drug warfarin (Coumadin). People taking this agent should not use ginseng unless they are being closely monitored by a physician. I? ginseng may potentiate the monoamine oxidase inhibitor phenelzine (Nardil) to produce maniclike symptoms.11o

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47. Vuksan V, Sievenpiper J, Koo VY, et al. American ginseng (Panax quinquefolius L) reduces postprandial glycemia in nondiabetic subjects with type 2 diabetes mellitus. Arch Intern Med 2000; 160:1009-1013. 48. Vuksan V, Stavro MP, Sievenpiper JL, et al. Similar postprandial glycemic reductions with escalation of dose and administration time of American ginseng in type 2 diabetes. Diabetes Care 2000; 23:1221-1226. 49.Franz MJ, Bantle JP, Beebe CA, et al. Nutrition principles and recommendations in diabetes. Diabetes Care 2004;27(Suppl 1): s36-s46.

50. Dey L, Xie JT,Wang A, et al. Anti-hyperglycemic effects of ginseng: comparison between root and berry. Phytomedicine 2003;lO: 600-605. 51. Attele AS, Zhou YP,Xie JT, et al. Antidiabetic effects of Panax ginseng berry extract and the identificationof an effective component. Diabetes 2002;51:1851-1858. 52. Nocerino E, Amato M, Izzo AA. The aphrodisiac and adaptogenic properties of ginseng. Fitoterapia 2000;71(Suppl l):Sl-S5. 53. Kim C, Choi H, Kim CC, et al. Influence of ginseng on mating behavior of male rats. Am J Chin Med 1976;4163-168. 54. Fahim MS, Fahim Z, Harman JM, et al. Effect of Punax ginseng on testosterone level and prostate in male rats. Arch Androl 1982;8261-263. 55. Punnonen R, Lukola A. Oestrogen-like effect of ginseng. Br Med J 1980;281:1110. 56. Yonezawa M. Restoration of radiation injury by intraperitoneal injection of ginseng extract in mice. J Radiat Res (Tokyo)1976;17111-113. 57. Palmer BV, Montgomery AC, Monteiro JC. Gin Seng and mastalgia. Br Med J 1978;1:1284. 58. Murphy LL, Lee TJ.Ginseng, sex behavior, and nitric oxide. Ann N Y Acad Sci 2002;962:372-377. 59. Price A, Gazewood J. Korean red ginseng effective for treatment of erectile dysfunction. J Fam Pract 2003;52:20-21. 60.Hong B, Ji YH, Hong JH, et al. A double-blind crossover study evaluating the efficacy of Korean red ginseng in patients with erectile dysfunction: a preliminary report. J Urol2002;168:2070-2073. 61. Wiklund M,Mattsson LA, Lindgren R, et al. Effects of a standardized ginseng extract on quality of life and physiological parameters in symptomatic postmenopausal women: a double-blind, placebocontrolled trial. Swedish Alternative Medicine Group. Int J Clin Pharmacol Res 1999;19:89-99. 62. Fulder SJ. The growth of cultwed human fibroblasts treated with hydrocortisone and extracts of the medicinal plant Panax ginseng. Exp Gerontol1977;12:125-131. 63. Yamamoto M, Masaka M, Yamada K, et al. Stimulatoryeffect of ginsenosides on DNA, protein and lipid synthesis in bone marrow and participation of cyclic nucleotides. Arzneimittelforschung 1978;282238-2241. 64.Radad K, Gille G, Moldzio R, et al. Ginsenosides Rbl and Rgl effects on survival and neurite growth of MPP+-affected mesencephalic dopaminergic cells. J Neural Transm 2004;111:37-45. 65. Mizumaki Y, Kurimoto M, Hirashima Y, et al. Lipophilic fraction of P a m ginseng induces neuronal differentiation of PC12 cells and promotes neuronal survival of rat cortical neurons by protein kinase C dependent manner. Brain Res 2002;950254-260. 66. Fu Y, Ji LL. Chronic ginseng consumption attenuates age-associated oxidative stress in rats. J Nutr 2003;1333603-3609. 67. Liu ZQ, Luo XY,Sun YX, et al. Can ginsenosidesprotect human erythrocytes against free-radical-inducedhemolysis? Biochim Biophys Acta 2002;157258-66. 68.Siddique MS, Eddeb F, Mantle D, et al. Extracts of Ginkgo biloba and Panax ginseng protect brain proteins from free radical induced oxidative damage in vitro. Acta Neur& Suppl2000;76:87-90. 69. Kim YK, Guo Q, Packer L. Free radical scavenging activity of red ginseng aqueous extracts. Toxicology 2002;172:149-156.

Panax Ginseng (Korean Ginseng) 70.Kwan CY, Kwan TK. Effects of Panax notoginseng saponins on i n 2000;21: vascular endothelial cells in vitro. Acta Pharmacol S 1101-1105. 71. Kim SH, Park KS. Effects of Panax ginseng extract on lipid metabolism in humans. Pharmacol Res 2003;48:511-513. 72. Jie YH, Cammisuli S, Baggiolini M. Immunomodulatory effects of Panax ginseng C.A. Meyer in the mouse. Agents actions 1984; 15:386-391. 73. Gupta S, Agarwal SS, Epstein LB, et al. Panax. A new mitogen and interferon producer. Clin Res 1980;28504A. 74. Singh VK,Agarwal SS, Gupta BM. Immunomodulatory activity of Panax ginseng extract. Planta Med 1984;50:462-465. 75. Shin JY, Song JY, Yun YS, et al. Immunostimulating effects of acidic polysaccharides extract of Panax ginseng on macrophage function. Immunopharmacol Immunotoxicol2002;24:469482. 76. Assinewe VA, Amason JT, Aubry A, et al. Extractable polysaccharides of Panax quinquefolius L. (North American ginseng) root stimulate TNFalpha production by alveolar macrophages. Phytomedicine 2002;9398-404. 77. Lim DS,Bae KG, Jung IS, et al. Anti-septicaemic effect of polysaccharide from Panax ginseng by macrophage activation. J Infect 2002;45:32-38, 78. Cho JY, Kim AR, Yo0 ES, et al. Ginsenosides from Panax ginseng differentially regulate lymphocyte proliferation. Planta Med 2002; 68:497-500. 79. Lim TS, Na K, Choi EM, et al. Immunomodulating activities of polysaccharidesisolated from Panax ginseng. J Med Food 2004;71-6. 80.Park EK, Choo MK, Han MJ, et al. Ginsenoside Rhl possesses antiallergic and anti-inflammatory activities. Int Arch Allergy Immunol2004;133113-120. 81. Choo MK, Park EK, Han MJ, et al. Antiallergic activity of ginseng and its ginsenosides. Planta Med 2003;6951&522. 82. See DM, Broumand N, Sahl L, et al. In vitro effects of Echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients. Immunopharmacology 1997;35:229-235. 83. McElhaney JE,Gravenstein S, Cole SK, et al. A placebo-controlled trial of a proprietary extract of North American ginseng (CVT-E002) to prevent acute respiratory illness in institutionalized older adults. J Am Geriatr SIX 2004;5213-19. 84. Scaglione F, Cattaneo G, Alessandria M, et al. Efficacy and safety of the standardised ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold. Drugs Exp Clin Res 1996;22.65-72. 85. Chong SK, Brown HA, Rimmer E, et al. In vitro effect of Panax ginseng on phytohaemagglutinin-induced lymphocyte transformation. Int Arch Allergy Appl Immunol1984;73:216-220. 86.Yeung HW, Cheung K, Leung KN. Immunopharmacology of Chinese medicine. 1. Ginseng induced immunosuppression in virus-infected mice. Am J Chin Med 1982;10:44-54. 87. Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: a prospective study in Korea. Int J Epidemiol1998;27359-364. 88. Yun TK. Panax ginseng-a non-organ-specific cancer preventive? Lancet Oncol2001;249-55. 89. Shin HR, Kim JY, Yun TK, et al. The cancer-preventive potential of Panax ginseng: a review of human and experimental evidence. Cancer Causes Control 2000;11:565-576.

90. Kim HS, Lee EH, KO SR, et al. Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate cancer cells. Arch Pharm Res 2004;27:429435. 91. Liu WK,Xu SX, Che CT.Anti-proliferative effect of ginseng saponins on human prostate cancer cell line. Life Sci 2000;671297-1306. Anticarcinogenic effect of long-term oral 92. Yun TK, Yun YS, Han IW. administration of red ginseng on newborn mice exposed to various chemical carcinogens. Cancer Detect Prev 1983;6515-525. 93.Lee KD, Huemer RP. Antitumoral activity of Panax ginseng extracts. Jpn J Pharmacol1971;21:299-302. 94. Chang YS, Seo EK, Gyllenhaal C, et al. Panax ginseng: a role in cancer therapy? Integr Cancer Ther 2003;213-233. 95. Liu SJ, Zhou SW. Panax notoginseng saponins attenuated cisplatininduced nephrotoxicity. Acta Pharmacol Sin 2000;21:257-260. 96. Sung J, Han KH, Zo JH, et al. Effects of red ginseng upon vascular endothelial function in patients with essential hypertension. Am J Chin Med 2O00;28:205-216. 97. Yamamoto M, Uemura T, Nakama S, et al. Serum HDL-cholesterol-increasing and fatty liver-improving actions of Panax ginseng in high cholesterol diet-fed rats with clinical effect on hyperlipidemia in man. Am J Chin Med 1983;11:96-101. 98. Yamamoto M, Kumagai A, Yamamura Y. Plasma lipid-lowering actions of ginseng saponins and mechanisms of the action. Am J Chin Med 1983;11:84-87. 99. Joo CN. The preventative effect of Korean (P. ginseng) saponins on aortic atheroma formation in prolonged cholesterol-fed rabbits. In Proceedings of the 3rd International Ginseng Symposium. Seoul Korean Ginseng Research Institute, 1980:27-36. 100. Matsuda H, Namba K, Fukuda S, et al. Pharmacological study on Panax ginseng C.A. Meyer. III. Effects of red ginseng on experimental disseminated intravascular coagulation. (2). Effects of ginsenosides on blood coagulative and fibrinolytic systems. Chem Pharm Bull (Toyko) 1986;34:1153-1157. 101.Oura H, Hiai S, Sen0 H. Synthesis and characterization of nuclear RNA induced by radix ginseng extract in rat liver. Chem Pharm Bull (Tokyo) 1971;19159&1605. 102. Oura H, Hiai S, Nabetani S, et al. Effect on ginseng extract on endoplasmic reticulum and ribosome. Planta Med 1975;28:76-88. 103. Oura H, Nakashima S, Tsukada K, et al. Effect of radix ginseng extract on serum protein synthesis. Chem Pharm Bull (Tokyo) 1972;20:980-986. 104.Hikino H, Kiso Y, Kinouchi J, et al. Antihepatotoxic actions of ginsenosides from Panax ginseng roots. Planta Med 1985;1:62-64. 105. Kim TH, Lee YS, Cho CK, et al. Protective effect of ginseng on radiation-induced DNA double strand breaks and repair in murine lymphocytes. Cancer Biother Radiopharm 1996;11:267-272. 106.Ben-Hur E, Fulder S. Effect of Panax ginseng saponins and Eleutherococcus senticosus on survival of cultured mammalian cells after ionizing radiation. Am J Chin Med 1981;9:48-56. 107. Siege1 RK. Ginseng abuse syndrome: problems with the panacea. JAMA 1979;241:16141615. 108. Hess FG Jr, Parent RA, Stevens KR, et al. Effects of subchronic feeding of ginseng extract G115 in beagle dogs. Food Chem Toxicol 1983;21:9597. 109. Hess FG Jr, Parent RA, Cox GE, et al. Reproduction study in rats of ginseng extract G115. Food Chem Toxicol 1982;20189-192. 110. Coon JT, Emst E. Panax ginseng: a systematic review of adverse effects and drug interactions. Drug Safety 2002;25:323-344.

Pancreatic Enzymes Anthony J. Cichoke, DC, PhD, DACBN CHAPTER CONTENTS Inhibitors 1135 Supplement Coating

Introduction 1131

1135

History 1131 Measuring Enzyme Activity

1136

Pancreatic Enzyme Supplements 1132 Enzyme Extraction Processes 1132 Rupturing the Cell Membrane 1133 Fractionation 1133 Crystallization 1133 Enzyme Isolation 1133 Absorption of Proteins 1133 Understanding the Absorption of Enzymes 1134

Clinical Applications 1136 Digestive Disorders 1137 Inflammatory Diseases 1138 Cancer 1138 Autoimmune and Immune Complex-Mediated Diseases 1139 Cardiovascular Disorders 1139 Viral and Bacterial Disorders 1139 Other Conditions 1139 Dosage 1139

Factors Affecting Enzyme Activity Optimal pH Range 1135 The Effects of Temperature 1135 Substrate Concentration 1135 Cofactors 1135 Metal Ions 1135

1134

INTRODUCTION Pancreatic enzymes produced by the body are well known for the integral role they play in the digestion of proteins, fats, and carbohydrates. Pancreatic juice contains numerous enzymes, including amylase, lipase, ribonuclease, and deoxyribonuclease'; and the proenzymes trypsinogen, chymotrypsinogen, and procarboxypeptidase, which are converted in the small intestine to their active forms trypsin, chymotrypsin, and carboxypeptidase, respectively. Protein leaves the stomach primarily in the form of proteases, peptones, and large polypeptides? Upon reaching the small intestine, they are further digested by the proteolytic enzymes, trypsin, chymotrypsin, and carboxypolypeptidase. Protein digestion occurs mainly in the duodenum and jejunum. Carbohydrates are digested by a-amylase in the pancreatic juice, which breaks down starches (converting them into maltose and other small glucose polymers), whereas pancreatic lipase digests fats?

Toxicology 1140 Oral Enzymes 1140 Enzyme Enemas 1141 Topical Application 1141 Injectable Enzymes 1141

Although critical for proper digestion, pancreatic enzymes also aid in a surprising variety of bodily functions, including detoxification, immunity, aging, blood fluidity, and tissue repair. Unfortunately, an inadequate production of, or an excessive need for, pancreatic enzymes can occur for a variety of reasons, including genetics, illness, injury, exercise, aging, and toxins (both endogenous and exogenous). In fact, many authorities believe that a deficiency of pancreatic enzymes, for whatever reason, may be a cause of numerous illnesses and degenerative conditions. When a deficiency occurs, enzymes from an external source may be necessary.

HISTORY Pancreatic enzymes have a long history of clinical use. In the early twentieth century, John Beard, a Scottish embryologist, successfully treated cancer using a pancreatic 1131

Pharmacology of Natural Medicines

extract, which he described in his book, The Enzyme Treatment of Cancer and its Scientific Basis. In 1934, Emst Freund, a Viennese physician, found a substance in the blood of people free from cancer that was able to dissolve cancer cells. Patients with cancer did not have this material, which Freund called "normal substance." In the early 1930s, Professor Doctor Max Wolf worked with Freund in Vienna and successfully identified "normal substance" as an enzyme that decomposes fatty materials and proteins. For his work in the field of enzymes, Wolf is generally considered the father of modem enzyme therapy. The work of Freund and John Beard sparked Wolf's interest in the possibilities of treating malignant diseases with enzymes. He subsequently founded the Biological Institute of New York City and, after studying various enzymes and enzyme combinations, developed what he regarded as an optimal preparation for the treatment of various acute and chronic conditions. His preparation was a combination of a fractionated hydrolysate of beef pancreas, calf thymus, Pisum sativum (common pea), Lens esculenta (edible lentil), mannitol, and papaya. In the 1960s, Irving Innerfield conducted landmark research in the area of pancreatic enzymes, primarily relating to the clinical use of trypsin, chymotrypsin, and pancreatin as well as streptokinase (a microbial proteolytic enzyme). In 1971, the late Professor Heinrich Wrba, at the time head of the Austrian Cancer Research Institute at the University of Vienna, stated, "Our present knowledge allows us to include this [enzyme] therapy into the small list of highly-effective causal anticancer compounds. It [enzyme therapy] will certainly play an important role in cancer treatment over the next few years." Dr. Wrba's interest in cancer was piqued when he lost a daughter to leukemia. He devoted his life to educating oncologists in Germany and around the world about enzyme therapy. It was the late Karl Ransberger, however, who continued and refined Wolf's research, bringing it to doctors, hospitals, and patients throughout the world. Ransberger encouraged and funded research projects in numerous hospitals and universities in Europe, the Americas, and elsewhere. His research, and that of others, has validated enzyme therapy's effectiveness in treating numerous conditions, including arthritis, cancer, multiple sclerosis, cardiovascular disease, human immunodeficiency virus (HIV), and acquired immunodeficiency syndrome (AIDS).

PANCREATIC ENZYME SUPPLEMENTS The pancreatic enzyme supplements most commonly used & health care are chymotrypsin, trypsin, and pancreatin (which contains proteolytic, amylolytic and lipolytic

properties), as well as pancrelipase (similar to pancreatin, but with a higher proportion of lipase). Chymotrypsin and trypsin are proteolytic enzymes that break proteins down into peptides. Chymotrypsin liberates the amino acids L-tyrosine, L-tryptophan, and L-phenylalanine and other molecules, including several synthetic esters and amides.' Trypsin hydrolyzes primarily lysyl and argjnyl residues. Pancreatin contains amylase, lipase, and protease. Amylase breaks down starch; lipase breaks down fats; and protease breaks down proteins. Pancrelipase is similar to panmatin, but with a higher concentration of lipase. These enzymes are primarily obtained from hog or ox pancreas, but some (such as lipase) can also be obtained from microbial sources (e.g., Aspergillus niger and Aspergillus oyzae). According to the U.S. Pharmacopoeia (USP), chymotrypsin and trypsin are routinely crystallized from ox pancreas gland extract, and pancreatin from both hog and ox sources, whereas pancrelipase is derived from hog pancreas? Porcine pancreas is especially rich in amylase and lipase and is similar to human pancreas.' Bovine pancreas contains considerable amounts of proteolytic enzymes but substantially lower amounts of lipase and amylase.' Germany, Japan, England, India, and other countries utilize their own pharmacopoeia, and foreign companies may use other sources to formulate their enzyme products. Age, sex, and species of pork or ox can affect enzyme concentration and activity levels. For example, sow glands (from pork) are high in lipase, whereas butcher hogs (young male hogs, up to 90 kg in weight and 6 months of age) are high in protease. Beef cows and bulls have different enzyme levels from those in steers or heifers. Beef, though providing all three basic enzyme types, does not exhibit the activity levels of pork (which has an activity level one third to one half higher). Furthermore, physiology of hogs is more similar to that of humans than to that of any other animal.

ENZYME EXTRACTION PROCESSES Enzymes are particularly sensitive to environmental changes, so it is especially important during extraction to control pH (usually with buffers), temperature (using precooled solutions and apparatus), substrate, and proteolysis (controlled through the use of inhibitors) to render a product that is enzymatically active: The following steps are typically involved in the production of pancreatic enzyme supplements: 1. Cell membrane rupture 2. Fractionation 3. Crystallization 4. Enzyme isolation

Pancreatic Enzymes

Rupturing the Cell Membrane

Pancreatin

Although many methods are employed in enzyme extraction, most entail rupturing the cell membrane of the animal tissue. Rupture can be achieved through mincing, homogenizing, shaking with fine glass beads (at high speed), grinding with sand, &zing (and subsequent thawing), oscillations(ultrasonicor sonic),autolysis (either alone or with toluene, ethyl acetate, or sodium sulfide), treatment with solvents (e.g., acetone), or lysis with added enzymes? Extracting enzymes from animal tissues is easier than extracting them from microorganisms.5In fact, in many cases, simple extraction with water may be sufficient. All extraction processes, however, must control pH and temperature to protect the enzymes from deactivation.

Pancreatin extraction can involve eliminating the insoluble tissue, then treating the mixture with organic solvents to dissolve the tissue and precipitate the enzymes.' However, because part of the lipase and other enzymes are inactivated during the manufacturing process, pancreatin that is isolated in this way is not very active.' Pancreatin can also be produced through lyophilization, that is, by drying under reduced pressure or with acetone. At this low temperature, the enzymes are more stable and less likely to be denatured.' After proper defatting, the pancreatin is stable, provided that it contains not more than a small percentage of m0isture.l However, it may contain undesirable microorganisms (such as Salmonella) and must, therefore, be decontaminated.' Under carefully controlled conditions, pancreatin can be decontaminated with a terminal heat treatment.' According to the USP,3 each milligram of pancreatin should exhibit the following characteristics:

Fractionation Once the enzyme is brought into a solution, it must be separated from the other substances in the solution. Gel filtration or dialysis can be used to remove the small molecules, leaving large molecules (primarily proteins, with some polysa~charides).~ Various fractionation methods can be employed for purifying the enzymes, including changing the pH, heating, using organic solvents and/or salts, adsorption, column chromatography, and electroph~resis.~ Inhibitor affinity chromatography and substrate affinity chromatography are also used? as is magnetic affinity separation7

Crystallization After an enzyme has been purified, it may be possible to crystallize it. Dixon and Webb5 regard crystallization as a final-stage method of fractionation. Crystallization can be achieved with ammonium sulfate solutions (the typical method) or at a constant salt concentration through a gradual change in the temperature or the pH.5

Enzyme Isolation Because each enzyme has its own distinct properties, isolation methods can vary by enzyme, as seen in the following discussion.

Chymotrypsin One method (used in Germany) for extracting chymotrypsin (in the form of its inactive precursor chymotrypsinogen) is by fractionated extraction, ultrafiltration, and subsequent chromatographic purification of pancreatic juice. The chymotrypsinogen is converted to the active chymotrypsin by treatment with trypsin in an acid environment.

Tiypsin Trypsinogen can be isolated from the animal pancreas by fractionated precipitation and then activation to trypsin in a slightly alkaline environment.

Not less than 25 USP units of amylase activity Not less than 2.0 USP units of lipase activity Not less than 25 USP units of protease activity The USP states, "One USP unit [or 1x1 of amylase activity is contained in the amount of pancreatin that decomposes starch at an initial rate such that one microequivalent of glucosidic linkage is hydrolyzed per minute" under the conditions listed in the USP to assay for amylase activity. "One USP unit [or 1x1 of lipase activity is contained in the amount of pancreatin that liberates 1.0 pEq of acid per minute at a pH of 9.0 and 37" C" under the conditions detailed in the USP to assay for lipase activity. "One USP unit [or 1x1 of protease activity is contained in the amount of pancreatin that digests 1.0'mg of casein" under the conditions enumerated in the USP to assay for protease a~tivity.~ Therefore a product labeled "4x" would be four times stronger than a product labeled "lx."

Pancrelipase Since it is isolated from the same organs, pancrelipase is isolated in much the same way as pancreatin. Pancrelipase is similar to pancreatin and according to the USP should exhibit the following characteristics: Not less than 100 USP units of amylase activity Not less than 24 USP units of lipase activity Not less than 100 USP units of protease activity

ABSORPTION OF PROTEINS In the past, the efficacy of enzyme therapy has been discounted, because the intestinal epithelial mucosa

Pharmacology of Natural Medicines had been thought to be impermeable to large protein molecules.g10 However, research over the past several decades has shown that the intestinal epithelium can be crossed by macromolecules, including intact proteins such as proteolytic enzymes.” These macromolecules normally penetrate the mucosal surface via the transcellular route as, in the healthy mucosa, the tight junctions (zonula occludens) between the enterocytes prohibit paracellular Binding to the luminal membrane of the enterocyte is followed by phagocytosis.16Some of the vacuole membrane vesicles formed fuse with lysosomes, and within the resulting phagolysome, the peptides and proteins may be hydrolyzed by lysosomal enzymes.14 Other macromolecules avoid intracellular digestion and are passed from the enterocytesthrough the basolateral membrane into the interstitial space.17In the interstitial space, the macromolecules become available to macrophages and lymphoid cells.’* Those molecules not taken up by macrophages or lymphatic cells eventually pass from the interstitial space into the blood or 1 y m ~ h . l ~ The transport of macromolecular material from the lumen to the interstitium has been extensively studied in the epithelium covering the lymphatic structures, such as Peyer’s patches and isolated follicles.16In these regions, specialized enterocytes, the follicle-associated epithelium cells (FAE cells)I3 or M cellsz0 (so called because of their occurrence in the microfolds of the luminal surface), transport macromolecular material in both dire~ti0ns.l~ The gut-associated immune system is thus supplied with antigenic macromolecules from the intestinal lumen.21-23The immunoglobulins (Igs) produced by the plasma cells in the lumina propria (mainly IgA) are transported transcellularly to the luminal surface. The exact level of intestinal absorption of intact molecules or large breakdown products of dietary proteins is not yet totally clear and can vary by individual.”s Although it is generally assumed that, apart from a very small proportion, all protein is hydrolyzed into amino acids or low-molecular-weight peptides before absorption by the mucosa, some research supports the hypothesis that a considerable proportion of dietary protein is taken up in the form of macromolecules and is only then hydrolyzed intercellularly in the peripheral tissue into amino acids (a process called “distributed digestion”).2628 Regardless of the nutritional significance, the transepithelial transfer of particulate matter is at least antigenically sufficient to elicit a response from the gutassociated immune system.I3 The production and secretion of the immunoglobulins promote binding and proteolysis of the antigen material on the mucosal brush border, thereby reducing its absorption (immunologic barrier).29

Understanding the Absorption of Enzymes Understanding the intestinal transport of macromolecules is especially important for understanding the functions and absorption of enzymes spe~ifically.~~ Hydrolases such as trypsin and elastase can be transported functionally intact into the blood from the lumen of the gut. These circulating proteinases are bound to antiproteinases such as alphas macroglobulin or alphal antiproteinasesl and can be resorbed from the main blood stream by pancreatic cells (enteropancreatic circulation as an enzyme conservation process).30Thus, the intestinal absorption of intact enzymes appears to be important for the balance between hydrolases and antiproteinases in the intracellular space31and is an important factor for the establishment and maintenance of the internal stability of the body. It should be kept in mind that, although there are a number of absorption mechanisms, the primary mechanism for enzymes and other macromolecular enteral absorption is pinocytotic transfer by the M cells of the small intestinal epithelium. After connection to a receptor in the mucosa of the intestinal wall, the enzymes are absorbed into the wall by pinocytosis, guided through the intestinal cells in vesicles, and finally released into the blood by exocyt~sis.~lJ~ To clarify rate of absorption, Steffen et aP3 investigated the absorption of an enzyme mixture “A” (EMA, which contained pancreatin, 100 mg; papain, 60 mg; lipase, 10 mg; amylase, 10 mg; trypsin, 24 mg; chymotrypsin, 1mg; bromelain, 45 mg; and the bioflavonoid rutin, 50 mg) in rabbits. Using electrophoresis, these researchers found that entire enzyme molecules were absorbed. Although enzyme particles were also present, the ratio to the entire amount administered was not measured. EMA was found in both lungs and liver after 1 to 2 hours. After 1 to 4 hours, approximately twice as much EMA was found in the liver as in the lungs. The absorption maximum in all animals occurred approximately 1hour after administration. After 24 hours, EMA was no longer found in either the lungs or liver. The absorption rate of individual and combined enzymes can be seen in Table 112-1.343The absorption rate of orally ingested EMA is more than 20% within 6 hours.= (For additional discussion of the intestinal absorption of intact macromolecules, see Chapters 19 and 53.)

FACTORS AFFECTING ENZYME ACTIVITY Numerous factors can affect the activity of supplemental enzymes; they include the following: PH Temperature Substrate and substrate concentration Cofactors

Pancreatic Enzymes

Absorption rate of individual and combined enzymes (within 6 hours) Enzvme Amylase

AbsorDtion rate (%) 45

Chymotrypsin

14-16

Pancreatin

18-19

Papain

6

Trypsin

26-28

Enzyme combination (bromelain, chymotrypsin, pancreatin, papain, and trypsin, with the bioflavonoid rutin)

22

Data from references 34 and 35.

Metal ions Inhibitors and coating

Optimal pH Range Each enzyme has an optimal pH range, depending on such variables as temperature and substrate concentration, at which the enzymatic catalytic reaction occurs most rapidly. Chymotrypsin is stable at a pH of 3 or 4, suffers reversible denaturation at a pH below 3.0, and becomes inactive at a pH above 10.0.' Trypsin, stable at a pH of 3.0 (and at low temperature), is irreversibly denatured at a pH of 8.0 or higher.l One must remember that enough the pH of the normal stomach is 1.5 to 3.03640~ to denature or inactivate some or all of the pancreatic enzyme supplement if it is not enterically coated or otherwise treated to protect it from a low-pH environment.

The Effects of Temperature In general, an increase of 50" F (10" C) in the enzymatic environment approximately doubles the rate of the chemical reaction.37 However, because enzymes are proteins, excessively high temperatures can denature them, thus destroying their activity. Optimal temperature or an enzyme is the temperature at which the catalyzed enzymatic reaction progresses most rapidly without damage to the enzyme. This is a good rationale for avoiding hot beverages when taking enzyme supplements. The enzymes in the human body develop high levels of activity at about body temperature, increasing to maximum at about the temperature of a severe fever, that is, 104" F (40" C).

accelerated by the addition of more substrate. This is why it is particularly important to ingest sufficient quantities of supplemental enzymes (which vary according to the condition being treated).

Cofactors Although all enzymes consist of protein, some are complex proteins, that is, they have a protein component and a "cofactor." If the cofactor is removed, the protein (no longer active enzymatically) is called the apoenzyme. A cofactor might be a metal (e.g., iron, magnesium, copper, or zinc), a prosthetic group (a moderately sized organic molecule), or a coenzyme (small organic compound). Prosthetic groups and metals can aid in the catalytic function of the enzyme, whereas coenzymes take part in the enzymatic reaction. Many vitamins, trace elements, and minerals essential to human bodily function are part of enzymatic cofactors. So the physician must ensure that his or her patients take multivitamins and multiminerals to "feed" their enzymes. Coenzymes are essential for the activity of many enzymes and serve as a type of substrate in certain reactions. In these reactions, the coenzyme is converted to a form no longer active in catalyzing the reaction. The reaction requires a mix that contains one molecule of cofactor for every molecule of substrate to be converted.

Metal Ions Specific metal ions are required for the activity of many enzymes. Some metal ions increase enzyme activity and others decrease or inhibit it. Calcium, cobalt, copper, iron, magnesium, manganese, molybdenum, potassium, and zinc are the most common enzyme activators in humans. Certain heavy metal ions inhibit enzyme reactions; they are barium, lead, and mercury, and they combine with the sulfhydryl reactive group (-SH) that is part of the active site of many enzymes.

Inhibitors Ions, atoms, or molecules that terminate or retard enzyme activity are called inhibitors. They are classified as either noncompetitive or competitive. A noncompetitive inhibitor combines with the enzyme at a location other than the active site. The noncompetitive inhibitor retards the conversion of the substrate by the enzyme, although it does not affect the bonding of the substrate of the enzyme. An inhibitor is classified as competitive if it combines with the active site of the enzyme, preventing the substrate from having access to the active site.

Substrate Concentration

Supplement Coating

The rate of any reaction is accelerated by raising the substrate concentration until the enzyme is saturated by substrate. At this level, the rate of reaction becomes independent of substrate concentration and is no longer

The normal human stomach has a pH of approximately 1.5 to 3.0.% This low pH inhibits bacterial growth and activates certain enzymes. This acidic nature, however, can destroy pH-sensitive supplemental enzymes. For this

Pharmacology of Natural Medicines reason, many enzyme products are enterically coated. The coating allows the product to reach the small intestine before disintegrating.’ Other products are encapsulated in “microspheres,”delaying disintegration. In one study, cellulose acetate phthalate (CAP) and maize starch were used as the coating materials to encapsulate pancreatic protease.% Results indicate that the coating materials were stable for at least 3 hours (time to pass through each part of the gastrointestinal tract) in simulated gastric conditions (pH 3.97) but disintegrated rapidly under simulated intestinal conditions (pH 6.82 and temperature 39.5”C).

MEASURING ENZYME ACTIVITY When considering enzymes and enzyme applications, the physician must understand the variables affecting their performance. Selection of an enzyme for therapeutic purposes requires more than knowing whether a given product contains amylase, protease, lipase, or other enzymes. The activity levels of the enzymes are critical. Unfortunately, the labels on most enzyme products sold in the United States do not indicate the activity levels of the enzymes contained therein. In addition, when the activity is stated, the consumer has no way of knowing which enzyme assay the manufacturer used unless the label also indicates that the product conforms to the guidelines of the USP. This is particularly confusing because activity levels are greatly affected by the conditions under which the assay was performed (including temperature, pH, and substrate). Adding to the confusion, enzyme manufacturers utilize diverse assay methodologies. Therefore directly comparing the enzymatic activity of competing products is difficult, if not impossible.The utilization of a single assay system (suchas detailed in the USP) is probably necessary to directly compare competitive products. Several standardized assay systems are available for enzyme suppliers and are found in the USP (for a definitive assay), the National Food Ingredients Association (NFIA) Laboratory Methods Compendium, and the Food Chemical Codex. Incomplete labeling and the inconsistent use of standardized assay methodologies make evaluation of competitive products extremely challenging. Price could be the first indication of inequities in assay procedures. For example, if company A is selling a product at 1000units/g for $30 a bottle and company B is selling a product at 5000 units/g for $10 a bottle, the units are most likely not the same. For clinical reliability, one must use only appropriately labeled products or obtain the assay procedures from each of the manufacturers. If possible, competitor products should be compared by means of assays performed in an independent laboratory.

CLINICAL APPLICATIONS Historically, enzyme therapy has been used in a wide variety of applications, ranging from the classic substitution of enzymes for intestinal deficiency to the centuries-old external application of enzymes to treat leg ulcers, topical wounds, wrinkles, blemishes, episiotomies, scars, and so on. Enzymes can be used individually or in complex enzyme mixtures. Because trypsin, chymotrypsin, lipase, and amylase are substratespecific, combinations of enzymes are frequently employed for a broader spectrum of activity. In addition, when combined, some enzymes act synergistically with others-hence the use of pancreatin (from animal pancreas) as well as products that include both enzymes from different sources and activating substances. For example, one German product contains an enzyme extract consisting of proteinases, triacylglycerol lipase, and alpha-glycosidase (amylase), minor amounts of elastase, nuclease, and carboxypeptidase, and calcium ions to boost activity. Enzyme combinations should not be viewed as simply intensified forms of pancreatin. An enzyme combination has a number of therapeutic advantages over a preparation with only one or two components. Combining enzymes from diverse sources-animal, plant, and fungi-results in a wider range of optimal pH, synergism of the combined enzymes, greater absorption, higher level of effectiveness, and broader range of application. Furthermore, as S t r e i ~ h h a nstates, ~ ~ enzyme combinations are better than single enzymes for the following reasons: Isoenzymatic activity differences of single biocatalysts are more readily balanced by combining uniformly acting hydrolases of varying origins. Giant molecular substrates are more quickly and more intensively fragmented by a multihydrolytic preparation because the differently acting hydrolases are able to simultaneously disintegrate the giant molecular substrates at many different locations. Certain enzymatic mixtures have a broader range of action than pancreatin, bromelain, or any other standardized monohydrolytic preparation-this is because certain enzyme mixtures characteristically possess differences in optimal pH and also differences in reactive properties of the proteolytic, lipolytic, and/or glycolytic acting hydrolases. Clinical uses of individual enzymes can be seen in Boxes 112-1 through 112-5,m95while clinical uses of combinations can be seen in Box 112-69”178(for more information on how enzymes can treat more than 150 conditions, please see my book, The Complete Book of Enzyme Therapy).

Pancreatic Enzymes

In debridement, treatment of abscesses and ulcerations, liquefaction of mucous secretionsm In ophthalmic cataract surgeries and therapy of eyeball hematomas and ophthalmorrhagia~~.~~ Before and after tooth extraction as well as in operative dentistvz$4 After episiotomy procedures" As an anthelmintic against enterozoic wormse In early recognition of tumor cellsM In histologic gastroenteric diagnosis47 In inflammatory conditions (local and systemic) to promote the dispersion of blood extravasates and effusions from fracture^^',^-^^ Surgical Sporting Accidental soft tissue trauma48-52*55 lntervertebraldisc lesionss For uveitis vitreous hemorrhage, diabetic retinopathy, and asthmatic symptoms57

In debridement of necrotizing wounds, ulcerations, abscesses, empyemas, hematomas, fistulas, and decubitus ulcers5s41 To accelerate healing in injuries, inflammations, phlogistic edemas, and traumatic changes*% As an auxiliary agent in meningitis therapyp2 As an ointment or dressing (wet or dry)' As a liquid or an aerosol to liquefy sputum in bronchial disorders and in the preparation of sputum for cytologic examination' As an antiinflammatory agent; oily suspensions are injected intramuscularly' As an aid in the treatment of intraocular hemorrhage, thrombophlebitis, intestinal obstruction (due to cirrhosis or carcinoma)63

Needs calcium ions for enzymatic activity Acts on starch, glycogen, and related polysaccharides and oligosa~charides~ In combination with other enzymes, as a digestanPs64.ffi As an antiinflammatory64 In treatment of deficiencies of exocrine pancreas, amylaceous dyspepsia, and cystic fibrosis'

-

In pancreatin-containing remedies to increase pancreaticllipolytic activities (replacement therapy)When given with pancreatin in combined preparations, it reduces fat level in stools7o7z Synergistically intensifiesthe activity of lipoproteid-lipase in the blood73and migration of agran~locytes~~ As a digestive aid7'

In pancreatic insufficiency, inadequate secretion of exocrine pancreas, and disturbed digestion, and after g a ~ t r e c t o m f ~ . ~ ~ - ~ ~ In chronic pancreatitis@and after surgery for chronic pancreatiti~~~ After pancreatectomy'V@ In ductal obstruction from neoplasm (e.g., of the pancreas or common bile duct)@ *To treat severe cases of steatorrhea (as found in cystic f i b r o s i ~ ) ~ - ~ ~

Soft tissue i n j u r i e ~ ~ . ~ ~ Sprained ankle97-w Reabsorption of hematomas96.1w Sports m e d i ~ i n e ' ~ ' - ' ~ ~ Meniscectomy (preoperative and postoperative therapy)108*i09 Traumatologyllo Prevention of posttraumatic and postoperative swelling1i1 Pancreatitisll' S~rgery~.~~~ Lower extremity bypass ~ u r g e r y " ~ Operative dentistry1I5 Proctology116 SinusitisIl7-120 Acute and chronic b r o n ~ h i t i s ~ ~ ~ - ~ ~ ~ Cystitis and lower urinary tract infections117~124~125 Prostatitis' 17.124.126 Pelvic inflammatory Postthrombotic syndrome124133 Pathologic venous p r o c e s s e ~ ~ ~ ~ ~ ~ ~ - ~ ~ Occlusive arterial disease139 Lymphedema140-145 Soft tissue rheumatism (nonarticular rheumatoid ~ y n d r o m e ) ' ~ * ~ ~ ~ Rheumatoid arthritis (chronic polyarthritis)'17~i22~131~142~148~i49~150-163 Ankylosing spondylitis (Bekhterev's d i ~ e a ~ e ) ~ ~ ~ ~ ~ ~ , ~ ~ Degenerative rheumatic joint d i s e a ~ e ' ~ , ~ ' ~ Monoarticular, activated o ~ t e o a r t h r o s i s ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ Multiple s ~ l e r o s i s ~ ~ ~ ~ ~ ~ ~ ~ ~ HIV infection^^^^-^^^ Fibrocystic breast d i s e a ~ e ~ " . ~ ~ ~ Ulcerative colitis and Crohn's disease117.122.1TI-178

.

Most conditions treated by enzymes can be assigned to one or more of the following categories: Digestive conditions Inflammatory conditions Cancer Autoimmune or immune disorders Cardiovascular disorders Viral and bacterial disorders Other conditions

Digestive Disorders Pancreatic enzymes have a long history of use in treating a myriad of digestive conditions, including indigestion,

Pharmacology of Natural Medicines pancreatic insufficiency, steatorrhea, pancreatitis, heartburn, gas, diarrhea, constipation-the list seems endless. Supplementing the diet with pancreatic enzymes can improve food digestion and therefore nutrient assimilation.This is especially true if the body’s own pancreatic enzyme production and/or supply is deficient, as can occur with age or because of an underlying health condition such as pancreatic insufficiency, chronic pancreatitis, steatorrhea, biliary tract disease, celiac disease, lactase deficiency or cystic fibrosis. In fact, individuals suffering from cystic fibrosis almost always take large quantities of pancreatin or pancrelipase to improve digestion. Any condition that can be improved by better nutrition can benefit from the addition of enzyme supplements. This is particularly true of those suffering from chronic pancreatitis-a condition marked by poor digestion. Enzyme therapy can help increase body weight and improve serum albumin levels (low levels reflect protein calorie maln~trition).”~

Inflammatory Diseases The inflammatory process is involved in numerous diseases and conditions, from sports injuries to arthritis to sinusitis to fibrositis. One of the basic concepts in systemic enzyme therapy is that all kinds of inflammatory processes respond to enzymes. The following steps describe the postulated mechanism of action:

1. In the damaged area, various repair mechanisms are activated, resulting among other effects in surrounding of the traumatized region by fibrin. 2. After having been partly or completely sealed off by microthrombi and/or a fibrin web, the injured area is cut off from the normal circulatory system. Stasis results, inhibiting the repair processes (nutrients cannot get into the damaged area and waste products cannot be removed). Pressure rises in the damaged capillaries, the blood vessels become highly permeable, and fluid is forced out into the surrounding tissue. The result is increased pressure, swelling, and pain. 3. Supplemental enzymes, after absorption, are bound in complexes (e.g., alpha2 macroglobulin-hydrolase) and circulate to the injured area from the blood stream. 4. Proteolytic enzymes directly attack the microclots and fibrin formation, lysing the fibrin and breaking open the clogged vessels, thus reestablishing circulation.

By restoring normal blood flow, postinflammatory pain and edema are reduced more rapidly and, equally important, the essential physiological inflammatory repair process is not blocked or diminished (as with antiinflammatory agents), but rather is accelerated and reinforced.

Even inflammatory diseases, such as arthritis and herpes zoster, have been shown to respond to the systemic application of enzymes.148J80J81 Despite the supportive research, the administration of enzymes in traumatology and injuries is not widely used. All types of injuries-sprains, strains, hematomas, dislocations, and even postoperative conditions-can be treated effectively with enzymes. Individual enzymes and enzyme combinations (particularly those including trypsin, chymotrypsin, pancreatin, amylase, lipase, papain, and bromelain, with rutin) are effective in treating inflammation because they help limit the injury, aid its rectification, and promote new, healthy tissue formation. They are inflammation activators, not inflammation inhibitors, effectively accelerating the inflammatory process (a necessary component of wound healing). This acceleration means, on the one hand, that the work of damage control, damage repair, and new tissue construction is carried out more actively and thus completed more swiftly. On the other hand, it means that there can be a temporary increase in the visual and sensory effects produced by the inflammation (i.e., more redness, swelling, heat, and pain). Because the inflammatory reaction is so universal, it appears that enzymes and enzyme mixtures can be effectively used to treat a wide variety of chronic disorders.

Cancer Just as Beard researched the effect of enzymes on cancer, so have modem researchers. Dr.William Kelley devised an anticancer program that employed detoxification, pancreatic enzymes (and other nutritional supplements), improved enzyme-rich nutrition, and coffee enemas.lS2 He started his treatment program in response to his own bout with pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer death in the United States, affecting nearly 30,000 people every year.183Unfortunately, survival rates for this disease are extremely low; in fact, most people do not live even 5 years after diagnosis. The survival rate is abysmal probably because pancreatic cancer is usually not diagnosed until it is quite advanced. Standard medical treatment for pancreatic cancer involves surgery, radiation therapy, and chemotherapy. However, even with treatment, pancreatic cancer still claims 99% of those diagnosed with the disease; hence, its reputation as one of the deadliest cancers.l@ Dr. Nicholas Gonzalez became aware of Kelley’s work in the 1980s and began reviewing the case histories of Kelley’s patients. He and Dr. Linda Isaacs are now using their own version of the Kelley program to treat pancreatic cancer with enzyme therapy. They have conducted a 2-year-long pilot study on 11 patients with inoperable, biopsy-proven pancreatic adenocarcinoma to see whether therapy with enzyme supplements

Pancreatic Enzymes

could help. Nine (81%)of the patients survived 1 year, five (45%)survived 2 years, and 4 survived 3 years.185 This compares favorably with survival rates reported in the National Cancer Data Base from 1995; 25% at 1year and 10%at 2 years." In fact, patients lived an average of 17 months, which is three times longer than patients with this type of cancer usually survive.187Researchers are currently conducting a Phase I11 clinical trial funded by the National Institute of Health's National Center for Complementary and Alternative Medicine to compare the effectiveness of pancreatic enzymes and dietary supplements with that of standard gemcitabine-containing chemotherapy regimens in the treatment of advanced pancreatic cancer. The trial is ongoing and, although no results have yet been released, we anxiously await the outcome of this trial.

Autoimmune and Immune Complex-Mediated Diseases In autoimmune disease, tissue-bound immune complexes activate the complement system. Activation of the enzyme cascade results in an intense protein-destroying inflammatory response leading to signhcant local tissue destruction. For instance, when immune complexes collect in the kidneys, complement activation causes inflammation, resulting in glomerulonephritis. Research shows that some enzymes can inhibit immune complex-mediated diseases, such as glomerulonephritis, by interrupting the complement cascade. Other disorders with similar mechanisms also respond to supplemental enzymes. Some of these conditions, such as Crohn's disease, pulmonary fibrosis, chronic rheumatism, and ankylosing spondylitis, have not responded well to conventional medical treatments.

Cardiovascular Disorders Cardiovascular disease, the primary killer in the United States, kills nearly a million Americans every year,'87 almost as many as cancer, accidents, pneumonia, influenza, and all other causes of death combined. But cardiovascular disease is not limited to the elderly; nearly 175,000 Americans younger than age 65 die from this disease every year.188 In normal circulation, there is a constant dynamic balance between blood clotting and fibrinoly~is.'~~ If fibrinolysis is impaired, clot formation is abnormal. If fibrinolysis increases, a tendency toward excessive bleeding results. Therefore, maintenance of proper equilibrium is extremely important for the circulatory system. One study examined the effects of various enzyme combinations on fibrinolysis and fibrin formation. The researchers induced fibrin deposition with calcium ions or staphylocoagulase in the plasma of centrifuged, acellular citrated blood from humans or rabbits and treated the clot with various concentrations of enzyme

suspensions. The higher the enzyme content of the solution, the more rapidly clots were deg~-aded.'*~J~~

Viral and Bacterial Disorders Enzyme therapy can be beneficial in treating infection caused by viruses or bacteria. But as more and more bacteria become resistant to antibiotics, researchers and physicians are looking for new treatment alternatives. Enzyme therapy is a valuable alternative to antibiotics in treating many conditions because it can help stimulate the immune system and strengthen the body as a whole. Enzymes also reduce inflammation and improve circulation. Many conditions can be helped with enzymes, including abscesses, acne, adenoiditis, adnexitis, bladder infection, boils, conjunctivitis, diarrhea, ear infections, empyemas, epididymitis, gingivitis, kidney disorders, laryngitis, pneumonia, rheumatic fever, sinusitis, staphylococcalinfections, and tonsillitis. Enzyme therapy can also aid in the treatment of viruses. The human body defends against viruses with the help of macrophages or natural killer (NK) cells. Oral enzyme combinations (such as papain, trypsin, and chymotrypsin) synergisticallyincrease the antiviral effects of tumor necrosis factor (TNF), macrophages, and NK cells and the breakdown of circulating immune complexes (CICs). Enzymes can aid in the treatment of numerous viral conditions including AIDS, chancre sores, chickenpox, colds and coughs, hepatitis, herpes simplex, herpes zoster, influenza, measles, pneumonia (viral), and warts.

Other Conditions Enzyme therapy may be of value in conditionsthat do not easily fit into one of the preceding categories. Autism is just one example. No causative agent has been found for this developmental disease, although many theories abound, including vaccinations, a genetic link,nutritional deficiencies, and reactions to chemicals or other environmental factors. Some research indicates that enzyme therapy to improve protein digestion may be of particular benefit in autism as well as many other conditions.1go

DOSAGE Enzymes may be administered rectally, topically, orally, or by injection, depending on the condition being treated. Rectal administration involves a retention implant. Topical treatment consists of ointment spread over the involved area. Oral forms include lozenges (dissolved in the mouth), oral tablets, and enteric-coatedtablets. A wide range in daily dosage has historically been used for the following reasons: There are individual differences in patient health. *The level of effective absorption in tablet strength can vary.

Pharmacology of Natural Medicines

There are a wide variety of influencing ranges in pH. Enzyme activity levels vary between products.

Composition of enzyme combinations (mg) Enzyme

A

B

100

100

0

Papain

60

60

100

Bromelain

45

45

0

Lipase

10

10

0

Amylase

10

10

0

Trypsin

24

24

40

1

1

40

50

0

0

0

0

40

Pancreatin

Chymotrypsin Rutin Thymus extract

For example, pancreatin dosage depends on the condition being treated as well as on the patient's diet and digestive requirements. Dosage can vary because of pancreatin's susceptibilityto inactivationin the stomach and duodenum.lY1 Table 112-2lY2indicatesthe composition of threeenzyme combinations(A, B, and C), whereas Table 112-3 lists some of the conditions effectively treated with these products, the dose required, and the treatment p e r i ~ d . ' ~ ' ~ ~

C

Modified from Stauder G, Pollinger W, Fruth C. Allgemein Medizin 1990; 19:188-191.

TOXICOLOGY Oral Enqmes In general, side effects of orally administered enzymes are few and due primarily to excessive dosages or hypersensitivity reactions. According to Wolf and

Dosage programs for specific conditions Condition

Frequency x dosage

Treatment period

Postthrombotic syndrome193

3x5

As needed

Oncology194

2x11

6 weeks or as needed

A

Lyrnphedemal4'

2x5

2 years

A

Fibrocystic breast disease175

2x10

6 weeks or as needed

Experimental hematomaw

3 x 10

24 hours

A A

Prophylactic treatment of karate injurieslal

3x5

During the season

Trauma and meniscus operationlW

3 x 10

Average of 17.7 days

Combination' A

Soft tissue injuries and distortions of the ankleg7

3 x 10 initially, then 3 x 1

As needed

Athletic soft tissue injuries'"

2x5

Spring football season

Dental ~ u r g e r y " ~

4x5

Day before surgery to seventh postoperative day

A

Sports injurieslm

3x10

As needed

Chronic polyarthritislH

4x8

6 months

A A

Active arthroseslg6

4x7

6 weeks

Extraarticular rheumatism146

3 x 10

As needed

Adnexitis'"

3x5

10-14 days

Prostatitis' l7.lz4

3x5

10 days

MastopathylS7

2x10

Multiple sclerosis167-170~178 Initially As symptoms improve

2 ampoules injection 2 ampoules injection

On injection-free days Later Finally

Daily Every 2 to 3 days, then at longer intervals

3 x 10 3x5 3x3

C C A A A

Herpes zoster18' Initially First 2 days

2 ampoules injection 3-4 x 1

First 2 days As indicated to 14 days

C A

HIV

25lday

12 months

A

'For composition of combination, see Table 112-2.

Ran~berger,'~~ high dosages (70 tablets of 17.5 g each) of a proteolytic enzyme mixture have been given without long-term side effects. Studies and literature searches commissioned by regulatory authorities such as the U.S. Food and Drug Administration (FDA) have apparently confirmed that enzyme preparations obtained from suitable sources (e.g., nontoxic, nonpathogenic sources) are safe to consume.199There is some indication that patients with cystic fibrosis who are undergoing long-term highdose pancreatic enzyme therapy may demonstrate colonic wall thickening, a condition called fibrosing colonopathy; however, the copolymer coating on the tablet, rather than the tablet's contents, may be the culprit.2O0 With normal use of pancreatic enzymes, stools can be pale or have a pungent odor. Transient intestinal upset, such as diarrhea and gas, may result from excessive dosage of pancreatin. Hypenuicosuria (excess uric acid in the urine) and hypenuicemia (excess uric acid in the blood) have been associated with extremely high doses of exogenous pancreatic enzymes. If the pancreatin preparations are held in the mouth before swallowing, stomatitis can result as can ulcerations and irritation of the mucosa, particularly in infants, in whom pancreatin may also cause perianal soreness.l~ol It is not known whether pancreatin given to pregnant women can harm the fetus, because animal reproductive studies have not been conducted. Therefore, pancreatin should probably not be used during pregnancy.2o1Also, because whether pancreatin is distributed into mother's milk is not known, caution should be exercised with use of this substance in nursing women.2o1 Sneezing, lacrimation, rash, and other hypersensitivity reactions have been reported in sensitive individuals. Pancrelipase (and any other enzyme derived from pork sources) is contraindicated in those who are hypersensitive or allergic to pork products. Enzymes should not be used by hemophiliacs, nor immediately before or after those surgical procedures with an increased risk of bleeding. Trypsin is especially contraindicated in those with blood-clotting mechanism disorders, in liver disease, and as an aerosol within a week of pulmonary hemorrhage.' A note about supplement safety: During the last few years, there has been increased concern regarding mad cow disease (also called bovine spongform encephalopathy [BSE]).In humans, this disease is called CreutzfeldtJakob disease (CJD). The disorder can be caused by eating beef that is infected with BSE, but it can also be transmitted through corneal transplant tissue, from hormone extracts (such as human growth hormone), and

possibly from ingesting contaminated glandular products. It may take as long as 20 years after infection for the characteristic symptoms of CJD to manifest. Since 1995, FDA has required that manufacturers of supplements ensure that any animal products used in their supplements do not originate in BSE countries (which as of this writing include the European Union countries and Japan).202Unfortunately, there is no test to see whether a supplement is infected with BSE. On an "up" note, the FDA considers tissues from cow pancreas (the source of some pancreatic enzymes) to be "low In addition, many manufacturers use pork sources for pancreatic enzymes. For anyone who is concerned about pancreatic supplements the National Nutritional Foods Association suggests checking the supplement's label to see whether a bovine source and a country of origin are listed.204If neither is indicated on the label, one can contact the manufacturer. One should also contact the manufacturer to see what measures they use to ensure BSE-free products.

Enzyme Enemas Enzyme enemas can sometimes cause the rectum or anus to itch or b u m . However, these are only minimal side effects in relation to the positive benefits obtained.

Topical Application Enzymatic activity directed toward proteinaceous components of the epithelium can cause irritation. For example, prolonged skin contact with proteolytic enzymes may cause irritation of the skin, mucous membranes of the throat, nose, and eyes.lW

Injectable Enzymes Injectable forms require more care, which is why they are normally administered in a hospital setting. Chymotrypsin, when injected, can occasionally create anaphylactic reactions.' Trypsin is more toxic when injected, and rapid infusion is far more toxic than slower infusion.' In addition, trypsin must not be administered intravenously.' Further, intradermal or scratch testing is advised before parenteral administration.' Other contraindications to trypsin's use are pork allergy and pancreatitis. It should be remembered that, at the beginning of therapy, an individual's symptoms may occasionally become more severe. This is a sign that a therapeutic reaction is occurring and should be evaluated positively. The medication need not be discontinued, although a temporary reduction in dose might be advisable.

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135. Mahr H. Zur enzymtherapie entzundlicher venenerkrankungen der tiefen beinvenenthrombose und des postthrombotischen syndroms. Erfahrungsheilkunde 1983;117. 136.Maehder K. Enzymtherapie venoser gefasserkrankungen. Die Arztpraxis 1972;2. 137. Kluken N. Venose krankheiten in klinik und praxis, systemische enzymtherapie, medizinische woche Baden-Baden, 1990.Natur und Ganzheitsmedizin 1991;28. 138. Vogler W. Enzymtherapie. Hessen Hausarz 1989;4116. 139. Rokitansky 0, v. Ozontherapie und enzyme bei der chronischarteriellen verschlusskrankeit. Systemische Enzymtherapie am 31.10.90. Medizinixhe Woche, Baden-Baden, 1990, Natur- und Ganzheitsmedizin 1991;(Suppl 14). 140.Keim H, et al. Methode zur lindecung der lymphstauung am arm nach behandlung des mammakarzinoms. Rontgenberichte 1972;l:l. 141. Scheef W, Pischnamazadeh M. Proteolytische enzyme als einfache und sichere methode zur verhutung des lymphodems nach ablatio mammae. Med Welt 1984;35:1032. 142. Streichhan P, Inderst R. Konventionelle und enzymtherapeutische massnahmen bei der behandlung brustkrebsbedingter armlymphodeme. Der Prakt Arzt 1991;13:37-38. 143. Ransberger K, Stauder G, Streichhan P. Wissenschaftliche monographie zur praklinik Wobenzym@N, Mulsal@N, Phlogenzym@. Forum Medizin, 1991. 144. Konig W. Erfahrungen der Robert-Janker-Klinik, Bonn, mit systemischer enzymtherapie und emulgierten vitaminen. Acta Medica Emperica 1988;3711. 145. Konig W. Proteolytische enzyme verhindern lymphodem. In Medizinische Enzym-Forschungesgellschaft e.V., ed.Systemische Enzymtherapie, Symposium Munich, 1986; Medizin Aktuell (Enzyme Series,) Informed International Congress Report 53,1986. 146. Uffelmann K, Vogler W, Fruth C. Der eisatz hydrolytischer enzyme beim extraartikularen rheumatismus. Allgemeinmedizin 1990;19:151-153. 147. Vogler W. Der stellenwert der enzymtherapie bei entzundlichrheumatischen erkrankungen. Systemische Enzymtherapie, Medizinische Woche, Baden-Baden, 1990. Natur- und Ganzheitsmedizin 1991;223. 148. Miehlke K. Enzymtherapie bei rheumatoider arthritis. Natur- und Ganzheitsmedizin 1988;108-111. 149. Inderst R. Enzymtherapie. Erfahrungsheilkunde 1989;38:305. 150. Horger I, Moro V, van Schaik W. Zirkulierende immunkomplexe bei polyarthritis-patienten.Natur-und Ganzheitsmedizin 1988; 1:117. 151. Steffen C, Smolen J, Miehlke K, Horger J, Menzel J. Enzymtherapie im vergleich mit immunkiomplexbestimmungenbei chonischler polyarthritis. Zeitschr f Rheumatologie 1985;44:51. 152. Reinbold H. Die biologische alternative in der therapie entzundlicher rheumatischer erkrankungen. Zeitschr Allgemeinmedizin 1981;34. 153. Reinbold H. Die therapie des morbus bechterew mit enzymen. Erfahrungsheilkunde 1980;lO. 154. Ekerot L, Ohlsson K, Necking L. Elimination of protease-inhibitor complexes from the arthritic joint. Int J Tissue React 1985;7 391-395. 155. Ballachi G. Hydrolytische enzyme bei aktivierten polyarthrosen. Rheuma 1988;8. 156. Goebel KM. Enzymtherapie bei spondylitis ankylosans. Lecture given at 17th Systemische Enzymtherapie Symposium, Vienna, 1991. 157. Horger I. Enzymtherapie bei einem rheumakollektiv. Therapiewoche 1983;33:3948. 158. Panijel M. Entzundlich-rheumatische erkrankungen. Zeitschr f Allgemeinmedizin 1985;61:1305.

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184. Lillemoe LD, Ye0 CJ, Cameron JL. Pancreatic cancer : state-of-theart care. CA Cancer J Clin 2000;50241-268. 185. Gonzalez NJ, Isaacs LL. Evaluation of pancreatic proteolytic enzyme treatment of adenocarcinoma of the pancreas, with nutrition and detoxification support. Nutr Cancer 1999;33117-124. 186. Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer 1995;761671-1677. 187. Preventing heart disease and stroke: Addressing the nation‘s leading killers. National Center for Chronic Disease Prevention and Health Promotion. Centers for Disease Control and Preventing. Available online at www.cdc.gov/nccdphp/nng/nng-cvd.htm [accessed April 10,20031. 188. 1991 Heart and stroke facts. Dallas: American Heart Association, 1991. 189. Haid-Fischer F, Haid H. Venenerkrankungen. Stuttgart: Thieme, 1985. 190. Brudnak MA, Rimland B, Kerry RE, et al. Enzyme-based therapy for autism spectrum disorders-is it worth another look? Med Hypotheses 2002;58:422-428. 191. Worschhauser S. [Conservativetherapy for sports injuries. Enzyme preparations for therapy and prophylaxis.] Allgemeinmedizin 1990;19:173-177. 192. Stauder G, Pollinger W, Fruth C. Systemische Enzymetherapie. Eine Ubersicht uber Neue Klinische Studient. Allgemein Medizin 1990;19:18&191. 193. Inderst R. Enzymtherapie bei Gefasserkrankungen [Enzyme therapy in vascular diseases]. Allgemein Medizin 1990;19: 154-157. 194. Wrba H. Kombinierte tumortherapie. Stuttgart: Hippokrates, 1992. 195. Klein G, Pollmann G, Kullich W. Klinische Erfahrungen mit der Enzymtherapie bei Patienten mit Chronischer Polyarthritis im Vergleich Zur Oralen Goldtherapie [Clinical experience with enzyme therapy in patients with rheumatoid arthritis in comparison with oral gold]. Allgemein Medizin 1990;19:144-147. 196. Gallacchi G. Der Einsatz Hydrolytischer Enzyme bei der Aktivierten Arthrose [The use of hydrolytic enzymes in activated arthrosis]. Allgemein Medizin 1990;19:148-150. 197. Dittmar F-W, Luh W, Phillipp E.Wobenzym@zur Behandlung der Mastopathie. Working paper, 1993. 198. Wolf M, Ransberger K. Enzyme therapy. Los Angeles: Regent House, 1972. 199. Sears A, Walsh G. Biotechnology in the feed industry: proceedings of Alltech’s ninth annual symposium. Nicholasville, KY Alltech Technical Publ, 1993. 200. Ramsden WH, Moya EF, Littlewood JM. Colonic wall thickness, pancreatic enzyme dose and type of preparation in cystic fibrosis. Arch Dis Child 1998;79:339-343. 201. McEvoy GK, ed. AHFS ’94 Drug Information, American Hospital Formulary Service. Bethesda, MD: American Society of Hospital Pharmacists, 1994. 202. Number of reported cases of bovine spongiform encephalopathy (BSE) worldwide. Office International des epizooties. Available [accessed April 10, online at www.oie.int/engln~/en-esbmo~ide.htm 20031. 203. Letter to Reiterate Certain Public health and safety concerns to firms manufacturing or importing dietary supplements that contain specific bovine tissues, US Food and Drug Administration, Center for Food Safety and Applied Nutrition, November 14,2000. Available online at wwzu.http:/~m.cfsan.fda.gov/-dms/dspltro5.html [accessed April 10,20031. 204. Mad Cow Disease and dietary supplements. National Nutritional Foods Association (“FA). Available online at http://www.nnfn. org/seruies/publication/fux/2001/02-20-01.hfm [accessed April 10, 20031.

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~~

Cichoke, AJ. The complete book of enzyme therapy. New York Avery Publishing, 1999. Cichoke AJ. Enzymes and enzyme therapy: how to jump start your way to lifelong good health, ed 2. New Canaan, CT: Keats, ZOOO. Cichoke AJ.Acute trauma and systemic enzyme therapy. Portland, OR Seven C's Publishing, 1993.

Cichoke AJ. A new look at chronic disorders and enzyme therapy. Portland, OR: Seven C's Publishing, 1993. Cichoke AJ. A new look at enzyme therapy. Portland, OR Seven C's Publishing, 1993.

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics Elizabeth Kutter. PhI) CHAPTER CONTENTS Introduction

1147

Historic Context 1147 Discovery 1147 Early Research 1147 Initial Attempts at Commercialization 1148 Specific Problems of Early Phage Therapy Work 1149

Toxicology 1158 Drug Interactions 1159 Conclusion

Bacteriophage Physiology 1149 Properties of Phages 1150 Phages and the Immune System

Clinical Applications 1153 Current Research 1153 Bacterial Pathogenicity 1157 Advantages of Phages 1158

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1152

INTRODUCTlON Phage therapy involves the use of specific virusesviruses that can attack only bacteria-to kill pathogenic microorganisms. The art was first developed early in the twentieth century, but since the advent of chemical antibiotics in the 1940s, it has been little used in the West. Today, however, the growing incidence of bacteria that are resistant to most or all available antibiotics is leading to widespread renewed research interest in the possibilities of phage Most of the recent articles appearing in the West reflect little knowledge of the extensive Eastern European research and clinical utilization of phage therapy. The good clinical results of Eastern European research provide a substantial basis for optimism and complement the limited animal work in the West. We need to draw as much as possible on the largely unknown body of knowledge that has accumulated in Poland and the former Soviet Union as we again explore phage therapy and to give credit where it is due for the many years of hard, careful work in the field even though it has primarily been done in a clinical rather than controlled-research mode. This chapter has been written to put phage therapy into historical and ecologic context and to explore some of the most interesting and extensive research in Eastern Europe, with the hope that

this modality will soon be available for implementation by physicians of all schools.

HISTORIC CONTEXT Discovery More than a century ago, Hankinlo reported that the waters of the Ganges and Jumna rivers in India had a marked antibacterial action that could pass through a porcelain filter, and then could be destroyed by boiling. He particularly studied the water’s effects on Vibrio cholerue and suggested that the substance responsible was what kept cholera epidemics from being spread by ingestion of the water of these rivers. However, he did not explore the phenomenon further. Edward Twort and Felix d’Herelle independently reported the isolation of filterable entities capable of lysing bacterial cultures and of producing small cleared areas on bacterial cultures, implying that discrete particles were involved.ll They are jointly given credit for the discovery of bacteriophages.

Early Research It was d’Herelle, a Canadian working at the Pasteur Institute in Paris, who gave these newly discovered organisms the name bacteriophages-using the suffix phage 1147

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”not in its strict sense of to eat, but in that of developing at the expense He carefully characterized them as viruses that multiply in bacteria, and he worked out the details of infection of different bacterial hosts by various phages under a variety of environmental conditions. The 90th Annual Meeting of the British Medical Association in Glasgow featured a very interesting discussion among d’Herelle, Twort, and several other eminent scientists of the day on the nature and properties of bacteriophages. The main question was whether the observed bacteriolytic principle was an enzyme produced by bacterial activity or a form of tiny virus. Gradually, it became clear that the phage is indeed viral in nature, able to reproduce and direct the synthesis of its own enzymes. DHerelle summarized the early phage work in a 300-page book, The Bacteriophage: Its Role in Immunity.12 He wrote classic descriptions of plaque formation and composition, infective centers, the lysis process, host specificity of adsorption and multiplication, the dependence of phage production on the precise state of the host, isolation of phages from sources of infectious bacteria, and the factors controlling stability of the free phage. He quickly became fascinated with the apparent role of phages in the natural control of microbial infections. He noted, for example, the frequent specificities of the phages isolated from recuperating patients for disease organism infecting them and the rather rapid variations over time of the phage populations. Throughout his life, he worked to develop the therapeutic potential of properly selected phages against the most devastating health problem of the day. However, he initially focused on simply understanding phage biology. Thus, the first known report of successful phage therapy came from Bruynoghe and Maisin,13who used phage to treat staphylococcal skin infections. After much travel, including the study of epidemics in Latin America and a year at the Pasteur branch in Saigon, d’Herelle left the Pasteur Institute in 1922. He worked in Holland and then became employed as a health officer by the League of Nations, based in Alexandria, Egypt. Phage therapy and sanitation measures were the primary tools in his arsenal to deal with major outbreaks of infectious disease throughout the Middle East and India. In 1928, he was invited to Stanford to give the prestigious Lane lectures; his discussions were published as the monograph The Bacteriophage and its Clinical Applicati~ns.’~ He gave many lectures for medical schools and societies as he crossed the country. He accepted a regular faculty position at Yale, where he was supported by George Smith, translator of his first two books into English. DHerelle continued to spend summers in Paris working with the phage company he had established there and returned permanently to France in 1933, with excursions to Tbilisi, Georgia, to help establish phage work there.

George Eliava, director of the Georgian Institute of Microbiology, saw bacteriocidal action of the water of the Koura River in Tbilisi (Tiflis) that he could not explain until he became familiar with d’Herelle’s work while spending 1920 to 1921 at the Pasteur Institute. He became a very early collaborator of d’Herelle’s; several of his phage papers are cited by d’Herelle.12 The two developed the dream of founding an Institute of Bacteriophage Research in Tbilisi-to be a world center of phage therapy for infectious disease, including scientific and industrial facilities, and supplied with its own experimental clinics. The dream quickly became a reality through the support of Sergo Oqonikidze, the People’s Commissar of Heavy Industry, despite KGB opposition to this ”foreign project.’’ A large campus on the river Mtkvari was allotted for the project in 1926. DHerelle sent supplies, equipment, and library materials. In 1934 and 1935, he visited Tbilisi for a total of 6 months and wrote a book, The Bacteriophage and the Phenomenon of R e c o ~ e t ywhich , ~ ~ was translated into Russian by Eliava. DHerelle intended to move to Georgia; in fact, a cottage built for his use still stands on the institute’s grounds. However, in 1937, Eliava was arrested as a ”people’s enemy” by Beria, then head of the KGB in Georgia and soon to direct the Soviet KGB as Stalin’s much-feared henchman. Eliava was soon executed, sharing the tragic fate of many Georgian and Russian progressive intellectuals of the time, and d’Herelle, disillusioned, never returned to Georgia. However, their institute survived and is still functioning at its original site on the Mtkvari (which it now shares with the more modem Institute of Molecular Biology & Biophysics and Institute of Animal Physiology). In 1938, the Bacteriophage Institute was merged with the Institute of Microbiology & Epidemiology under the direction of the People’s Commissary of Health of Georgia. In 1951, it was formally transferred to the AllUnion Ministry of Health set of Institutes of Vaccine and Sera, taking on the leadership role in providing bacteriophages for therapy and bacterial typing throughout the former Soviet Union. Under orders from the Ministry of Health, hundreds of thousands of samples of pathogenic bacteria were sent to the institute from throughout the Soviet Union to isolate more effective phage strains and to better characterize their usefulness. In 1988, an official Scientific Industrial Union ”Bacteriophage” was formed, centered in Tbilisi with branches in Ufa, Habarovsk, and Ghorki. Their later work is further discussed here.

Initial Attempts at Commercialization From the beginning, a major commercial use of phages has been for bacterial identification through a process called phage typing-the use of patterns of sensitivity to a specific battery of phages to precisely identify microbial strains. This technique takes advantage of the fine

Phage Therapy: Ba

specificity of many phages for their hosts and is still in common use around the world. However, the sophisticated ability of phages to destroy their bacterial hosts can also have a very negative commercial impact; phage contaminants occasionally spread havoc and financial disaster for the various fermentation industries that depend on bacteria, such as cheese production and fermentative synthesis of chemicals and medications.16 Phage therapy has been evaluated extensively, with many successes being reported for a variety of diseases, including dysentery, typhoid and paratyphoid fevers, pyogenic and urinary tract infections, and cholera. Phages have been given orally, through colon infusion, and as aerosols as well as poured directly into lesions. They have also been given as injections: intradermal, intravascular, intramuscular, intraduodenal, intraperitoneal, and even into the lung, carotid artery, and pericardium. The early strong interest in phage therapy is reflected in some 800 papers published on the topic between 1917 and 1956. Many of these works have been reviewed in some detail by Ackermann and DuBow.I7 The reported results were quite variable. Many of the physicians and entrepreneurs who initially became excited by the potential clinical implications jumped into applications with very little understanding of phages, microbiology, or basic scientific process. Thus, many of the studies were anecdotal and/or poorly controlled; many of the failures were predictable, and some of the reported successes did not make much scientific sense. Often, uncharacterized phages, at unknown concentrations, were given to patients without specific bacteriologic diagnosis, and there is no mention of follow-up, controls, or placebos. Much of the understanding gained by d’Herelle was ignored in this early work, and inappropriate methods of preparation, “preservatives,” and storage procedures were often used. On one occasion, d’Herelle reported testing 20 preparations from various companies and finding that not one of them contained active phages! On another occasion, a preparation was advertised as containing a number of different phages, but it turned out that the technician responsible had decided it was easier to grow them up in one large batch than in separate batches. Not surprisingly, a check of the product showed that one phage had out-competed all the others, and this was not, in fact, a polyvalent preparation. In general, there was no quality control except in a few research tenters. Large clinical studies were rare, and the results of those that were carried out were largely inaccessible outside Eastern Europe.

Specific Problems of Early Phage Therapy Work Many still believe (erroneously)that phage therapy was proven not to work; however, it simply was never

adequately researched, and the work that was done well is not known widely enough. It is thus important to carefully consider the reasons for the early problems and the question of efficacy. They were as follows: Paucity of understanding of the heterogeneity and ecology of either the phages or the bacteria involved Failure to select phages of high virulence against the target bacteria before using them in patients Use of single phages in infections that involved mixtures of different bacterial species and strains Emergence of resistant bacterial strains, which can occur through selection of resistant mutants (a common occurrence if only one phage strain is used against a particular bacterium) or through lysogenization (if temperate phages are used, as discussed later) Failure to appropriately characterize or titer phage preparations, some of which were totally inactive Failure to neutralize gastic pH prior to oral phage administration Inactivation of phages by both specific and nonspecific factors in bodily fluids Liberation of endotoxins as a consequence of widespread lysis of bacteria within the body (the herxheimer reaction), which can lead to toxic shock (which can also be caused by antibiotics) Lack of availability or reliability of bacterial laboratories for carefully iden-g the pathogens involved (necessitatedby the relative specificity of phage therapy)

BACTERIOPHAGE PHYSIOLOGY Viruses are like spaceships that are able to carry genetic material between susceptible cells and then reproduce in those cells, just as human immunodeficiency virus (HIV) specifically infects human T lymphocytes that carry the CD4 surface protein. In the case of bacteriophages, the targets are specific kinds of bacterial cells; they cannot infect the cells of more complex organisms. Each virus consists of a piece of genetic information, determining all of the properties of the virus, which is carried around packaged in a protein coat (Figure 113-1). Most phages have tails, the tips of which have the ability to bind to specific molecules on the surfaces of their target bacteria (Figure 113-2). The viral DNA is then ejected through the tail into the host cell, where it directs the production of progeny phages; often more than 100 are produced in just half an hour. Each strain of bacteria has characteristic protein, carbohydrate, and lipopolysaccharide molecules present in large quantities on its surface. These molecules are involved in forming pores, motility, and binding of the bacteria to particular surfaces. Each such molecule can act as a receptor for particular phages. Development of resistance to a particular phage generally reflects mutational loss of its specific receptor; this

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is then transferred to a fresh culture of the bacteria in a liquid medium, allowing the culturing of a homogeneous stock of that particular phage, whose properties can then be studied.

Properties of Phages

Figure 113-1

Phage diagram (bacteriophage T4).

Figure 113-2 Electron micrograph of phage infecting a bacterium.

loss often has negative effects on the bacterium and does not protect it against the many other phages that use different receptors. Each kind of bacterium has its own phages, which can be isolated wherever that bacterium grows: from sewage, feces, soil, even ocean depths and hot springs. The process of isolation is easy. The sample is placed in an appropriate salt solution; the supernatant is separated and then is passed through a filter with a pore size small enough to remove the bacteria. The solution is then mixed (at several different dilutions) with a culture of the bacteria in question. A few drops are spread on a block of appropriate nutrient-agar medium. The next day, a dense lawn of bacteria is seen, dotted with round cleared areas called plaques. Each plaque contains about a billion phages, all of them progeny of a single initial phage that multiplied at a high rate and destroyed the bacteria there in the process. An individual plaque

One major source of confusion in the early phage work was the perception that all phages were fundamentally similar, though subject to adaptive change according to the recent conditions of growth. One consequence of this belief was that new phages were often isolated for each series of experiments, so there was little continuity or basis for comparison. Phages specific for virtually every studied bacterial species have now been isolated, but few have been well classified. A second early source of confusion affecting therapeutic use of phages was the question whether the lytic principle termed bacteriophage simply reflected an inherent property of the specific bacteria or required regular reinfection by an external agent. During the 1930s and 1940s, it became increasingly clear that in some senses both were true-that there were in fact two quite fundamentally different groups of bacteriophages. Lytic phages always have to infect from outside, reprogram the host cell, and release a burst of phage through breaking open, or lysing, the cell after a relatively fixed interval. Temperate phages, on the other hand, have another option; they can actually integrate their DNA into the host DNA, much as HIV can integrate the DNA copy of its RNA. Key technical developments that helped clarify the general nature and properties of bacteriophages were (2) the concentration and purification of some large phages by means of very-high-speed centrifugation and the demonstration that they contained equal amounts of DNA and proteinls and (2) visualization of phages by means of the electron microscope (EM).'9,20 Soon after these developments, RuskaZ1reported the first attempts to use the electron microscope for phage systematics. This has since become a key tool of the field.17 Each phage was found to have its own specific shape and size, from the "lunar lander"-style complexity of T4 and its relatives to the globular heads with long or short tails of lambda and T7, to the small filamentous phages that looked much like bacterial pili (Figure 113-3).

Lytic Phages A much better understanding of the interactions between lytic phages and bacteria began with one-step growth curve experiment^.^,^^ These demonstrated an eclipse period, during which the DNA began replicating and there were no free phages in the cell; a period of accumulation of intracellular phages; and a lysis process that released the phage to go in search of new hosts. This phage infection cycle is illustrated in Figure 113-4.

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics

In 1943, an event occurred that was to have a major impact on the orientation of phage research in the United States and much of western Europe, strongly shifting the emphasis from practical applications to basic science. Physicist-turned-phage - - biologist - Max Delbruck

d M

0 Mi

0 L

0 CY

Lysogenic Phages SSVl Figure 113-3

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met with Alfred Hershey and Salvador Luria to form the “Phage Group,” which eventually expanded largely through the influence of the summer “Phage Course” at Cold Spring Harbor, Long Island, in 1945. The influence of this group on the origins of molecular biology has been well d o c ~ u n e n t e d . ~A~ major , ~ ~ element of the successes of phages as model systems for working out fundamental biologic principles was that Delbruck persuaded most phage biologists in the United States to focus on one bacterial host (Escherichiu coli B) and seven of its lytic phages. These were arbitrarily chosen and named types T1 through T7. As it turned out, T2, T4,and T6 were quite similar to one another, defining a family now called the T-men phages. These phages were key in demonstrating that DNA is the genetic material, that viruses can encode enzymes, that gene expression is mediated through special copies in the form of ”messenger RNA,” that the genetic code is triplet in nature, and many other fundamental concepts. The negative side of this strong focus on a few phages growing under rich laboratory conditions, however, was that there was very little study or awareness of the ranges, roles, and properties of bacteriophages in the natural environment, or of potential applications.

LI

II Various phages.

The integration of lysogenic phage DNA into the host DNAleadsto virtually permanent association of a prophage

I

I

I

I

I

5

10

15

20

25

Minutes after Infection Figure 113-4 Bacteriophageintracellular growth cycle. Noteworthy features: nucleolytic action on host chromosome furnishes DNA precursors; replicating DNA is much longer than virion DNA; several phagecoded proteins become associated with the host membrane: maturation of phage head occurs at a membrane site.

I

Pharmacology of Natural Medicines with a specific bacterium and all its progeny. The prophage diredsthe synthesis of a repressor, which blocks the reading of the rest of its own genes and also those of any closely related lysogenic phages-a major advantage for the bacterial cell, giving it protection it from infection by a signrficant class of phages as well as a potential weapon against many competing bacteria. Occasionally, a prophage escapes from regulation by the repressor, cuts its DNA back out of the genome by a sort of site-specific recombination, and goes ahead to make progeny phage and lyse open the cell. Sometimes the cutting-out process makes mistakes, and a few bacterial genes are carried along with the phage DNA to its new host; this process, called transduction, plays a significant role in bacterial genetic exchange. Such lysogenic phages are bad candidates for phage therapy, owing both to their mode of inducing resistance and to the fact that they can potentially lead to transfer of genes involved in bacterial pathogenicity; this issue is discussed in more detail later. However, their specificity often makes them very useful for phage typing in distinguishing between bacterial strains.

PHAGES AND THE IMMUNE SYSTEM A number of early experiments involving the injection of phages into animals led to the widespread impression that phage therapy could not in fact succeed because the phages were too rapidly cleared by the immune system; the remarks in thisregard by Gunter StentZ6had a particularly strong impact on the phage community. Two early experiments involving rabbits showed rapid disappearance of the particular phages used from the blood and organs, but long-term survival in the Subsequent experiments in rats and mice also showed rapid loss from the circulation. When Nungester and WatrousZ9ainjected lo9 plaque-forming units (pfu) of a staphylococcal (staph) phage intravenously into albino rats, a blood concentration of only 105 pfu/ml was seen after 5 minutes, which dropped to 40 pfu/ml by 2 hours. There is one major concern with these early articles on phage pharmacokinetics in animal models: The experiments were done in the absence of host bacteria in which the phage could multiply and find protection. Furthermore, they were carried out by the very unnatural mode of intravenous injection, exposing the phage almost immediately to the reticuloendothelial system. Results of many later studies have made it clear that phages are often seen in the mammal circulatory system; however, this generally occurs under conditions in which they are entering the circulatory system from some sort of reservoir in other tissues and in which the mammal is dealing with an infection by a bacterium that they can infect-precisely the sort of situation seen in gene therapy as currently practiced in Eastern Europe.

One of the best early sets of experiments was published in 1943 by the noted Harvard bacteriologist Renb Dubos and They injected white mice intracerebrally with a dose of a smooth Shigella dysenteriae strain that was sufficient to kill more than 95% of the mice in 2 to 5 days and treated them with intraperitoneal injection of a phage mixture isolated from New York City sewage, grown in the same bacteria, and purified only by sterile filtration. With no treatment or when treated with filtrates of staph cultures or with heat-killed phage, only 3 of 84 mice (3.6%)survived; in contrast, 46 of 64 (72%) of the mice given lo7 to lo9phages survived. These researchers also carried out pharmacokinetic studies. When phages were given to uninfected mice, they appeared in the blood stream almost immediately, but the levels started to drop within hours and very few were seen in the brain. In the infected animals, however, brain phage levels quickly greatly exceeded blood levels; around lo7 to 109phage/g were often seen between 8 and 114 hours after administration, with the level starting to drop anywhere between 75 and 138 hours. After the first 18 hours, blood levels were far lower than brain levels, but phages were still present in blood at 104 to lo5 phage/ml in those subjects in which the brain levels were still more than lo9phage/g. These findings clearly established that (1)the phages themselves were responsible, not something in the lysate that just stimulated normal immune mechanisms, (2) phages could rapidly find and multiply in foci of infection anywhere in the body, and (3) phages could be maintained in the circulation as long as there was a privileged reservoir of infection where phages were continually being produced. Without providing data or pharmacokinetics, the researchers mention that the mice were also rescued by phages administered subcutaneously or intravenously but not by stomach tube or in drinking water. Carefully controlled experiments carried out in 1943 through 1945 by Henry Morton and Enrique Perez-Otero at the University of Pennsylvania supported those of Dubos et al. These investigators further showed the lack of any protection when lysates of phage with inappropriate host specificities were used. A final review authorized by the Council on Pharmacy and Chemistry discussed the major advantages of phages, such as the ability to replicate into problem areas and treat localized infections that are relatively inaccessible via the circulatory system and the fact that their high specificity greatly aided in reducing later resistance problems.32The review also emphasized that almost all of the earlier research had been so poorly conceived and/or carried out that it offered no proof either for or against the promise of phages as antibiotics. The background of these experiments, as described by Hausler,” is very interesting. In 1942, both The Lancet and the British Medical Journal published editorials about

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics

the apparently successful use of antidysentery phages by the Soviet military in the Middle and Far East. The U.S. National Research Council Committee on Medical Research (NRC/CMR) immediately approached Morris Rakieten, d‘Herelle’s close associate in his phage work at Yale, to discuss the possibilities offered by phages for dealing with this perpetual scourge of armies. (The German army was already producing massive amounts of phage, without prior efforts at research, because 155,000 German soldiers had been affected by dysentery in World War I, with 8600 deaths). By November of 1942, the NRC was supporting antidysentery phage research in several top U.S. bacteriology laboratories that do not appear to have previously been engaged in phage work; the group at University of Pennsylvania mentions that their work was started in November of 1942 with NRC support, but they were initially required to keep the results secret. Others involved in this NRC-supported work were Arthur Schade and Leona Caroline at the Overly Biochemical Research Foundation, New York. U.S. work with dysentery phages largely ended in 1944, when the end of World War I1 made penicillin available to the general public. The military secrecy, the end of the war emergency funding, the rapid rise in antibiotic availability and their broad spectra, and Max Delbruck’s success in persuading the phage community to shift its focus to basic mechanistic research involving a few model systems probably all contributed to the fact that there was little U.S. follow-up to these interesting and successful results; few people even knew about them or about two successful subsequent human applications. Penicillin worked against only some kinds of bacterial infections. Typhus, for example, was not treatable, and some excellent phage work was carried out in the interim. It was known that the strains of Salmonella fyphi that created the main pathogenicity problems were those carrying one particular antigen, named Vi (for “virulence”). In 1936, a pair of Canadians had identified phages specific against the Vi antigen. In the early 1940s, Walter Ward,%of the Los Angeles County Hospital, was trying to deal with repeated serious outbreaks of typhoid that were killing one in five of those afflicted. He tested the Vi-specific phages against mouse typhus and found that the death rate fell to 6%, versus 93% in the controls. Some of his colleagues then used these phages to treat patients with typhoid; only 3 of their 56 treated patients died, compared with the 20% mortality for the other treatments available at the time?5 Most impressively, the rest of the patients receiving phage therapy rapidly changed from being largely comatose to full of vigor, with renewed appetite, in 24 to 48 hours. In 1948-1949, near Montreal, Desranleau treated nearly 100 patients with dysentery by giving them a cocktail of six Vi-specific phages, and the death rate dropped from

20% to 2%. By 1947, however, chloramphenicolhad been shown to work well against typhoid, and it was much easier for pharmaceutical companies to deal with, so that seems to have been the end of phage clinical trials in the Western hemisphere. The high specificity of phages still plays a strong role in the Phage Typing sets used for detecting and following problem strains of such bacteria as Shigella, Salmonella, and Cholera, but phage therapy itself is only beginning to stage a comeback.

CLINICAL APPLICATIONS Current Research The growing understanding of phage biology has the potential to facilitate more rational thinking about the therapeutic process and the selection of therapeutic phages. However, there was generally little interaction between those who were so effectively using phages as tools to understand molecular biology and those working on phage ecology and therapeutic applications. Many in the latter group were spurred on by a concern about the rising incidence of nosocomial infections and of bacteria resistant against most or all known antibiotics as well as by the fact that phages are far more effective than antibiotics in areas of the body where the circulation is bad and in not disrupting normal flora. This strong sense of the potential importance of phages was particularly seen in Poland, France, Switzerland,and the former Soviet Union, where use of therapeutic phages never fully died out and there has been some ongoing research and clinical experience. In France, Dr. JeanFranqois Vieu led the therapeutic phage efforts until his retirement some 15 years ago. He worked in the Service des Entirobactiries of the Pasteur Institute in Paris and, for example, prepared Pseudomonas phages on a caseby-case basis for patients. His experience there is discussed in two arti~les.~J’ In Vevey, Switzerland, the small pharmaceutical firm Saphal made “Coliphagine,” “Intestiphagine,” ”Pyophagine,” and “Staphagine” in drinkable and injectable forms, salves, and sprays into the 1960~:~The owner, Harrmann Glauser, had been encouraged and trained by d’Herelle’s old colleague Paul Hauduroy, who had become a professor of microbiology at the University of Lausanne during the second world war, The preparations were officially approved and were paid for by insurance there. Phage therapy was used extensively in many parts of eastern Europe as a regular part of clinical practice, and companies in Russia now make phages for this purpose. However, most of the research and much of the phage preparation came under the direction of key centers in Tbilisi, Georgia, and Wroclaw, Poland. In both cases, the close interactions between research scientists and physicians play an important role in the high degree

Pharmacology of Natural Medicines

of success obtained, just as appears to have been the case for d’Herelle’s early work.

Institute of Immunology and Experimental Medicine, Polish Academy of Sciences The most detailed publications documenting phage therapy have come from the group led by Stefan Slopek, director for many years of the Institute of Immunology and Experimental Medicine, Polish Academy of Sciences, Wroclaw. They published a series of extensive papers describing work carried out from 1981 to 1986 with 550 patients.This set of studies involved 10 Polish medical centers-including the Wroclaw Medical Academy Institute of Surgery Cardiosurgery Clinic, Children’s Surgery Clinic, and Orthopedic Clinic, the Institute of Internal Diseases Nephrology Clinic, and Clinic of Pulmonary Diseases. The patients ranged in age from 1 week to 86 years. In 518 of the cases, phage use followed unsuccessful treatment with all available other antibiotics. The major categories of infections treated were as follows: Long-persisting suppurative fistulas Septicemia Abscesses Respiratory tract suppurative infections and bronchopneumonia Purulent peritonitis Furunculosis

In a final summary paper, these investigators carefully analyzed the results with regard to such factors as nature and severity of the infection and monoinfection versus infection with multiple bacteria.40Rates of success ranged from 75% to 100% (92%overall), as measured by marked improvement, wound healing, and disappearance of titratable bacteria; 84% of subjects demonstrated full elimination of the suppurative process and healing of local wounds. Infants and children did particularly well. Not surprisingly, the poorest results occurred in elderly patients and those in the final stages of extended serious illnesses, two groups with weakened immune systems and generally poor resistance. The bacteriophages all came from the extensive collection of the Bacteriophage Laboratory of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw. In the later studies, some of the specific phages were named. All were virulent, capable of completely lysing the bacteria being treated. In the first study alone, 259 different phages were tested (116 for Staphylococcus, 42 for Klebsiella, 11 for Proteus, 39 for Escherichia, 30 for Shigella, 20 for Pseudomonas, and 1 for Salmonella); 40% of them were selected to be used directly for therapy. All of the treatment was conducted in a research mode, with the phage prepared at the institute by standard methods and tested for sterility.

Treatment generally involved 10 ml of sterile phage lysate given orally half an hour before each meal, with gastric juices neutralized by the taking of (basic) Vichy water, baking soda, or gelatum. In addition, phagesoaked compresses were generally applied three times a day where dictated by localized infection. Treatment ran for 1.5 to 14 weeks, averaging 5.3 weeks. For intestinal problems, short treatment sufficed, whereas long-term use was necessary for such problems as pneumonia with pleural fistula and pyogenic arthritis. Bacterial levels and phage sensitivity were continually monitored, and the phage(s) were changed if the bacteria lost their sensitivity. Therapy was generally continued for 2 weeks beyond the last positive test result for the bacteria. Few side effects were observed; those that were seen seemed to be directly associated with the therapeutic process. On about days 3 to 5, pain in the liver area lasting several hours was often reported. The investigators suggested that this pain might be related to the extensive liberation of endotoxins as the phage is destroying the bacteria most effectively. In severe cases of sepsis, patients often ran a fever for 24 hours on about days 7 to 8.38 Various methods of administration were successfully used, including oral, aerosols, and infusion either rectal or in surgical wounds. Intravenous administration was not recommended for fear of possible toxic shock from bacterial debris in the l y s a t e ~ However, .~~ it was clear that the phages readily entered the body from the digestive tract and multiplied internally wherever appropriate bacteria were present, as measured by their presence in blood and urine as well as by therapeutic effects.4l This interesting and rather unexpected finding has been replicated in many studies and systems.“-45 Detailed notes were kept throughout on each patient. The final evaluating therapist also filled out a special inquiry form that was sent to the Polish Academy of Science research team along with the notes. The Computer Center at Wroclaw Technical University carried out extensive analyses of the data. These researchers used the categories established in the World Health Organization (WHO) (1977) International Classification of Diseases in assessing results. They also looked at the effects of age, severity of initial condition, type(s) of bacteria involved, length of treatment, and other concomitant treatments. The reports included many specific details on individual patients that helped to give some insight into the ways phage therapy was used as well as an in-depth analysis of difficult cases. After Slopek’s retirement, Dr. Beatta WeberDabrowska carried on with the treatment work, publishing a summary in English of the results for the next 16 patients.& In 1998, immunologist A. G6rski took over as Institute director and revived a strong focus on phage work, with special emphasis on the immunologic

consequences of phage treatment?’ These researchers are also now working with the basic phage group of Dr.M. Lobocka in Warsaw to sequence and further characterize key phages-an important step in eventually making them available to the outside world.

Bacteriophage Institute, Tbilisi The most extensive and least widely known work on phage therapy was carried out under the auspices of the Bacteriophage Institute at Tbilisi, in the former Soviet republic of Georgia. According to various physicians there, phage therapy is part of the general standard of care, used especially extensively in pediatric, bum, and surgical hospital settings. Phage preparation was carried out on an industrial scale, employing 700 people in the factory and several hundred more in the research arm of the Institute just before the breakup of the Soviet Union, and many tons of a variety of products were regularly shipped throughout the former Soviet Union. They were available both over the counter and through physicians. The largest use was in hospitals, to treat both primary and nosocomial infections, alone or in conjunction with other antibiotics and particularly when antibioticresistant organisms were found. The military is still one of the strongest supporters of phage therapy research and development, because phages have proved so useful for wound and burn infections as well as for preventing debilitating gastrointestinal epidemics among the troops. The International Science and Technology Centers program, set up jointly by the United States, Europe, and Japan to give constructive opportunities to scientists formerly working with Soviet military projects, is now one of the strongest supporters of basic and applied research in this area in Tbilisi. From the Bacteriophage Institute’s inception, the industrial part was run on a self-supporting basis, and its scientific branch was government supported. The latter included the electron microscope facility, permanent strain collection, laboratories studying phages of the enterobacteria, staphylococci, and pseudomonads, and formulating new phage cocktails, and p u p s involved in immunology,vaccine production, Lactobacillus work, and other therapeutic approaches. The Institute also carried out the very extensive studies needed for approval by the Ministry of Health in Moscow of each new strain, therapeutic cocktail, and means of delivery. This careful study of the host range, lytic spectrum, cross-resistance, and other fundamental properties of the phages being used was a major factor in the reported successes of the phage therapy work carried out through the institute, as was their method for initially selectinghighly virulent phages from among the myriad potentially available against any given host. All of the phages used for therapy are lytic, avoiding the problems engendered by lysogeny. The problems of bacterial resistance were

largely solved through the use of well-chosen mixtures of phages with different receptor specificities against each type of bacterium as well as of phages against the various bacteria likely to be causing the problem in multiple infections. The situation was further improved whenever the clinicians typed the pathogenic bacteria and monitored their phage sensitivity. Where necessary, new cocktails were then prepared to which the given bacteria were sensitive. Not infrequently, using a phage in conjunction with carefully chosen other antibiotics was shown to give better results than either the phage or the antibiotic alone. The depth and extent of the work involved are very impressive. For example, in 1983 through 1985 alone, the Institute’s Laboratory of Morphology and Biology of Bacteriophages carried out studies of growth, biochemical features, and phage sensitivity on 2038 strains of Stuphylococcus, 1128 of Streptococcus, 328 of Proteus, 373 of P. ueruginosa, and 622 of Clostridium received from clinics and hospitals in towns across the former Soviet Union. New broader-acting phage strains were isolated using these and other institute cultures and were included in a reformulation of their extensively used Piophage preparation; it now inhibited 71% of their Staphylococcus strains instead of 58%; 76% of Pseudomonas instead of 55%;51% of E. coli instead of 11%;30%of Proteus instead of 3%: 60% of Streptococcus instead of 38%; and 80% of Enterococcus instead of 3%.& In the years since, the formulation has continued to be improved on the basis of further studies, and phages against Klebsiellu and Acinetobucter have been isolated and developed into therapeutic preparations. The other major product, used very extensively by the military, by pediatric centers, and in regions with extensive diarrheal problems, is IntestiPhge, which consists of 23 different phages active against a range of enteric bacteria and was often prepared in tablet form. A good deal of work has gone into developing and providing the documentation for Ministry of HeaIth approval of specialized new delivery systems, such as a spray for use in respiratory tract infections, in treating the incision area before surgery, and in sanitation of hospital problem areas such as operating rooms. An enteric-coated pill was also developed, using phage strains that could survive the drying process, and accounted for the bulk of the shipments to other parts of the former Soviet Union. Much of the focus in the last 20 years has been on combating nosocomial infections, in which multidrugresistant organisms have become a particularly lethal problem and it is also easier to cany out proper long-term research. Clinical studies of the effectivenessof the phage treatment and appropriate protocols were carried out in collaboration with a number of hospitals, but little has been published in accessible form. Zemphira Alavidze

Pharmacology of Natural Medicines

and her colleagues, who are currently doing most of the actual therapeutic development and clinical application, have manuscripts in preparation that describe their work in institutions such as the Leningrad (St. Petersburg) Intensive Burn Therapy Center, the Academy of Military Medicine in Leningrad, the Karan Trauma Center, and the Kemerovo Maternity Hospital. Some of the most intensive studies were carried out in Tbilisi at the Pediatric Hospital, the Burn Center, the Center for Sepsis, and the Institute for Surgery. Special mixtures were developed for dealing with strains causing nosocomial infections in various hospitals, and they were very effectively used in sanitizing operating rooms and equipment, water taps, and other sources of spread of the infections (most of them predominantly involving Staphylococcus). The number of sites testing positive for the problem bacteria decreased by orders of magnitude over the several months of the trial at each site. An exciting new product completed the approval process and was licensed in 2000 by the Georgian Ministry of Health. PhagoBioDerm is a biodegradable, nontoxic polymer composite that is impregnated with the Pyophage cocktail of phages, along with other antimicrobial age11ts.4~ Markoishvilim reported the results of a study of PhagoBioDerminvolving 107patients with ulcers that had failed to respond to conventional therapysystemic antibiotics, antibiotic-containing ointments, and various phlebotonic and vascular-protecting agents. The ulcers were treated with PhagoBioDerm alone or in combination with other interventions during 1999 and 2000. The wounds or ulcers healed completely in 70% of the 96 patients for whom there was follow-up data. In the 22 cases for which complete microbiologic analyses were available, healing was associated with the concomitant elimination or very marked reduction of the pathogenic bacteria in the ulcers.

Recent Work in the West Levin and Bull' and Barrow and Soothil14have provided good reviews of much of the animal research carried out in Britain and the United States since interest in the possibilities of phage therapy began to resurface in the early 1980s. The results, in general, are in very good agreement with the clinical work just described in terms of efficacy, safety, and importance of appropriate attention to the biology of the host-phage interactions, reinforcing trust in the reported extensive eastern European results. In Britain, Smith and H ~ g g i n s " carried ~~ out a series of excellent, well-controlled studies on the use of phages in systemic E. coli infections in mice and then in diarrhetic disease in young calves and pigs. For example, they found that injecting 106colony-forming units (CFUs) of a particular pathogenic strain intramuscularly killed 10 out of 10 mice, but none died if the researchers simultaneously injected 104 pfu of a phage selected against the

K1 capsule antigen of that bacterial strain. This phage treatment was more effective than using such antibiotics as tetracycline, streptomycin, ampicillin, and trimethoprim/ sulfafurazole. Furthermore, the resistant bacteria that emerged had lost their capsule and were far less virulent. In calves, these researchers found very high and specific levels of protection. They had to isolate different phages for each of their pathogenic bacterial strains, because they did not succeed in isolating phages specific for more general pathogenicity-related surface receptors such as the K88 or K99 adhesive fimbriae, which play key roles in attachment to the small intestine. Still, the phage was able to reduce the number of bacteria bound there by many orders of magnitude and to virtually stop the fluid loss. The results were particularly impressive if (1)the phage was present before or at the time of bacterial presentation and (2) multiple phages with different attachment specificities were used. Furthermore, the phages could be transferred from animal to animal, supporting the possibility of their prophylactic use in a herd. If the phages were given only after the development of diarrhea, the severity of the infection was still substantially reduced, and none of the animals Levin and Bull' carried out a detailed analysis of the population dynamics and tissue phage distribution of the 1982 Smith and Huggin@ study, which can be helpful in assessing the parameters involved in successful phage therapy and its apparent superiority to antibiotics. They have gone on to perform interesting animal studies of their own and conclude that phage therapy is at least well worth further study.' Barrow and So0thill4 carried out a series of studies preparatory to using phages for infections in bum patients. Using guinea pigs, they showed that skin graft rejection could be prevented by prior treatment with phages against Pseudomonas aeruginosu. They also saw excellent protection of mice against systemic infections with both Pseudomonas and Acinetobucter when appropriate phages were used.4 In the latter case, as few as 100 phages protected against infection with lo8 bacteriaseveral times the LDW(dose at which 50% of the subjects died)! Merrill et al5I have carried out a series of experiments designed to better the understanding of the interactions of phages with the human immune system, and helped Richard Carlton, MD, start a company called Exponential Therapeutics to explore the possibilities of phage therapy. They initially worked with lytic derivatives of the lysogenic phages lambda and P22-a poor choice for therapeutic use, as discussed earlier and later in this chapter-but they gathered some very interesting data about factors affecting interactions between these phages and the innate immune system and patented a process for isolating longer-circulating phages. They have now published successful animal studies with

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics

phages against vancomycin-resistant Enterococcus, and Exponential Biotherapies has completed successful phase 1clinical trials with these phages.

Bacterial Pathogenicity Most bacteria are not pathogenic; in fact, they play crucial roles in the ecologic balance in the digestive system, mucous membranes, and all body surfaces. They often actually help protect against pathogens. This is one reason why broad-spectrum antibiotics have such a broad range of side effects and why more narrowly targeted bacteriocidal agents would be highly advantageous. Interestingly, most of the serious pathogens are close relatives of nonpathogenic strains. Studies clarifying the mechanisms of pathogenesis at the molecular level have progressed remarkably in recent years, crowned by the determination of the complete sequence of (nonpathogenic) E. coli K12 and several other bacterial species, and extensive cloning and sequencing of pathogenicity determinants. Generally, a number of genes are involved, and they are clustered in so-called pathogenicity islands, or Pais, which may be 50,000 to 200,000 base pairs long. They generally have some unique properties, indicating that the bacterium itself probably acquired them as a sort of “infectious disease” at some time in the past and then kept them because they helped the bacterium infect new ecologic niches where there was less competition. Many of these Pais are carried on small extrachromosomal circles of DNA called plusmids, which can also be carriers of drugresistance genes. Others reside in the chromosome, where they are often found embedded in defective lysogenic prophages that have lost some key genes in the process and cannot be induced to form phage particles. However, the prophages can sometimes recombine with related infecting phages. Therefore it makes sense to avoid using lysogenic phages or their lytic derivatives for phage therapy to avoid any chance of picking up and moving such pathogenicity islands. For bacteria in the human gut, pathogenicity involves the following two main factors: The production of toxin molecules, such as shiga toxin (from Shigellu and some pathogenic E. coli) or cholera toxin; these toxins mod* proteins in the target host cells and thereby cause the problem The acquisition of cell-surface adhesions that allow the bacterium to bind to specific receptor sites in the small intestine, rather than just moving on through to the colon They also all contain the components of so-called type 111 secretion machinery, related to those involved in the assembly of flagella (for motility) and of filamentous phages, and instrumental in many plant pathogens. For all the pathogenic enteric bacteria, the infection process

triggers changes in the neighboring intestinal cells. They include degeneration of the microvilli, formation of individual ”pedestals” cupping each bacterium above the cell surface, and, in the case of Sulrnonel2u and Shigellu, induction of cell-signaling molecules that trigger engulfment of the bacterium and its subsequent growth inside the cell. Recently, E. coli 0157 has been the subject of much concern, its contamination of such products as hamburgers and unpasteurized fruit juices leading to serious problems. Particularly in young children and the elderly, deaths have occurred from hemorrhagic colitis (bloody diarrhea) and from hemolytic-uremic syndrome, in which the kidneys are affected. Antibiotic therapy has shown no benefit; it is actually generally contraindicated because it leads to increased toxin release.52My colleagues and I have isolated a phage from sheep resistant to inoculation with E. coli 0157H7 at the U.S. Department of Agriculture in College Station, Texas. A major concern of this facility is to eliminate this human pathogen, which is found in the normal flora of one quarter of the cattle in the United States, from which it contaminates water sources and creates massive recalls for industries from meat packers to apple juice producers; this phage turns out to also be T4-like and to infect virtually all tested 0157 strains. Studies are suggesting that this and additional phages we have isolated from sheep are good candidates for controlling 0157 in the gastrointestinal tracts of nun in ant^.^^,^

T-Even Phages A substantial fraction of the phages in the therapeutic mixes for gram-negative bacteria are relatives of bacteriophage T4, which has played such a key role in the development of molecular biology. This family is often called the T-even phages, from an historical accident reflecting the fact that T2, T4, and T6 from the original collection of Delbruck‘s Phage Group all turned out to be related. Large sets of T-even phages have been isolated for study from all over the world: Long Island sewage treatment plants, animals in the Denver Zoo, and patients with dysentery in eastern Europe (the last using Shigellu as host). The laboratory of Harald Bruessow at Nestle, Inc., in Lausanne, Switzerland, has become interested in the possibility of using phages to treat infant diarrhea in underdeveloped countries-a longstanding concern of theirs, and no other approaches have worked for the 27% that involve coliform bacteria. These researchers have isolated a number of broad-spectrum phages from patients at the world-famous Diarrheal Center in Bangladesh; all of them are T4-like They have now selected a group of therapeutic candidates and are carrying out various in vitro and animal studies in preparation for potential human trials.

Pharmacology of Natural Medicines T4-like phages are found infecting all of the enteric bacteria and their relatives.57Most of the T-even phages use 5-hydroxymethylcytosine instead of cytosine in their DNA, which protects them against most of the restriction enzymes that bacteria make to protect themselves against invaders and gives them a much more effective host range. T4's entire DNA sequence is known, and we know a great deal about its infection process in standard laboratory conditions and about the methods it uses to target bacteria so effectively.5859We can potentially use this knowledge to develop more targeted approaches to phage therapy, particularly as more is learned about the similaritiesand differences in its extended family.60*61 We know that different members of the T-even phage family use different outer membrane proteins and oligosaccharides as their receptors, and we understand the tail-fiber structures involved well enough to potentially predict which phages will work on given bacteria and to engineer phages with new specificities.6*@ The T-even bacteriophages share a unique ability that contributes significantly to their widespread occurrence in nature and to their competitive advantage. There have still been far too few studies of T4 ecology and its behavior under conditions more closely approaching the natural environment and the circumstances it will encounter in phage therapy, often anaerobic and/or with frequent periods of starvation. The limited available information in that regard has been summarized by A variety of studies are shedding light on the ability of these highly virulent phages to coexist in balance with their hosts in nature. For example, they can reproduce in the absence of oxygen as long as their bacterial host has been growing anaerobically for several generations. They are also able to control the timing of lysis in response to the relative availability of bacterial hosts in their environment. When E . coli are singly infected with T4, they lyse after 25 to 30 minutes at body temperature in rich media, releasing about 100 to 200 phages/cell. However, when additional T-even phages attack the cell more than 4 minutes after the initial infection, the cell does not lyse at the normal time. Instead, it continues to make phages for as long as 6 h o ~ r s .We ~ ,have ~ ~ found that the phages can also survive for a period of time in a hibemation-like state inside starved cells, allowing their host to readapt when nutrients are again supplied, and produce a few additional phages. This is particularly interesting and important because bacteria undergo many drastic changes to survive periods of starvation that increase their resistance to a variety of environmental insults.% Thus, for many reasons, the T4-like phages make excellent candidates for therapeutic and prophylactic use against enteric and other gram-negative bacteria, and studies of their ecology and distribution are now being carried out with these goals in mind in Tbilisi,

Bangladesh, Lausanne, and College Station, Texas, and at The Evergreen State College.

Advantages of Phages Phages have many potential advantages, as follows: They are self-replicating but also self-limiting because they multiply only as long as sensitive bacteria are present. They can be targeted far more specifically than most antibiotics to the problem bacteria, causing much less damage to the normal microbial balance in the gut. The bacterial imbalance or "dysbiosis" caused by many antibiotic treatments can lead to serious secondary infections involving relatively resistant bacteria, and often increasing hospitalization time, expense, and mortality (see Chapters 12 and 14).Particular resultant problems are Pseudomonads, which are especially difficult to treat, and Clostridium dzficile, the cause of serious diarrhea and membranous c0litis.6~ Phages can often be targeted to receptors on the bacterial surface that are involved in pathogenesis, so any resistant mutants are attenuated in virulence. Few side effects have been reported for phage therapy. Phage therapy would be particularly useful for people with allergies to antibiotics. Appropriately selected phages can easily be used prophylactically to help prevent bacterial disease at times of exposure or to sanitize hospitals and help protect against hospital-acquired (nosocomial) infections. Especially for external applications, phages can be prepared fairly inexpensively and locally, facilitatingtheir potential applications to underserved populations. Phages can be used either independently or in conjunction with other antibiotics to help reduce the development of bacterial resistance.

TOXIC0LOGY From a clinical standpoint, phages appear to be very safe. This feature is not surprising, given that humans are exposed to phages from birth. Bergh et a P reported that nonpolluted water contains about 2 x 108phages/ml. Phages are normally found in the gastrointestinal tract, skin, urine, and mouth, where they are harbored in saliva and dental p l a q ~ e . ~They ~ - ~also l have been shown to be unintentional contaminants of sera and thence of commercially available vaccines,"-75 which were given dispensation to be sold despite this discovery because of the general consensus that phages are safe for humans. Extensive preclinical animal testing was required for approving new phage formulations in the former Soviet Union, but few of these studies were published. Bogovazova et a176*"evaluated the safety and efficacy of Klebsiella phages produced by the Russian company

Phage Therapy: Bacteriophages as Natural, Self-LimitingAntibiotics Immunopreparat. Pharmacokinetic and toxicologic studies using intramuscular, intraperitoneal, or intravenous administration of phages were carried out in mice and guinea pigs. The researchers found no signs of acute toxicity or gross or histologic changes, even using a dose/g 3500-fold higher than the projected human dose. They then evaluated the safety and efficacy of the phages in treating 109 patients infected with Klebsiellu. The phage preparation was reported to be nontoxic for humans and to be effective in treating Klebsiellu infections, as manifested by marked clinical improvements and bacterial clearance in the phage-treated patients. Side effects such as occasional liver pain and fever reported in the early days of Western phage therapy may have been due to bacterial byproducts contaminating phage preparations used i n t r a v e n o ~ s l yConcern . ~ ~ ~ for this possibility is a major reason that the Polish phage therapy group never administers their phages intravenously. The same is true for almost all of the therapeutic work carried out in Tbilisi and probably helps explain the group’s virtually total lack of significant problems. Because the phage readily enter the blood stream after infusion in or near wounds and other sites of localized infection and then travel to sites of infection throughout the body, as discussed previously in descriptions of the work by DuBow, there generally seems to be no particular reason for undergoing the extra risks of intravenous administration.

DRUG INTERACTIONS No negative effects on the efficacy or safety of other drugs have been reported as a result of phage administration in the long history of work in Eastern Europe. No systematic studies have been carried out in this regard, but phages are so specific in their actions that it is hard to see where such interactions might be predicted to occur. On the other hand, at least some antibiotics would tend to interfere with phage treatment of localized infections in areas with poor circulation, by killing off the most accessible of the bacteria in which the phages need to multiply as they work their way deeper into the lesion; this would be a particular problem in cases in which the phages can still attach and infect but cannot complete their replication cycle. (Many of the Georgian physicians believe that antibiotics should never be used topically for wounds and deep-seated infections, because the decrease in antibiotic concentration below the surface provides a strong selection for antibiotic resistance and this problem does not occur with phages.)

CONCLUSION Clearly the time has come to look more carefully at the potential of phage therapy, both by strongly supporting

new research and by scrutinizing the research already available: such as the very interesting human antityphoid phage research carried out in this country in the 1940s that has come to lighP5 as well as the earlier European work and the very extensive applications in the former Soviet Union. As Barrow and So0thill4conclude: Phage therapy can be very effective in certain conditions and has some unique advantages over antibiotics. With the increasing incidence of antibiotic-resistant bacteria and a deficit in the development of new classes of antibioticsto counteract them, there is a need to investigate the use of phage in a range of infections. Phages are quite specific as to the bacteria they attack, and the stipulations of Ackermann & DUBow[”~ are important here. The specificity of phages means that: Phages have to be tested against the patient’s bacteria] just as antibiotics [should be], and the indications have to be right, but this holds everywhere in medicine. However, phage therapy requires the creation of phage banks and a close collaboration between the clinician and the laboratory. Phages have at least one advantage. . . . While the concentration of antibiotics decreases from the moment of application, phage numbers should increase. Another advantage is that phages are able to spread and thus prevent disease. Nonetheless, much research remains to be done . . . on the stability of therapeutic preparations; clearance of phages from blood and tissues; their multiplication in the human body; inactivation by antibodies, serum or pus; and the release of bacterial endotoxins by lysis. . . . In addition, therapeutic phages should be characterized at least by electron microscopy.

With the exploding possibilities and decreasing costs of genomic analysis since the last edition of this book, it is now possible to perform at least partial genomic sequencing of phages to be included in general cocktails so as to know more about the phage families involved and exclude phages from temperate families and those likely to carry or acquire genes related to pathogenicity or toxin production; this is now standard done procedure for phages being developed in the West. Such modern techniques are now also being applied to some of the Georgian phage preparations with help from grants from the International Science and Technology Centers (ISTC) and Civilian Research and Development Foundation (CRDF) programs, both of which were set up to support civilian applications of science formerly funded by the Soviet military. This is an important step in considering the importation of such phages for topical use in the Western world. Although it seems premature to broadly introduce injectable phage preparations in the West without further extensive research, their carefully implemented use in external applications and for a variety of agricultural purposes could potentially help reduce the emergence of antibiotic-resistant strains and deal with problems we have difficulty handling today. Furthermore, compassionate use of appropriate phages seems warranted

Pharmacology of Natural Medicines

Special thanks to Drs. Liana Gachechiladze, Zemphira Alavidze, Davi Gamrekeli, Guram Gvasalia, Ramaz Katsarava, lnga Georgadze, Mzia Kutateladze, Rezo Adamia, Amiran Meipariani, Taras Gabisonia, Teimuraz and Nino Chanishvili and their colleagues in Tbilisi, and to Beata Weber-Dabrowski and Andre Gorski in Wroclaw for their

hospitality and efforts to help me understand the extensive therapeutic work carried out there. Others who have been particularly helpful with information and communication include Dr. Marina Shubladze, pediatrician in Tbilisi for 10 years, now residing in Seattle; Nino Mzavia, Nino Trapaidze, Timur and Natasha Zurabishvili, who have worked in my laboratoy ; Bill Summers (Yale), Hans-Wolfgang Ackermann (Lava1 University), Eduard Kellenberger (Basel) and Bruce Levin (Emory); Kathy d'Acci, clinical laboratoy director, St Peter's Hospital, Olympia; physicians Jess Spielholz, MD, and Robin Moore, ND; and especially, the many colleagues and students involved in our laboratory in Olympia, particularly Barbara Anderson, Burt Guttman, Pia Lippincot, Mark Mueller, Stacy Smith, Elizabeth and Chelsea Thomas, Jim Neitzel, Andrew Brabban, and Raul Raya.

1. Levin B, Bull JJ. Phage therapy revisited: the population biology of a bacterial infection and its treatment with bacteriophage and antibiotics.Am Nat 1996;147881-898. 2. LederbergJ. Smaller fleas ...ud infiniturn: therapeutic bacteriophage redux. Proc Natl Acad Sci U S A 1996;933167-3168. 3. Radetsky P.The good virus.Discover 1996;1750-58. 4. Barrow PA, Soothill JS. Bacteriophage therapy and prophylaxis: rediscovery and renewed assessment of the potential. Trends Microbiol1997;5:268-271. 5.Alisky J, Iczkonski K, Rapoport A, et al. Bacteriophage shows promise as antimicrobial agents. J Infection 1998;36:5-13. 6.Sulakvelidze A, Alavidze Z, Moms J. Bacteriophage therapy. Antimicrobial Agents Chemother 2001;45:649-659. 7.Summers WC. Felix d'Herelle and the origins of molecular biology. New Haven, CT: Yale University Press, 1999. 8. Kutter E, SulakvelidzeA. Bacteriophages: biology and applications. Boca Raton, FL: CRC Press, 2004. 9. Merril CR, M o l l D, Adhya SL. The prospect for bacteriophage therapy in Western medicine. Nat Rev Drug Discov 2003;2:489-497. 10. Hankin EH. L'action bactericide des eaux de la Jumna et du Gange sur le vibrion du cholera. Ann de l'lnst Pasteur 1896;10511. 11. D'Herelle F, Twort FW,Bordet J, et al. Discussion on the bacteriophage (bacteriolysin): from the Ninetieth Annual Meeting of the British Medical Association, Glasgow, July, 1922. Br Med J 1922;2:289-97; reproduced in Stent G. Papers on bacterial viruses, 2nd ed. Boston: Little, Brown, 1965. 12. DHerelle F (SmithGH, trans). The bacteriophage: its role in immunity. Baltimore: Williams & Wilkins, 1922. 13. Bruynoghe R, Maisin J. Essais de therapeutique au moyen du bacteriophage du staphylocoque. C R Soc Biol 1921;85:1120-1121. 14. DHerelle F. The bacteriophage and its clinical applications. Springfield, IL:CC Thomas, 1930. 15. Eliava G. Bakteriofagi fenomenvyzdorovieniya. Tbilisi, Georgia: Tbilis National University Publications, 1935. 16.Saunders ME. Bacteriophages in industrial fermentationsin. In Webster RG, Granoff A, eds. Encyclopedia of virology. San Diego: Academic Press, 1994116-121. 17. Ackermann HW,DuBow MS. V i s of prokaryotes. I. General properties of bacteriophages. In Practical applications of bacteriophages. Boca Raton, FL:CRC Press, 1987.

18. Schlesinger M. Reindarstellungeines bakteriophagen in mit freiem auge sichtbaren mengen. Biochem Z 1933;264:6. 19. Ruska H. Die sichtbarmachung der bakteriophagen lyse im ubermikroskop.Naturwissenxhaften 1940;28:45. 20. Pfankuch E, Kausche G. Isolierung U. Uebermikroskopische abbildung eines bakteriophagen. Natunvissemchaften 1940;28:46. 21. Ruska H. Ergeb. Hyg BakteriolImmunforsch Exp Ther 1943;25:437. 22. Ellis EL, Delbrueck M. The growth of bacteriophage. J Gen Physiol 1939;22:365-384. 23. Doermann AD. The intracellular growth of bacteriophages. I. Liberation of intracellular bacteriophage T4 by premature lysis with another phage or with cyanide. J Gen Physiol1952;35645-656. 24. Caims J, Stent GS, Watson JD. Phage and the origins of molecular biology. Long Island, Ny: Cold Spring Harbor Laboratory Press, 1966. 25. Fischer E, Lipson C. Thinking about science: Max Delbrueck and the origins of molecular biology. New Yolk Norton, 1988. 26.Stent G. Molecular biology of bacterial viruses. San Francisco: WH Freeman, 1963:8. 27. Appelmans R. Le bacteriophage dans l'organisme. C R Seances Soc Biol Fil 1921;85722-724. 28. Evans AC. Inactivationof antis~ptococcusbacteriophageby animal fluids. Public Health Reports 1933;48:4114. Cited by Merril C, S Adhya S. Phage therapy. In Calendar R, ed. The Bacteriophages ed 2. Oxford: Oxford University Press, in press. 29.Nungester WJ, Watrous RM. Accumulation of bacteriophage in spleen and liver following its intravenous inoculation. Proc Soc Exp Biol Med 193431:901-905. 30.Geier MR, Trigg ME,Merril CR. Fate of bacteriophage lambda in non-immune germ-free mice. Nature 1973;246:221-223. 31. Dubos RJ, Straus JH, Pierce C. The multiplication of bacteriophage in vivo and its protective effects against an experimental infection with Shigellu dysenteriue. J Exp Med 1943;78:161-168. 32.Morton HE, Engely FB. Dysentery bacteriophage: review of the literature on its prophylactic and therapeutic uses in man and in experimental infections in animals. J Am Med Assoc 1945;127 584-891. 33. Hausler T. Gesund durch Viren. Miinchen, Germany: Piper, 2003. 34. Ward WE. Protective action of VI bacteriophage in Eberthella typhi infections in mice. J Infect Dis 1943;72:172-176.

in cases in which bacteria resistant to all available antibiotics are causing life-threatening illness. Phages are especially useful in dealing with recalcitrant nosocomial infections, in which large numbers of particularly vulnerable people are being exposed to the same strains of bacteria ina closed hospital setting. In this case, the environment as well as the patients can be effectively treated.

Acknowledgments

Phage Therapy: Bacteriophages as Natural, Self-Limiting Antibiotics 35. Knouf EG, Ward WE, Reichle PA, et al. Treatment of typhoid fever with type specific bacteriophage. J Am Med Assoc 1946;132 134-138. 36. Vieu JF. Les bacteriophages. In Fabre J, ed. Traite de therapeutique, Serums et vaccins. Paris: Flammarion, 1975:337-430. 37. Vieu JF, Guillermet F, Minck R, et al. Donn&s actuelles sur les applications therapeutiques des bacteriophages. Bull Acad Natl Med 1979;163:61. 38. Slopek S, Durlakova I, Weber-Dabrowska B, et al. Results of bacteriophage treatment of suppurative bacterial infections. I. General evaluation of the results. Arch Immunol Ther Exp 1983;31:267-291. 39. Slopek S, Kucharewica-Krukowska A, Weber-Dabrowska 8, et al. Results of bacteriophage treatment of suppurative bacterial infections. Vl. Analysis of treatment of suppurative staphylococcalinfections. Arch Immunol Ther Exp 1985;33261-273. 40. Slopek S, Weber-Dabrowska B, Dabrowski M, et al. Results of bacteriophage treatment of suppurative bacterial infections in the years 1981-1986.Arch Immunol Ther Exp 1987;35:569-583. 41. Weber-Dabrowska B, Dabrowski M, Slopek S. Studies on bacteriophage penetration in patients subjected to phage therapy. Arch Immunol Ther Exp (Warsz) 1987;35:363-368. 42. Smith HW, Huggins RB. Successful treatment of experimental E. coli infections in mice using phage: its general superiority over antibiotics. J Gen Microbiology 1982;128:307-318. 43. Smith HW, Huggins RB. Effectiveness of phages in treating experimental E. coli diarrhoea in calves, piglets and lambs. J Gen Microbiology 1983;129:2659-2675. 44.Smith HW, Huggins RB. The control of experimental E. coli diarrhea in calves by means of bacteriophage. J Gen Microbiology 1987; 13311111-1126. 45. Smith HW, Huggins RB, Shaw KM. Factors influencing the survival and multiplication of bacteriophages in calves and in their environment. J Gen Microbiology 1987;1331127-1135. 46. Weber-Dabrowska 8, Mulczyk M, Gorski A. Bacteriophage therapy of bacterial infections: an update of our institute’s experience. Arch Immunol Ther Exp 2000;48:547-551. 47. Weber-Dabrowska B, Zimecki M, Mdczyk M, et al. Effect of phage therapy on the turnover and function of peripheral neutrophils. FEMS Immunol Med Microbiol2002;34:135-138. 48. Alavidze Z. Personal communication, 1998. 49. Katsarava R, Beridze V, Arabuli N, et al. Amino acid-based bioanalogous polymers. Synthesis and study of regular poly(ester amide)s based on bis(a-amino acid), alpha, omega-alkylene diesters, and aliphatic dicarboxylic acids. J Polymer Sci 1999;37391407. 50. Markoishvili K., Tsitlanadze G, Katsarava R, et al. A novel sustained-release matrix based on biodegradable poly(ester amide)s and impregnated with bacteriophages and an antibiotic shows promise in management of infected venous stasis ulcers and other poorly healing wounds. Int J Dermatol2002;41:453458. 51. Merrill C, Biswis B, Carlton R, et al. Long-cirdating bacteriophages as antibacterial agents. Proc Natl Acad Sci U S A 1996;93: 3188-3192. 52.Greenwald D, Brandt L. Recognizing E. coli 0157:H7 infection. Hosp Pract (Off Ed) 1997;32123-6,129-30,133. 53. Wendelsdorf K, Hoyle N, DiSalvo S, et al. Characterization of bacteriophages against Pseudomonus ueruginosu for therapeutic uses. Presented to American Society for Microbiology General Meeting, New Orleans, May 2427,2004. 54. Raya R, Dyen M, Callaway TR, et al. Isolation of phages from sheep and their use in in vitro and in vivo assays to reduce contamination levels of Escherichiu coli 0157H7 in ruminants. Presented to American Society for Microbiology General Meeting, Washington DC,May 18-22,2003. 55. Chibani-chennoufi S, Sidoti J, Bruttin A, et al. Isolation of T4like bacteriophages from the stool of pediatric diarrhea patients in Bangladesh. J Bacteriol2004;186:8287-8294.

56. Chibani-Chennoufi S, Sidoti J, Bruttin A, et al. In vitro and in vivo bacteriolytic activities of Escherichin coli phages: implications for phage therapy. Antimicrob Agents Chemother 2004;48:2558-2269. 57. Ackermann H, Krisch H. A catalogue of T4-type bacteriophages. Archi Virol1997;142:2329-2345. 58.Kutter E, Kellenberger E, Carlson K, et al. Effects of bacterial growth conditions and physiology on T4 infection. In Karam JD, Drake J, eds. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology, 1994406-420. 59. Kutter E, Stidham T, Guttman B, et al. Genomic map of bacteriophage T4. In Karam JD, Drake J, eds. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology, 1994~491-519. 60. Jacob F, Monod J. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol1961;3:318-356. 61.Kutter E, Gachechiladze K, Poglazov A, et al. Evolution of T4-related phages. Virus Genes 1995;11:285-297. 62. Henning U, Hashemolhosseini S. Receptor recognition by T-even-type coliphages. In Karam JD, Drake J, eds. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology, 1994291-298. 63. Tetart F, Desplats C, Krisch HM. Genome plasticity in the distal tail fiber locus of the T-even bacteriophage: recombination between conserved motifs swaps adhesin specificity.J Mol Biol1998;282:543-556. 64.Doermann AH. Lysis and lysis inhibition with E. coli bacteriophage. J Bacteriol 1948;55:257-275. 65.Abedon S. Lysis and the interaction between free phages and infected cells. In Karam JD,Drake, J, eds. Molecular biology of bacteriophage T4. Washington, DC: American Society for Microbiology, 1994397-405. 66. Kolter R. Life and death in stationary phase. ASM News 1992; 58:75-79. 67. Fekety R. Antibiotic-associated diarrhea and colitis. Cur Opin Infect Dis 1995;8:391-397. 68. Bergh 0,Borsheim KY, Bratbak G, et al. High abundance of viruses found in aquatic environments. Nature 1989;340:467-468. 69. Caldwell JA. Bacteriologic and bacteriophagic study of infected urines. J Infect Dis 1928;43:353-362. 70. Yeung MK, Kozelsky CS. Transfection of Actinornyces spp. by genomic DNA of bacteriophages from human dental plaque. Plasmid 1997;37141-153. 71. Bachrach G, Leizerovici-Zigmond M, Zlotkin A, et al. Bacteriophage isolation from human saliva. Lett Appl Microbiol 2003;36:50-53. 72. Merril CR, Friedman TB, Attallah AF, et al. Isolation of bacteriophages from commercial sera. In Vitro 1972;8:91-93. 73. Geier MR, Attallah AF, Menil CR. Characterization of Escherichin coli bacterial viruses in commercial sera. In Vitro 1975;11:55-58. 74. Milch H, Fomosi F. Bacteriophage contamination in live poliovirus vaccine. J Biol Stand 1975;3307-310. 75. Moody EE, Trousdale MD, Jorgensen JH, et al. Bacteriophages and endotoxin in licensed live-virus vaccines. J Infect Dis 1975;131: 588-591. 76. Bogovazova GG, Voroshilova NN, Bondarenko VM. The efficacy of Klebsiellu pneumonine bacteriophage in the therapy of experimental Klebsiellu infection. Z h Mikrobiol Epidemiol Immunobiol 1991;5-8. 77.Bogovazova GG, Voroshilova NN, Bondarenko VM, et al. [Immunobiological properties and therapeutic effectiveness of preparations from Klebsiellu bacteriophages.] Zh Mikrobiol Epidemiol Immunobiol1992;Mar:30-33. 78. Larkum NW. Bacteriophage as a substitute for typhoid vaccine. J Bacteriol1929;1742. 79. Larkum NW. Bacteriophage from Public Health standpoint. Am J Pub Health 1929;19:31-36. 80.King WE, Boyd DA, Conlin JH. The cause of local reactions following the administration of Stuphylococcirs bacteriophage. Am J Clin Pathol1934;4336-345.

Phosphat idylserine Parris

M.Kidd. PhD

CHAPTER CONTENTS Introduction 1163

Clinical Applications 1164

Physiologic Roles 1163

Dosage 1164

Pharmacology

Toxicology and Drug Interactions 1164

1163

INTRODUCTION Phosphatidylserine ("1 is a phospholipid substance ubiquitous in all known life forms, including all human are moleCdeS/ each with a characteristic headgroup, a middle piece derived from glycerol, and one or two tailpieces that usually consist of fatty acids.' Phospholipids have unique self-assembly and side-by-side packing properties that suit them for making cell membranes, the predominant cellular matrices on which energy is generated and utilized to promote metabolism. Phosphatidylserine is functionally and structurally indispensable for the membranes of all known cells; toget6er with other phospholipids PS makes up the bulk matrix of the membrane, into which are inserted a plethora of proteins that catalyze cell-level biochemistry. Phosphatidylserine's clinical benefits are most apparent in brain-related functions, including cognition, mood, and stress management? The substance occurs most abundantly in nervous tissues, wherein it facilitates electrical stimulus initiation, cell-tocell stimulus transmission by way of synapses, and electrical circuit integration across the brain? These prohomeostatic central nervous system benefits translate into a clinically unique, optimizing and revitalizing effect on the brain.

PHYSIOLOGIC ROLES The involvement of PS in life processes is profound, because all known life forms rely on the cell-level membrane systems for which PS is structurally and functionally essential. Through its characteristic headgroup shape and molecular charge distribution, PS defines many of the physical and chemical characteristics of cell

membranes.' Membrane-level processes specifically linked to PS include the f0llowing3r4: The movement of electrolytes into and out of cells (especially sodium, potassium, magne~ium)~ The reception of molecularmessages from outside the cell (receptor functions)6 Signal transduction, via the enzymes adenylate cyclase and protein kinase C73 The secretion process, via intracellular vesicle fusion with the outer cell membrane The recognition and recycling of dead and dying body cells by immune cells Another, perhaps underrecognized function of PS is in energetics. PS is utilized by mitochondria as a backup metabolic source of phospholipids for their membrane systems. The mitochondria1 membranes have a central role in generating the energy required to sustain life. Though not an enzyme, PS plays a quasicatalytic role in normal clotting. It also aids in the routine elimination of nonfunctional cells from the body. PS is normally located in the inner leaflet of the cell's outermost membrane, bordering the cytoplasm. It is held there by an active enzymatic process. As the cell begins to die, it can no longer keep the enzyme active, and PS flips from the inner leaflet to the outer. There it is recognized by circulating immune cells as a signal to eliminate the cell. This phenomenon facilitates timely clearance of nonproductive cells from the tissues.

PHARMACOLOGY The pharmacology of PS is consonant with its many known roles in membrane functions. These contribute to the efficiency of initiation and propagation of electrical 1163

stimuli, and their subsequent passage from cell to cell via chemical transmitter release at the synapses, involving membrane vesicle fusion also facilitated by PS. By enabling membrane-to-membrane fusion processes, PS uniquely facilitates the cellular secretion of transmitters, hormones, and other messenger substances.' In animal studies PS enhanced the synaptic release, turnover, or receptor actions of at least nine major transmitter system^.^,^ There are also indications that PS has a trophic effect in the brain. In aging rats, PS both conserved the youthful densities of receptors for nerve growth factor and protected the nerve circuits against the usual age-related atrophy.'O PS is well absorbed by mouth. With its absorption into the intestinal lining cells (enterocytes) the fatty acid component at position 2 in the molecule is cleaved from the glycerol backbone. After absorption, this fatty acid position as well as position 1 can be substituted with other fatty acids, in a kind of tail group shuffling facilitated by transacylase enzymes. This enables local modification of the molecule to facilitate its optimal use by that particular cell and tissue. The specific fatty acid profile of PS thus varies with the tissue location: For example, in the brain positions 1and 2 are mostly oleic acid (18:ln6) and docosahexaenoic acid (C22:6n3) (DHA), whereas in the platelets they are mostly stearic acid (18:O) and arachidonic acid (C20:4n6).11 Oripally,PS was prepared through laborious isolation from bovine brain, but with the advent of "mad cow disease'' alternative commercial preparation from soybean lecithin became necessary. Phosphatidylserine is now usually available as a PSenriched soy lecithin complex that also contains the other phospholipids phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol. Responsible manufacturers list the amounts of each on the product label. Although the earlier, definitive clinical trials on PS were conducted with bovine brain PS, which carries some DHA, the effectiveness of soy-derived phosphatidylserine has now been proven in double-blind However, other lines of research indicate that PS and DHA have synergistic roles in brain cell metabolism.15 With DHA so undersupplied in the Western diet, cosupplementation with DHA should predictably improve the overall benefit of PS supplementation.

CLINICAL APPLICATIONS The primary use of PS has been for the treatment of impaired mental function in the middle-aged and elderly, and especially for the mild to moderate cognitive impairments that presage Alzheimer's disease and other dementias. In 13doubleblind trials,PS administered as a dietary supplement produced consistent improvement in memory, learning, word recall, and other cognitive functions, most markedly in the middle-aged and elderly.l2JGB

For the most severely cognitively impaired, the benefits of PS generally were modest, but activities of daily living and other performance in daily life were someIn the largest such trial, a total times of 425 elderly patients (between ages 65 and 93 years) with moderate to severe senility were given either PS (100 mg three times daily) or a placebo for 6 Statistically sigruficant (p c 0.01) improvements in mental function, mood, and behavior were noted in the P S treated group compared with placebo. Phosphatidylserine appears to positively affect mood in depressed elderly s u b j e ~ t s . 2This ~~~ effect ~ ~ could also explain some of its positive effects on memory and cognition-the link between depression and impaired mental function is well-established in the geriatric population. In one small double-blind study of 10 depressed elderly patients, PS was shown to improve depressive symptoms, memory, and behavior.30Unlike typical antidepressant drugs, PS promoted this improvement without influencing the levels of serotonin and other monoamine neurotransmitters, suggesting another mechanism of action. Improved brain cell membrane function is one obvious rationale. Another is the repeated finding that PS can d u c e cortisol secretion in response to stress in both young and aging subjects21-3 Typically, cortisol levels are elevated in depressed patients. PS has improved adaptation to stressful challenges in four double-blind trials.13J4,31,32 Another, controlled study indicated PS lessened anxiety, insomnia, and difficulty with recall in feeble elderly women.% Dietary PS supports hypothalamic-pituitary-adrenal integration (the HPA axis)3335*36 as well as daily hormone rhythms from the pit~itary.3~ Human electroencephalographicand imaging studies indicate that PS improves energy production and utilization throughout the brak1.3~

DOSAGE ~

~~

The standard dosage recommendation for phosphatidylserine is 100 mg by mouth with meals, three times daily. Intake up to 500 mg daily is well tolerated.

TOXICOLOGY AND DRUG INTERACTIONS No adverse side effects or adverse drug interactions have been reported for PS. This is consistent with PS's being an orthomolecule, its molecular structure being familiar to living cells ever since life began. Animal studies determined that PS (bovine) given orally was extremely well tolerated. Dogs tolerated up to 70 g per day for 1 year without any apparent side effect. In more than 35 clinical studies PS was administered to more than 900 subjects, without major side effect at standard dosage (100 mg three times daily). Stomach upset has been reported, but very rarely.

Phosphatidylserine

1. Alberts B, Johnson A, Lewis J, et al. Molecular biology of the cell. New York: Garland Science, 2002. 2. Kidd PM. The phospholipids as anti-aging nutraceuticals. In Klatz RM, Goldman R, eds. Anti-aging medical therapeutics, vol IV. Chicago: American Academy of Anti-Aging Medicine, 2000. 3. Nunzi MG, et al. Therapeutic properties of phosphatidylserine in the aging brain. In Hanin I, Pepeu G, eds. Phospholipids: biochemical, pharmaceutical, and analytical considerations. New York: Plenum Press, 1990. 4. Borghese CM, Gomez RA, Ramirez OA. Phosphatidylserine increases hippocampal synaptic efficacy. Brain Res Bull 1993;31: 697-700. 5. Morrot G, Zachowski A, Devauz PF. Partial purification and characterization of the human erythrocyte Mg2tATPase: a candidate aminophospholipid translocase. FEBS Lett 1990;26629-32. 6. Cohen SA, Miiller WE. Age-related alterations of NMDA-receptor properties in the mouse forebrain: partial restoration by chronic phosphatidylserine treatment. Brain Res 1992;584:174180. 7. Malkiewicz-Wasowicz B, G m t 0, Stromme JH. The influence of changes in the phospholipid pattern of intact fibroblasts on the activities of four membrane-bound enzymes. Biochim Biophys Acta 1977;482358-369. 8. Newton AC, Johnson JE. Protein kinase C: a paradigm for regulation of protein function by two membrane-targeting modules. Biochim Biophys Acta 1998;1376155-172. 9. Samson JC. The biological basis of phosphatidylserine pharmacology. Clin Trials J 1987;241-8. 10. Nunzi MG, Guidolin D, Petrelli L, et al. Behavioral and morphofunctional correlates of brain aging: a pmlinical study with phosphatidylserine. In Bazan NG, Murphy MG, Toffano G, eds. Neurobiology of EssentialFatty Acids. New York Plenum Press, 1992. 11. Alling C, Jonsson G, Gustavsson L, et al. Anionic glycerophospholipids in platelets from alcoholics. Drug Alcohol Depend 1986; 16309-320. 12.Gindin J, Novikov M, Kedar D, et al. The effect of plant phosphatidylserine on age-associated memory impairment and mood in the functioning elderly. Rehovot, Israel Geriatric Institute for Education and Research, and Department of Geriatrics, Kaplan Hospital, 1995. 13. Fahey TD, Pearl MS. The hormonal and perceptive effects of phosphatidylserine administration during two weeks of resistive exercise-induced overtraining. Biol Sport 1998;15135-144. 14. Benton D, Donohue RT, SiLlance B, Nabb S. The influence of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. Nutr Neurosci 2001;4169-178. 15. Salem N, Niebylski CD. The nervous system has an absolute molecular species requirement for proper function. Mol Membr Biol 1995;12131-134. 16. Amaducci L, Crook TH, Lippi A, et al. Use of phosphatidylserine in Alzheimer’s disease. Ann N Y Acad Sci 1991;640245-249. 17.Crook TH, Tinklenberg J, Yesavage J, et al. Effects of phosphatidylserine in age-associated memory impairment. Neurology 1991;41:644-649. 18. Crook T, Petrie W, Wells C, Massari DC.Effects of phosphatidylserine in Alzheimer’s disease. Psychopharmacol Bull 1992;28:61-66. 19. Crook TH. Treatment of age-related cognitive decline: effects of phosphatidylserine. In Klatz RM, Goldman R, eds. Anti-aging medical therapeutics, vol II. Chicago: American Academy of AntiAging Medicine, 1998. 20. Cennacchi T, Bertoldin T, Farina C, et al. Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on

efficacy of phosphatidylserine administration. Aging (Milano) 1993;5:123-133. 21. Delwaide PJ, Gyselynck-Mambourg AM, Hurlet A, Ylieff M. Double-blind randomized controlled study of phosphatidylserine in demented patients. Acta Neurol Scand 1986;73136-140. 22. Engel RR, Satzger W, Gunther W, et al. Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacol 1992;2149-155. 23. Fuenfgeld EW. Double-blind study with phosphatidylserine (PS)in parkinsonian patients with senile dementia of Alzheimer’s type (SDAT).Prog Clin Biol Res 1989;3171235-1246. 24. Nerozzi D, Aceti F, Melia E, et al. [Phosphatidylserine and memory disorders in the aged]. Clin Ter 1987;120399-404. 25. Palmieri G, Palmieri R, Inzoli MR, et al. Double-blind controlled trial of phosphatidylserine in patients with senile mental deterioration. Clin Trials J 1987;2473-83. 26.Ransmayr G, Plorer S, Gerstenbrand F, Bauer G. Doubleblind placebo-controlled trial of phosphatidylserine in elderly patients with arteriosclerotic encephalopathy. Clin Trials J 1987; 2462-72. 27.Villardita C, Grioli S, Salmeri G, et al. Multicentre clinical trial of brain phosphatidylserine in elderly patients with intellectual deterioration. Clin Trials J 1987;2484-93. 28. Hershkowitz M, Fisher M, Bobrov D, et al. Long-term treatment of dementia Alzheimer type with phosphatidylserine: effect on cognitive functioning and performance in daily life. In Bazan NG, Horrocks LA, Toffano G, eds. Phospholipids in the nervous system: biochemical and molecular pathology. Padova: Liviana Press, 1989. 29. Amaducci L. Phosphatidylserine in the treatment of Alzheimer’s disease: results of a multicenter study. Psychopharmacol Bull 1988; 24:130-134. 30.Maggioni M, Picotti GB, Bondiolotti GP, et al. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand 1990;81:265-270. 31. Monteleone P, Beinat L, Tanzillo C, et al. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinology 1990;52:243-248. 32. Monteleone P, Maj M, Beinat L, et al. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenalaxis in healthy men. Eur J Clin Phannacol 1992;42:385-388. 33.Nerozzi D, Magnani A, Sforza V, et al. Early cortisol escape phenomenon reversed by phosphatidylserine (Bros) in elderly normal subjects. Clin Trials J 1989;26:33-38. 34. Manfredi M, Pranteda G, Sacca A, et al. [Clinical results of phosphatidylserine in 40 climacteric and elderly women with psychoorganic disorders]. Clin Ter 1987;120:33-36. 35. Masturzo P,Murialdo G, de Palma D, et al. TSH circadian secretions in aged men and effect of phosphatidylserine treatment. Chronobiologia 1990;17267-274. 36. Rabboni M, Maggioni FS, Giannelli A, Beinat L. Neuroendocrine and behavioural effects of phosphatidylserine in elderly patients with abiotrophic or vascular dementia or mild depression. Clin Trials J 1990;27230-240. 37. Klinkhammer P, Szelies 8, Heiss WD. Effect of phosphatidylserine on cerebral glucose metabolism in Alzheimer’s disease. Dementia 1990;1:197-201.

Piper methysticum (Kava) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Analgesic Effects 1170 Anxiolytic Effects 1170 Antiischemia Effects 1 170

General Description 1167 Chemical Composition 1167 History and Folk Use 1167 The Kava Ceremony 1168 The Effects of Drinking Kava

Clinical Applications

1169

Pharmacology 1169 Isolated Kavalactones Compared with Crude Extracts 1169 Sedative Effects 1170

Piper rnethysticum (family: Piperaceae) Common name: kava

GENERAL DESCRIPTION Kavu is a hardy, slow-growing perennial that generally resembles other members of the pepper family. It is an attractive shrub and can attain heights of more than 9 feet. The plant does not have many leaves, but those it does have are thin, single, heart-shaped, alternate, petiolate, 4 to 10 inches long, and sometimes wider than they are long. Although Piper rnethysticurn does flower, it is incapable of self-reproduction; its propagation is vegetative and now due solely to human effort.l s 2 For medicinal purposes, it is the rootstock that is used. The rootstock is knotty, thick, and sometimes tuberous with holes or cracks created by partial destruction of the parenchyma. In other words, the rootstock is often somewhat pithy. From the main rootstock, there are extensions of lateral roots up to 9 feet long.*,2

CHEMICAL COMPOSITION Analysis of the composition of the dried kava rootstock indicates that it contains approximately 43% starch, 12% water, 3.2%simple sugars, 3.6%proteins, 3.2%minerals (primarily potassium), and 15% kavalactones (Table 115-1).1,2

Dosage

1170

1171

Side Effects and Toxicology

1171

Drug Interactions 1172

On the basis of detailed analysis of the active ingredients of kava, a laborious process over the past 110 years, many experts now believe that the pharmacologic activities of kava are due mostly, if not entirely, to the presence of compounds known as kuvuluctones (also referred to as kava alpha-pyrones). These compounds are found in the fat-soluble resin of the root. Although the kavalactones are the primary active components, other components appear to contribute to the sedative and anxiolytic activities of kava, as one study found the sedative activity of a crude preparation to be more effective than the isolated kavalactones (Figure 115-1).3 The kavalactone content of the root can vary between 3% and 20%.

HISTORY AND FOLK USE Oceania-the Pacific island communities of Micronesia, Melanesia, and Polynesia-is one of the few geographic areas of the world that did not have alcoholic beverages before European contact in the eighteenth century. However, these islanders did possess a "magical" drink used in ceremonies and celebrations because of its calming effect and ability to promote sociability. The drink, also called kava, is still used today in this region of the world, where the people are often referred to as the happiest and friendliest in the world. The origins of kava use are not known as it predates written history in Oceania.lt2It was first described for

1167

Pharmacology of Natural Medicines Kavalactones R

ComDound

R”

R’

R”’

C5-6

C7-8

Kavain 7,8-Di hydrokavain 5,6-Dihydrokavain Yangonin

OMe

5,6,7,8-Tetrahydroyangonin Methysticin Dihydromethysticin 5,6-Dehydromethysticin 5,6-Dihydroyangonin

OMe

7,8-Dihydroyangonin

OMe

10-Methoxy-yangonin

OMe

11-Methoxy-yangonin

OMe

OMe

11-Hydroxy-yangonin

OMe

HO

OH

OMe

0-CH2-0 0-CHZ-0 0-CH2-0 OMe OMe

Hydroxykavain 11-Methoxy-1Phydroxy dehydrokavain

‘Single dashes represent a single band, and double dashes represent a double band.

OCH,

R’ Figure 115-1 Kavalactones.

the Western world by captain James Cook in the account of his voyage to the South Seas in 1768. Many myths and legends surround the early use of kava. The plant itself probably originated in the New Guinea/Indonesia area and was spread from island to island by early Polynesian explorers in canoes, along with other plants. Each culture has its own story on the origins of kava. For example, in Samoa a story is told about the origins of kava and sugar cane. The story goes that a Samoan girl went to Fiji where she married a great chief. After some time, she returned to Samoa, but before doing so, she noticed two plants growing on a hill. She saw a rat chewing on one of the plants and noticed that the rat seemed to go to sleep. She concluded that the plant was a comforting food. She decided she would take this plant, sugar cane, back to Samoa, but then she noticed that the rat awoke and began to chew the root of another plant, kava. The animal that had been weak and shy became bold, strong, and more energetic. She decided that she would take both plants back with her to plant in Samoa. The plants grew very well in Samoa,

and soon a chief from a neighboring island exchanged two laying hens for roots of the two plants. Hence, the Samoans take credit for the spread of both sugar cane and kava. In Tonga, a legend is told about a great chief named Loau who lived on the island of Euaiki. He went to visit his servant Feva’anga, who wanted to give a feast in honor of the chief, but it was a time of great famine. In desperation, he and his wife killed and cooked their only daughter to be served to the chief. However, Loau recognized the human flesh in the food when it was served and would not eat it. He instructed Feva’anga to plant the food in the ground and to bring him the plant that would spring forth. On receiving the mature plant, Loau instructed that a drink be prepared from it and consumed with due ceremony.

The Kava Ceremony Regardless of exactly how kava originated, it has been used in ceremonies by the Oceanic people for thousands of years. There are three basic kava ceremonies: the full ceremonial as enacted on every formal occasion, the one performed at the meeting of village elders, chiefs, and nobles and for visiting chiefs and dignitaries, and the less formal kava circle common on social occasions.lP2 The first step of any kava ceremony was the preparation of the beverage. The following description of the classic process was written in 1777 by Georg Forster, a young naturalist on James Cook‘s second Pacific voyage: [Kava] is made in the most disgustful manner that can be imagined, from the juice contained in the roots of a species of pepper-tree. This root is cut small, and the pieces chewed by several people, who spit the macerated mass into a bowl,

Piper rnefhysficurn (Kava) where some water (milk) of coconuts is poured upon it. They then strain it through a quantity of fibres of coconuts, squeezing the chips, till all their juices mix with the coconut-milk; and the whole liquor is decanted into another bowl. They swallow this nauseous stuff as fast as possible; and some old topers value themselves on being able to empty a great number of bowls.

As this traditional method of preparation became frowned upon or made illegal by colonial governments and missionaries, more "sanitary" methods of preparation, involving grinding or grating, took its place in many parts of Oceania. The full kava ceremony, reserved for very highly honored guests, involves leading all the guests to a platform. The ceremony begins with the arrival of a group of young men dressed in ceremonial attire and carrying a bowl of the kava drink and necessary utensils. The bowl is placed between the kava preparers and the visitors. The kava is poured in a cup by a specially selected individual who then turns and faces the visitor and delivers the beverage to the chief guest. The guest is instructed to hold the cup with both hands and drink from it. If the whole cup is drained without stopping, everyone says "a maca" (pronounced "a matha," meaning "it is empty") and claps three times with cupped hands. The cupbearer then returns to the kava bowl and proceeds to serve the person next in rank or importance. Important people who visit Fiji and other islands of Oceania still participate in the kava ceremonies. For example, during a 1992 presidential campaign visit to Hawaii, Hillary Clinton participated in a kava ceremony conducted by the Samoan community on Oahu.

The Effects of Drinking Kava Kava drinkers relate a pleasant sense of tranquility and sociability upon consumption. Subjective reports given by scientists who have sampled kava themselves are relatively abundant. One of the first scientific studies of kava was performed by the noted pharmacologist Louis Lewin in 1886. A later description written in 1927 is as followsl: When the mixture is not too strong, the subject attains a state of happy unconcern, well-being and contentment, free of physical or psychological excitement. At the beginning, conversation comes in a gentle, easy flow and hearing and sight are honed, becoming able to perceive subtle shades of sound and vision. Kava soothes temperaments. The drinker never becomes angry, unpleasant, quarrelsome or noisy, as happens with alcohol. Both natives and whites consider kava as a means of easing moral discomfort. The drinker remains master of his consciousnessand his reason. When consumption is excessive, however, the limbs become tired, the muscles seem no longer to respond to the orders and control of the mind, walking becomes slow and unsteady and the drinker looks partially inebriated. He feels the need to lie down. . . . He is overcome by somnolence and finally drifts off to sleep.

A later description is provided by researcher R. J. Gregory, who writes the following from his own experience: Kava seizes one's mind. This is not a literal seizure, but something does change in the processes by which information enters, is retrieved, or leads to actions as a result. Thinking is certainly affected by the kava experience, but not in the same ways as are found from caffeine, nicotine, alcohol, or marijuana. I would personally characterize the changes I experienced as going from lineal processing of information to a greater sense of "being" and contentment with being. Memory seemed to be enhanced, whereas restriction of data inputs was strongly desired, especially with regard to disturbances of light, movements, noise and so on. Peace and quiet were very important to maintain the inner sense of serenity. My senses seemed to be unusually sharpened, so that even whispers seemed to be loud while loud noises were extremely unpleasant.

Drinking about half a coconut shell (100 to 150 ml) of certain varieties of kava is enough to put most people into a deep, dreamless sleep within 30 minutes. Unlike alcohol and other sedatives, kava does not produce a morning hangover. The kava drinker awakens having fully recovered normal physical and mental capacities.

PHARMACOLOGY Many of the first comprehensive studies on the activities of kavalactones were conducted by a team of scientists from the Freibwg University Institute of Pharmacology in Germany, led by Hans J. Meyer, during the 1950s and 1 9 6 0 ~ .This ~ research determined that kavalactones exhibit sedative, analgesic, anticonvulsant, and musclerelaxing effects in laboratory animals. These studies seemed to confirm earlier empirical and subjective observations. Later studies have utilized better-defined kava extracts.

Isolated Kavalactones Compared with Crude Extracts Some evidence suggests that the whole complex of kavalactones and other compounds naturally found in kava produce greater pharmacologic activity. In addition, studies have shown that kavalactones are more rapidly absorbed when given orally as an extract of the root rather than as the isolated kavalactones. The bioavailability of lactones, as measured by peak plasma concentrations, is up to 3 to 5 times higher from the extract than when given as isolated s~bstances.~ Further evidence that kava root extracts are superior to isolated kavalactones is offered by an animal study showing that although isolated kavalactones are well absorbed by brain, crude kava preparations produce brain concentrations of lactones 2 to 20 times higher! This evidence suggests that crude extracts standardized for kavalactone content may offer the greatest therapeutic benefit.

Pharmacology of Natural Medicines Several clinical trials have featured a kava extract standardized to contain 70% kavalactones. However, this high percentage of kavalactones may be sacrificing some of the other constituents that may contribute to the pharmacology of kava. More important than the actual percentage of kavalactones is the total dosage of the kavalactones and the assurance that the full range of kavalactones and other important constituents are present. Standardized preparations of kava are now gaining greater popularity in Europe and the United States as mild sedatives and anxiolytics.

Sedative Effects Recent studies have confirmed and/or elaborated on the sedative effects of kava. Most notable are studies demonstrating that kavalactones exert many of their effects through nontraditional mechanisms. For example, most sedative drugs, including the benzodiazepines (e.g., diazepam, triazolam, cloraepate dipotassium) work by binding to specific receptors (benzodiazepine or GABA receptors) in the brain, leading to the neurochemical changes (potentiation of GABA effects) that promote sedation. Studies in animals have shown that the kavalactones do not bind to benzodiazepine or GABA receptors? Instead, the kavalactones are thought to somehow m o d e receptor domains rather than interact specifically with receptor binding sites. In addition, other studies have indicated that the kavalactones appear to act primarily on the limbic system, the ancient part of the brain that affects all other brain activities and is the principal seat of the emotions.6 It is thought that kava may also promote sleep by altering the way in which the limbic system modulates emotional processes. It appears that many of the laboratory models of identifying how a substance works to promote a calming effect are simply not sophisticated enough to evaluate the physiologic effects of kava.

Analgesic Effects In another example of the unusual pharmacologic qualities of kava, a study designed to evaluate its pain-relieving effects could not demonstrate any binding to opiate receptors? The signhcance of this finding is that the study used experimental models in which nonopiate analgesics like aspirin and other nonsteroidal antiinflammatory drugs are ineffective. In addition, it was determined that the sedative or muscle-relaxing effects were not responsible for the pain-relieving effects. These findings indicate that kava reduces pain in a manner unlike morphine, aspirin, or any other pain reliever.

Anxiolytic Effects An interesting difference of kava from other anxiolytics is that unlike the drugs, kava does not lose effectiveness

with time. Kavalactones, even when administered in large dosages, demonstrated no loss of effectiveness in animal studies.8 This is another example of the unusual qualities of kava.

Antiischemia Effects Another pharmacologic activity of kava of importance is its ability to protect against brain damage due to i ~ h e r n i a .This ~ effect has been demonstrated in two animal models of focal cerebral ischemia. The effectiveness of the kavalactones was due to their ability to limit the infarct area as well as to provide a mild anticonvulsant effect. Kava extract may prove useful in the recovery from a stroke.

CLINICAL APPLICATIONS The primary clinical application of kava is in the treatment of anxiety. This application is well-supported by clinical research.'O Early clinical trials used D,L-kavain, a purified kavalactone, at a dosage of 400 mg/day. For example, in one double-blind placebo-controlled study of 84 patients with anxiety symptoms, kavain was shown to improve vigilance, memory, and reaction time." In another double-blind study, kavain was compared with oxazepam (a drug similar to diazepam [Valium])in 38 patients.12 Both substances caused progressive improvements in two different anxiety scores (Anxiety Status Inventory and the Self-rating Anxiety Scale) over a 4week period. However, although oxazepam and similar drugs are addictive and cause side effects, kavain appeared to be free of these complications. In one of the early studies with kava extracts, a 70% kavalactone extract was shown to exhibit significant therapeutic benefit in patients suffering from anxiety.13 The study was double-blind; 29 patients were assigned to receive 100 mg of the kava extract three times daily and 29 other patients received a placebo. Therapeutic effectiveness was assessed using several standard psychological assessments, including the Hamilton Anxiety Scale (HAMA).The result of this 4-week study indicated that individuals taking the kava extract had a statistically significant reduction in symptoms of anxiety, including feelings of nervousness, and somatic complaints, such as heart palpitations, chest pains, headache, dizziness, and feelings of gastric irritation. No side effects were reported with the kava extract. Studies have also compared the effects of a kava extract standardized to contain 30% kavalactones with buspirone and omipramol. In the double-blind study, 129 patients with generalized anxiety disorder were given either 400 mg kava (30%kavalactones), 10 mg buspirone, or 100 mg opipramol daily for 8 weeks. Detailed analysis showed that no significant differences could be observed regarding all efficacy and safety measures.

Piper rnethysticum (Kava)

traditionally prepared kava drink contains approxiAbout 75% of patients were classified as responders mately 250 mg of kavalactones, and in Oceania, several (50% reduction of the HAMA score) in each treatment bowls may be consumed at one sitting. Dosages are as group, and about 60%achieved full remis~i0n.l~ Kava has also been shown to be particularly effective follows: in relieving anxiety in perimenopausal and postAnxiolytic dosage: 45-70 mg of kavalactones three menopausal women.15-17In one double-blind study, two times/ day groups of 20 women with menopause-related symptoms Sedative dosage: 180-210 mg of kavalactones 1 hour were treated for a period of 8 weeks with the 70%kavalacbefore retiring tone extract (100 mg three times daily) or placebo.18The measured variable was once again the HAMA. The group receiving the kava extract demonstrated significant SIDE EFFECTS AND TOXICOLOGY improvement at the end of the very first week of treatIn November 2001, German health authorities anment. Scores continued to improve over the course of the nounced that 24 cases of liver disease (including hep8-week study. In addition to symptoms of stress and anxatitis, liver failure, and cirrhosis) associated with the use iety, a number of other symptoms also improved. Most notably there was an overall improvement in subjective of kava had been reported in Germany; of the affected well-being, mood, and general symptoms of menopause, persons, one died and three required a liver transplant. The true nature of kava-induced liver damage is clouded including hot flashes. As with previous studies, no side by the fact that in 18 of these cases, conventional preeffects were noted. scription or over-the-counter pharmaceutical drugs with Additional studies have shown that unlike benzodiknown or potential liver toxicity were also being used. It azepines, alcohol, and other drugs, kava extract is not is entirely possible that the use of kava by these individassociated with depressed mental function or impairment in driving or the operation of heavy e q ~ i p m e n t . ' ~ , ~uals ~ was a coincidence rather than the cause of the liver problem; alternatively, the problem may have stemmed In one of these studies, 12 healthy volunteers were tested in a double-blind crossover manner to assess the effects from using kava well above recommended levels or from an interaction with some of these hepatotoxic drugs, of oxazepam (placebo on days 1to 3/15 mg on the day before testing, 75 mg on the morning of the experiment), thereby increasing their toxicity.A survey of 400 German the extract of kava standardized at 70% kavalactones medical practices showed that 78% of the kava prescriptions that were written sigruficantlyexceeded the recom(200 mg three times daily for 5 days), and a placebo on mended intake." Nonetheless, there have been reports behavior and event-related potentials (ERPs) in electroencephalographic (EEG) readings on a recognition of hepatitis in patients using kava at dosages equal to or only slightly higher than recommended levels.= memory task. The subjects' task was to identdy within a High daily dosages of kava consumed over a prolist of visually presented words those that were shown for the first time and those that were being repeated. longed period (a few months to a year) are associated Consistent with other benzodiazepines, oxazepam with a number of side effects beyond liver damage, including the development of "kava dermopathy"-a inhibited the recognition of both new and old words as condition of the skin characterized by a peculiar genernoted by Em.In contrast, kava allowed a slightly greater alized scaly eruption known as kar~i.*~ The skin becomes recognition rate and a larger ERP difference between old dry and covered with scales, especially the palms of the and new words. The results of this study once again hands, soles of the feet, forearms, the back, and shins. It demonstrate the unusual effects of kava. In this case, it was thought at one time that kava dermopathy may be improves anxiety, but unlike standard anxiolytics, kava due to interference with niacin. However, in a doubleactually improves mental function and, at the recomblind, placebmontrolled study niacinamide (100 mg/day) mended levels, does not promote sedation. Another demonstrated no therapeutic effect.= It appears that the study indicated that kava helped improve reflex vagal only effective treatment for kava dermopathy is reduction control of heart rate in generalized anxiety disorder or cessation of kava consumption. No cases of kava patients.2I dermopathy have been reported in persons taking standardized kava extracts at recommended levels. DOSAGE Other reported adverse effects of extremely high doses of kava (e.g., more than 310 g/week) for prolonged In clinical studies using pure kavalactones or kava periods are as followsz6: extracts standardized for kavalactones, the dosage is based on the level of kavalactones. Because the kavalacBiochemicalabnormalities(low levels of serum albumin, tone content of the root varies between 3% and 20%, protein, urea, and bilirubin) preparations standardized for kavalactone content are Elevated liver enzymes preferred to crude preparations. A standard bowl of

Presence of blood in the urine Increased red blood cell volume Decreased platelet and lymphocyte counts Shortness of breath

Kava is not recommended for use by pregnant or breastfeeding women.

DRUG INTERACTIONS

At this time, kava is not recommended for use by anyone who has any liver problems or who is a regular consumer of alcohol. Use of kava for more than 4 weeks requires close monitoring of liver enzymes (once every 4 to 6 weeks). Patients should be instructed to discontinue use of kava if symptoms of jaundice (e.g., dark urine, yellowing of the eyes) occur. Nonspecific symptoms of liver disease include nausea, vomiting, light-colored stools, unusual tiredness, weakness, stomach or abdominal pain, and loss of appetite.

Kava may potentiate the effects of benzodiazepines, barbiturates, and prescription sedatives. Kava also inhibits a number of the cytochrome enzymes that play a role in the breakdown of many medi~ations.~~ Therefore it has the potential to interact with a wide range of medications. There is evidence that kava interferes with dopamine or other drugs used in the treatment of Parkinson’s disease; therefore until this issue is resolved, kava extract should not be used by patients with Parkinson’s disease.24

1.Lebot V, Merlin M, Lindstrom L. Kava. The pacific drug. New Haven, CT:Yale University Press, 1992. 2. Sin& Y. Kava: an overview. J Ethnopharmacol1992;3713-45. 3. Meyer HJ.Pharmacologyof kava. In Efron D, Holmstedt B, Kline NS, eds. Ethnopharmacologic search for psychoactive drugs. New York: Raven Press. 1979133-140. 4. Keledjian J, Duffield PH, Jamieson DD. Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J Pharm Sci 1988;7731003-1006. 5. Davies LP, Drew CA, Duffield P, et al. Kava pyrones and resin: studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. Pharmacol Toxic01 1992;71:120-126. 6. Holm E, Staedt U, Heep J, et al. [The action profile of D,L-kaVain. Cerebral sites and sleep-wakefulness-rhythm in animals.] Arzneimittelforschung 1991;41:673-683. 7. Jamieson DD, Duff3eld PH. The antinociceptive action of kava components in mice. Clin Exp Pharmacol Physiol1990;17495-507. 8. Duffield PH, Jamieson D. Development of tolerance to kava in mice. Clin Exp Pharmacol Physiol 1991;18:571-578. 9. Backhauss, Krieglstein J. Extract of kava (Piper methysticum) and its methysticum constituents protect brain tissue against ischemic damage in rodents. Eur J Pharmacol1992;215265-269. 10. Pittler MH, Emst E. Efficacy of kava extract for treating anxiety: systematic review and meta-analysis. J Clin Psychopharmacol 2000;2084-89. 11. Scholing WE, Clausen HD. [On the effect of D,L-kavain: experience with neuronika (author’s transl).] Med Klin 1977;721301-1306. 12. Lindenberg D, Pitule-Schodel H. [D,L-kavain in comparison with oxazepam in anxiety disorders. A double-blind study of clinical effectiveness.] Forschr Med 1990;108:49-50, 53-54. 13. Kinzler E, Kromer J, Lehmann E. [Clinical efficacy of a kava extract in patients with anxiety syndrome. Double-blind placebo controlled study over 4 weeks.] Arzneimittelforschung 1991;41:584-588. 14. Boemer RJ, Sommer H, Berger W, et al. Kava-Kava extract LI 150 is as effective as opipramol and buspirone in generalised anxiety disorder-an %week randomized, double-blind multi-centre clinical trial in 129 out-patients. Phytomedicine 2003;1O(Suppl4):38-49.

15. Cagnacci A, Arangino S, Renzi A, et al. Kava-Kava administration reduces anxiety in perimenopausal women. Maturitas 2003;44: 103-109. 16. De Leo V, la Marca A, Morgante G, et al. Evaluation of combining kava extract with hormone replacement therapy in the treatment of postmenopausal anxiety. Maturitas 2001;39:185-188. 17. De Leo V, La Marca A, Lanzetta D, et al. [Assessment of the association of Kava-Kava extract and hormone replacement therapy in the treatment of postmenopause anxiety.] Minerva Ginecol 2000;52263-267. 18. Wamecke G. [Psychosomatic dysfunctions in the female climacteric. Clinical effectiveness and tolerance of kava extract WS 1490.1 Fortxhr Med 1991;109:119-122. 19. Herberg KW. [Effect of kava-special extract WS 1490 combined with ethyl alcohol on safety-relevant performance parameters.] Blutalkohol 1993;30:96-105. 20. Munte TF, Heinze HJ, Matzke M, et al. Effects of oxazepam and an extract of kava roots (Piper methysticum) on event-related potentials in a word recognition task. Neuropyschobiology 1993;2746-53. 21. Watkins LL, Connor KM, Davidson JR. Effect of kava extract on vagal cardiac control in generalized anxiety disorder: preliminary findings. J Psychopharrnacol2001;15283-286. 22. Schroder-Bemhardi D, Dietlein G. Compliance with prescription recommendations by physicians in practices. Int J Clin Pharmacol Ther 2001;39:477-479. 23. Escher M, Desmeules J, Giostra E, Mentha G. Hepatitis associated with kava, a herbal remedy for anxiety. BMJ 2001;322:139. 24.Schelosky L, Raffauf C, Jendroska K, et al. Kava and dopamine antagonism [letter]. J Neurol Neurosurg Psychiatry 1995;58: 639-640. 25.Norton SA, Ruze P. Kava dermopathy. J Am Acad Dermatol 1994;31:89-97. 26. Ruze P. Kava-induced dermopathy. A niacin deficiency. Lancet 1990;335:1442-1445. 27. Mathews JM, Etheridge AS, Black SR. Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab Dispos 2002;301153-1157.

Policosanol hfichael T. hlurray, N D Joseph E. Pizzorno Jr, N D C: H A P T E R C: 0 N T E N T S General Description 1173 Chemical Composition 1173 History and Folk Use 1173 Pharmacology 1173 Clinical Applications 1174 Cholesterol Lowering 1174 Diabetes 1176

GENERAL DESCRIPTION Policosanol refers to a patented mixture of higheraliphatic primary alcohols isolated and purified from the wax of sugar cane (Saccharurn oficinarum, L.).

CHEMICAL COMPOSITION As the name implies, policosanol is a mixture of many (poly) cosanols, cosanols being long-chain alcohols (LCAs). The components of policosanol are 1-octacosanol, 1-dotriacontanol, 1-triacontanol, 1-tetracosanol, 1-tetratriacontanol, 1-hexacosanol, 1-heptacosanol, and 1-nonacosanol. The patented Cuban policosanol contains eight LCAs in specific amounts. Erroneously, the term ”octacosanol” is sometimes used to refer to policosanol, even in the biomedical literature. Although octacosanol is contained in policosanol, studies show that octacosanol has only mild, if any, blood lipid-modifying effects compared with results of studies on the patented material.’

HISTORY AND FOLK USE The development of policosanol began in 1964 when Che Guevara, Cuba’s minister of industry, created the first postrevolution state-sponsored research center, the Cuban Institute for Research on Sugar Cane Derivatives.2 The Institute’s intent was to identify high-value bioactive sugar cane derivatives that would

Hypertension 1176 Elderly Patients 1177 Type I1 Hypercholesterolemia and Disturbances of Hepatic Function 1177 Antiplatelet Effects 1177 Angina 1178 Intermittent Claudication 1178

Toxicology 1178 Drug Interactions 1179

ultimately surpass the value of refined white sugar. The first product with such potential was policosanol. It is sold as a patented agent for lowering cholesterol in more than 40 countries. One notable exception is the United States, a result of this country’s current trade embargo against Cuba. The sources for imitation policosanol products marketed in the United States include sugar cane wax extracts produced outside Cuba, rice bran wax, and beeswax. However, it must be kept in mind that the clinical research on policosanol is with the Cuban policosanol derived from sugar cane wax?

PHARMACOLOGY The pharmacologic effects of policosanol, derived from experimental models, can be summarized as follows: Policosanol produces a dose-dependent and significant reduction of serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. High-density lipoprotein cholesterol (HDL-C) values are also increased in a dose-dependent manner. Triglycerides are also signhcantly reduced, but the reduction is not dose-dependent.45 Policosanol lowers serum total cholesterol and LDL-C by (1)inhibiting cholesterol synthesis at a point between the formations of acetate and mevalonate, (2) exerting no direct inhibition on 3-hydroxy-3-methylglutaryl 1173

Pharmacology of Natural Medicines

coenzyme A (HMG-CoA) reductase, and (3) sigruficantly increasing LDL-receptor dependent processing as demonstratedby increasing the incorporationof LDL into the hepatocyte and stimulating its ~atabolisrn.6,~ Policosanol not only effectively decreases serum cholesterol levels but also reduces the cholesterol content in different tissues, such as liver, heart, and fatty tissue? The cholesterol-lowering effects of policosanol are persistent, and it does not lose its effect over time. Policosanol diminishes platelet aggregation by altering prostaglandin synthesis. Specifically, policosanol lowers sem levels of the proaggregatory thromboxane A2 and raises those of the antiaggregatory prostaglandin prostacyclin?-" Policosanol prevents and reverses atherosclerotic lesions and thrombosis.12-16 Policosanol prevents intimal thickening and smooth muscle cell proferati~n.'~J~ Policosanol is an effective antioxidant in preventing LDL 0xidation.'~2O Pharmacokinetics indicate that Policosanol is rapidly absorbed, on the basis of radioactive absorption studies in experimental animals (rats, rabbits, and monkeys) and humans. Peak levels have been achieved from 30 to 120 minutes after treatment in different animal species and humans. Radioactivity is distributed mainly in the liver, but radioactivity levels in the systemic circulation are low. This effect is an advantage for a cholesterol-lowering agent because the liver is the main organ for synthesis and regulation of cholesterol metabolism. Excretion studies in animals and human healthy volunteers have demonstrated that feces is the main route for radioactivity excretion after oral administration; urinary excretion is not relevant.

CLINICAL APPLICATIONS The primary application of policosanol is as a cholesterollowering agent. However, it also exhibits antiplatelet

effects and has shown clinical usefulness in angina and intermittent claudication.

Cholesterol Lowering Exceptional clinical documentation demonstrates the efficacy, safety, and tolerability of policosanol in patients with type I1 hypercholesterolemia and in patients with secondary hypercholesterolemia associated with diabetes mellitus or nephrotic syndrome.3J1-26 This agent works to lower cholesterol levels by several mechanisms. It inhibits cholesterol manufacture but does so before the level of HMG-CoA reductase. In addition, policosanol affects LDL-C metabolism. Specifically, policosanol increases LDL receptor processing. It exerts this effect by increasing the binding of LDL to its receptor, improving the transport of LDL into the liver cell, and significantly enhancing the breakdown of LDL-C. In addition to lowering LDL, policosanol has also been shown to increase HDL, to protect against free radical damage to LDL-C, and to inhibit excessive platelet aggregation. All together, policosanol exerts many pharmacologic actions of benefit in the prevention and treatment of atherosclerosis. The clinical research into this agent included shortand long-term, randomized, placebo-controlled studies as well as studies comparing it with statins (lovastatin, pravastatin, and simvastatin), fibrates (bezafibrate and gemfibrozil), acipimox, and probucol that have involved nearly 3000 subjects. In these studies, policosanol in dosages ranging from 5 to 20 mg/day has demonstrated significant improvements in LDL-C, total cholesterol, HDL-C, and the ratios of total cholesterol to HDL-C and LDL-C to HDL-C. Policosanol produces cholesterol-lowering effects within the first 6 to 8 weeks of use. At doses of 10 to 20 mg per day, policosanol lowers total cholesterol by 17%to 21% and LDL-C by 21% to 29%and raises HDL-C by 8% to 15%.3 The combined LDL reduction and HDL increase can produce dramatic improvements in the LDL/HDL ratio. Although the effects are somewhat dose-dependent (Figure 116-1),27a 40-mg dose has no

Figure 116-1 The lipid-lowering effects of policosanol are dosedependent percent changes compared to placebo in 8 weeks treatment periods). (Data from Pons P, Rodriguez M. Robaina C, et al. Int J Clin Pharmacol Res 1994;14:27-33.)

Policosanol advantage over a 20-mg dose according to the results of a double-blind study?* These improvements in lipid profiles compare quite favorably to results observed with statin drugs. From comparative studies it can be concluded that 10 mg of policosanol is equivalent in efficacy to 20 mg lovastatin, 10 mg pravastatin, or 10 mg simvastatin. Although these drugs have well-known side effects, policosanol is apparently safe. It has not been shown to produce any adverse drug interaction, and it can be used in diabetic patients, elderly patients, and even patients with impaired liver function or severe liver damage. In addition to its effects on cholesterol levels, policosanol also exerts additional positive effects in atherosclerosis. It prevents excessive platelet aggregation without affecting coagulation, prevents smooth muscle cell proliferation into the intima of the artery, and exerts good antioxidant effects in preventing LDL oxidation (Figure l16-2).29

Double-Blind Comparative Studies Policosanol has been compared with statin drugs (lovastatin, simvastatin, and pravastatin), fibrates (gemfibrozil), acipimox, and probucol in randomized, doubleblind, short-term clinical trials conducted in patients with type I1 hypercholesterolemia.

Versus Lovastatin In two studies, policosanol administered for 8 weeks at 10 mg/day has shown an efficacy similar to that of lovastatin administered at 20 mg/day.3031 In the first study, 36 patients were randomly assigned to receive either policosanol(10mg/day) or lovastatin (20 mg/day) tablets for 8 weeks. Policosanol significantly lowered serum LDL by 29.9%, total cholesterol by 21.1, triglycerides by 13.6%,and the LDL/HDL ratio by 36.7Y0 and raised HDL by 12.5%.In contrast, lovastatin significantly lowered LDL by 25%, total cholesterol by l8%, triglycerides by 10.9%,and the LDL/HDL ratio by 30.4% and raised HDL by 8.3%.Policosanol, but not lovastatin, significantly lengthened the lag time (20.9%) of CU+~-

induced LDL peroxidation and increased total plasma antioxidant activity by 24.2%. These results clearly demonstrate that policosanol (10 mg/day) was slightly more effective than lovastatin (20 mg/day). Another advantage for policosanol is that it has no hepatotoxic effect. Lovastatin sigruficantly, but moderately, raised serum transaminase and creatine phosphokinase values but policosanol did not. Other side effects were also more common in lovastatin-treated patients. In the second study, policosanol was compared with lovastatin in patients with moderately severe intermittent claudication. Twenty-eight patients were randomly assigned to receive either policosanol10 mg or lovastatin 20 mg tablets once daily. Walking distances on a treadmill (constant speed 3.2 km/hr, slope 10 degrees, temperature 25" C) were assessed before and after 20 weeks of treatment. In comparison with baseline values, policosanol sigruficantly increased the initial claudication distance from 160.39 m to 211.31 m (+33.7"/0) and the absolute claudication distance from 236.39 m to 288.09 m (+24.3%).In contrast, there was no change in the group receiving the lovastatin. In this study, policosanol sigruficantly lowered total cholesterol and LDL levels by 17.5% and 31.0%, respectively, and also increased HDL levels by 31.5%. Lovastatin reduced total cholesterol 18.0%, LDL 22.6%,and triglycerides 9.8%;no effect was seen on HDL. In addition, policosanol, but not lovastatin, moderately but siphcantly reduced fibrinogen levels. Versus Atomastatin In a single-blind, parallel-group study conducted in older patients (60-80 years) with type I1 hypercholesterolaemia after 4 weeks of a cholesterol-lowering diet, 75 patients were randomly assigned to receive either policosanol or atorvastatin, 10-mg tablets taken once daily with the evening meal for 8 ~ e e k s . 3 After ~ 8 weeks, policosanol had lowered total cholesterol and LDL levels by 16.4% and 23.1%, respectively, whereas atorvastatin reduced them by 22.6% and 29.8%, respectively. However, policosanol, but not atorvastatin, significantly increased serum HDL-C levels by 5.3%. Policosanol was better

Figure 116-2 The efficacy of 10 mg of policosanoldaily is maintained in long-term therapy (comparisonvs placebo).(Data from Canetti M, Morera M, Mas R. et al. Int J Clin Pharmacol Res 1995;15:159-165.)

Pharmacology of Natural Medicines tolerated than atorvastatin, as revealed by patient withdrawal analysis and overall frequency of adverse events.

Versus Pravastatin Policosanol administered at 10 mg/day was compared with the same dosage of pravastatin for 8 weeks.33The policosanol group demonstrated greater changes in LDL-C and HDL-C than the pravastatin group. Side effects were more common in the pravastatin group. Although pravastatin signhcantly increased the serum levels of alanine and aspartate aminotransferases (ALT and AST, respectively), policosanol exhibited no hepatotoxicity (Figure 116-3). Versus Simvastatin Policosanol and simvastatin were found to be equally effective at dosages of 10 mg/day for 8 weeks in In patients patients with type II hypercholester~lernia.~~~ with type II hypercholesterolemia and concomitant noninsdindependent diabetes mellitus (NIDDM), policosanol, but not simvastatin, significantly raised HDL-C levels.%As with the other agents, more adverse experiences were and have been reported in simvastatin-treated patients than in policosanol-treated patients. Versus Fibrates Different studieshave compared the effects of policosanol and fibrates, such as gemfibrozil and bezafibrate.sB The results have shown that policosanol produces slightly higher reductions of serum total cholesterol, LDL-C, apolipoprotein B (ApoB), and the atherogenic ratios of cholesterol to HDL-C and LDL-C to HDL-C, whereas the fibrates have reduced triglycerides more effectively. The two agents had similar results in raising HDL-C levels. However, as with the statin drugs, fibrates but not policosanol have increased serum transaminase levels, and the adverse experiences reported by fibrate-treated patients have been more common than those reported by policosanol-treated patients. Versus Acipimox A comparative double-blind clinical trial of policosanol versus acipimox for 8 weeks in patients with type Il

hypercholesterolemia has shown that policosanol is more effective than acipimox in reducing LDL-C and total chole~terol.~~ In addition, serum lipoprotein(a) (Lp(a))levels were significantly reduced by policosanol treatment in both the whole study population (32.6% reduction) and the stratum showing initial high Lp(a) levels (>30 mg/dl) (57.4%reduction). Lp(a) is a plasma lipoprotein that in structure and composition closely resembles LDL, but with an additional molecule of an adhesive protein called apolipoprotein(a).Elevated plasma levels of Lp(a)are an independent risk factor for coronary heart disease, particularly in patients with elevations of LDL-C. In fact, a high level of Lp(a) has been shown to carry a ten times greater risk for heart disease than an LDL-C elevation. That is because LDL on its own lacks the adhesive apolipoprotein(a).As a result, LDL does not easily stick to the walls of the artery. Levels of Lp(a) below 20 mg/dl are associated with a low risk for heart disease; levels between 20 and 40 mg/dl with a moderate risk; and levels exceeding 40 mg/dl with an extremely high risk.

Versus Probucol A comparative study of policosanol (10 mg/day) and probucol (1000 mg/day) for 8 weeks in patients with type I1 hypercholesterolemia showed that policosanol was more effective in reducing LDL-C and total cholesterol than probucol.40Both drugs were safe and well tolerated (Figure 116-4).

Diabetes Policosanol administered to patients with NIDDM and type II hypercholesterolemia sigruficantlylowered LDL-C, serum total cholesterol, and atherogenic ratios while raising HDL-C levels. In addition, policosanol does not impair glycemic control in diabetic patients, as assessed through the evaluation of its effects on blood glucose and glycosylated hemoglobin (HgbA,,) values (Table 116-1).41*a

Hypertension Policosanol has been studied specifically in patients with hypertension and hypercholesterolemia. In the first

Flgure 116-3 The efficacy of policwanol vs. pravastatin in type II hypercholesterolemia. (Data from Benitez M, Romero C. Mas R. et al. Cum Ther Res 1997;58:859-867.)

Policosanol

Figure 116-4

The efficacy of policosanol vs. probucol in type I I hypercholesterolemia. (Data from Pons P, lllnait J, Mas R, et al. Curr Ther Res 1997;58:26-35.)

study policosanol sigrulicantly reduced LDL-C (-19.1Y0), total cholesterol (-13%) and the ratios of cholesterol to HDL-C (-20%) and LDL-C to HDL-C (-24.2%) in hypertensive patients with hypercholesterolemia while significantly raising HDL-C levels (+17.1’%0)!~ After 12 months of therapy the policosanol group had significantly lower systolic pressure (-10 mm Hg), but the values in the placebo group remained unchanged. Many of the patients were also taking beta-blockers and diuretics, two classes of drugs known to adversely affect blood lipid levels. In the second study after 6 weeks of a standard step I cholesterol-lowering diet, 589 patients were randomly assigned to receive either policosanol (5 mg) or placebo tablets, to be taken once daily for 12 months.44The dosage of placebo or policosanol was doubled to 10 mg/day if total cholesterol values were higher than 6.1 mmol/L after 6 months of therapy. Policosanol significantly lowered LDL by 20.5%, total cholesterol by 15.4%, triglycerides by 11.9%, and the LDL/HDL ratio by 22.2% and raised the HDL level by 12.7%.The frequency of vascular and all-cause serious adverse events (SAEs) was lower in the policosanol recipients (2 vascular SAEs, 0.7”/,; 5 all-cause SAEs, 1.7%) than in the placebo recipients (6 vascular SAEs, 2.0%; 12 all-cause SAEs, 4.1%). Policosanol sigrulicantly decreased systolic blood pressure to 10 mmHg lower than baseline and placebo values, which could be an additional advantage in this population at high risk of coronary events.

Elderly Patients

Treatment

Baseline

Total Cholesterol (mmoUL) Policosanol 7.51

12 weeks

Percent change

5.35

-28.9

Placebo LDL-C (mmoUL) Policosanol

7.94

8.01

+0.4

5.27

3.05

-44.4

Placebo HDL-C (mmolk) Policosanol

5.32

5.56

+3.4 +23.5

1.47

1.58

Placebo 1.51 Triglycerides (mmoVL) Policosanol 2.06

1.52

+0.7

1.96

-2.4

Placebo 2.45 Total Cholesterol to HDL-C Policosanol 5.88

2.1 1

+6.5

Placebo LDL-C to HDL-C Policosanol

5.72

6.03

4.25

2.01

-51.6

Placebo

3.99

4.16

+2.9

Modified from Torres 0, Agramonte 18~393-397.

-38.3

3.52

AJ, Illnail J.

+3.8

et al. Diabetes Care 1995;

Type II Hypercholesterolemia and Disturbances of Hepatic Function

The efficacy pattern of policosanol in patients with type II Policosanol administered for short- or long-term therhypercholesterolemia and concomitant disturbances of apy in patients older than 60 years with hypercholesterolemia has been effective, safe, and well t0lerated.4~~~hepatic function is similar to that shown in hypercholesterolemic patients without impairment of liver In this population policosanol has a similar efficacy profile to that observed in younger patients. Table 116-2 function.48Policosanol reduced total cholesterol (-13.6%), LDL-C (-19.1Y0), and the LDL-C/HDL-C ratio (-25.5%) summarizes the major results obtained at months 6 and and raised HDL-C (+11.5%). In addition, policosanol 12 in a long-term study of performed in elderly patients. was shown to reduce levels of ALT and gammaOf particular importance in this population is the fact glutamyl transpeptidase (GGT) toward normal. that no drug-related adverse experiences occurred. Elderly patients are at risk for such problems because Antiplatelet Effects of impaired renal and hepatic clearance as well as a high Policosanol reduces platelet aggregation by altering coexistence of concomitant diseases and medication prostaglandin synthesis. Specifically, this agent lowers consumption.

Pharmacology of Natural Medicines

Effect of policosanol on the serum lipid profile in elderly patients with hypercholesterolemia Treatment

Baseline

Total Cholesterol (mmoVL) Policosanol 7.68

6 months

12 months

6.67

6.43

Percent change -16.4

Placebo LDL-C (mmovl) Policosanol

7.33

7.46

7.57

+0.03

5.40

4.34

4.10

Placebo HDL-C (mmoVL) Policosanol

4.99

5.22

5.24

+4.8

1.28

1.28

1.36

+5.9

Placebo

1.28

1.25

1.25

-2.4

-24.1

serum levels of the proaggregatory thromboxane A2while raising levels of the antiaggregatoryprostaglandin prostacyclin. Clinical trials in humans have shown that policosanol sigruficantlyinhibits platelet aggregation without affecting coagulation Policosanol's effects on platelet aggregation compare quite favorably with those of low-dose aspirin."B Similar to its effects in lowering cholesterol, taking 40 mg of policosanol does not increase the effect of taking 20 mg. In both healthy volunteers and patients with hypercholesterolemia, policosanol at 20 mg/day and 40 mg/day inhibited aggregation induced by a variety of agents at nearly identical levels in the two groups.51

showed considerable benefit. The study consisted of a 6-week single-blind, placebo-controlled run-in phase followed by a 2-year double-blind, randomized treatment step. Fm-six patients with intermittent claudication were randomly assigned to receive placebo or policosanol 10 mg twice daily. Walking distances on a treadmill (constant speed 3.2 km/hr, slope 10 degrees, temperature 25" C) were assessed before and after 6,12,18, and 24 months of treatment. After 6 months of therapy, policosanol significantly increased (p < 0.01) the initial claudication distance from 125.9 m to 201.1 m and the absolute claudication distance from 219.5 m to 380.7 f 50.2 m. The two variables remained unchanged in the placebo group. These effects did not wear off but improved after long-term therapy, so that final values were increases of 333.5 m for the initial claudication distance and 648.9 m for the absolute claudication distance; both sigruficantly greater (p < 0.0001) than those obtained in the placebo group, which showed values of 137.9 m for the initial claudication distance and 237.7 m for the absolute claudication distance. Policosanol, but not placebo, sigruficantly increased the ankle/arm pressure index. In addition, from month 6 to study completion, the frequency of patients reporting improvement of lower limb symptoms was greater in the policosanol group than in the placebo group. Sixteen patients withdrew from the study (12 placebo, 4 policosanol). Eight patients in the placebo group experienced a total of 10 serious adverse events, 8 of which were vascular events, compared with none in the policosanol gr0up.5~

Angina

TOXICOLOGY

Policosanol was shown to improve the clinical evolution, and exercise-electrocardiography(ECG)testing responses of patients with coronary heart disease (CHD) and myocardial ischemia,documented by exercise myocardial perfusion s~intigraphy.~~ In the double-blind study, 15 patients were treated with 5 mg of policosanol twice daily; another 15 patients were administered the same dose plus 125 mg aspirin; and a third group of 15 patients received placebo plus the same aspirin dose. They were monitored for 20 months, and results of treadmill exercise and serum lipid measurementswere compared with baseline values. Beneficial changes among the two policosanol groups and the placebo group showed an increment on functional capacity class, a decrement on rest and exercise angina, and a significant decrease in cardiac events, and in ischemic ST segment response, especially in the policosanol plus aspirin group.

Policosanol exhibits an exemplary safety profile. In all controlled studies, policosanol has exerted no negative effect on any clinical or laboratory parameter. Side effects were comparable to a placebo. In fact, the withdrawal rate for policosanol in short- and long-term clinical studies was comparable to or even lesser than that of placebo; only 0.2% policosanol-treated patients withdrew before conclusion of a study as a result of an adverse experience, compared with 0.6% of the placebo group. Comparative studies have shown the rate of dropout due to side effects of 0.9%in policosanol-treated patients compared with a 4.4% rate for those treated with other lipid-lowering drugs (e.g., statins, fibrates, probucol, and acipimox). In a large postmarketing surveillance study, the tolerability of policosanol was assessed in 27,879 patients (17,225patients for 2 years and 10,654 patients for 4 years). All of the patients had been treated for at least 1month. During the study, 86 patients (0.31%) reported adverse effects, the most common of which was weight loss. Twenty-two (0.08%) discontinued treatment because of presumed side effects.%

Intermittent Claudication Policosanol is showing promise in the treatment of intermittent claudication. In addition to the study comparing it with lovastatin already described, another study

Policosanol A single dose (1000 mg/day) as much as 50 times the maximum recommended dose (20 mg/day) administered to healthy volunteers produced no adverse reaction; hence no overdose symptoms have been detected. Animal studies show that policosanol is virtually nontoxic; the oral LDso (dosage at which 50% of the animals died) in rats, mice, rabbits, and dogs was more than 5000 mg/kg. Body weight gain, behavioral assays, and biochemical and hematologic determinations in surviving animals at the end of the test (14 days) did not reveal differences between treated and control groups. Moreover, weight organ analysis and histopathologic study did not reveal differences between gr0ups.5~S The effects of successive dosage increases of policosanol administered orally to Macaca arctoides monkeys demonstrated that even the highest dose administered (500 mg/kg) policosanol was tolerated. Similar results have been shown in oral subchronic and chronic toxicity models in rats, dogs, and monkey^?^-^^ Policosanol did not produce any adverse effects on fertility and reproduction in animal studies, nor has it exerted any mutagenic or carcinogenic Specifically, policosanol administered orally up to 1000 mg/kg during the organogenesis period did not produce embryotoxic nor teratogenic effects in rats or rabbits, and a multigenerational study did not show any toxicity. Although policosanol neither induced teratogenic effects in rats or rabbits nor affected rat fertility and reproduction, policosanol is not recommended for use in pregnant women. The reason for this restriction is that cholesterol and associated metabolic products are required for adequate fetal development. Because hypercholesterolemia and atherosclerosisare chronic diseases, the suspension of lipid-lowering therapy for 9 months cannot be considered an additional coronary risk factor. It is not known whether the product or some active metabolite

is excreted via the human milk during nursing, so policosanol therapy during lactation is also not recommended. Efficacy and safety of policosanol in children has not been well established. Thus, treatment of children with policosanol is not recommended at present.

Policosanol has demonstrated synergism with the antiplatelet properties of aspirin in experimental animal models and healthy human volunteers as well as in different experimental animal models of ischemia and thrombosis. Pretreatment with policosanol inhibited aspirin-induced gastric ulcer in experimental animals. Single or repeated doses of policosanol administered orally did not significantly affect fibrinolytic activity or bleeding time in rats. In these studies interaction between policosanol and heparin or warfarin have been ruled out.65 Antipyrine is a model drug used to investigate interaction with drugs metabolized by liver microsomal enzymes (the Pm system). Policosanol administered orally to Beagle dogs for 3 to 4 weeks did not affect antipyrine or theophylline pharmacokinetics, suggesting that it does not interact with drugs metabolizing processes involving the microsomal system. No specific clinical trials have been developed to evaluate the possible pharmacologic interactions of policosanol, but in short and long-term clinical studies, this agent has been employed simultaneously with calcium antagonists, inhibitors of angiotensin-convertingenzyme, beta-blockers, meprobamate, diuretics, nitroderivative vasodilators, nonsteroidal antiinflammatorydrugs, anxiolytics, antidepressants, neuroleptics, oral hypoglycemic agents, digoxin, warfarin, thyroid hormones, antiulcer drugs, as well as others without evidence of clinically relevant adverse interactions.

1.Castano G, Femandez L, Mas R, Illnait J, et al. Comparison of the efficacy, safety and tolerability of original policosanol versus other mixtures of higher aliphatic primary alcohols in patients with type II hypercholesterolemia. Int J Clin Pharmacol Res 2002; 255-66. 2.Carr K. Cuban biotechnology treads a lonely path. Nature 1999;398:A22-A23. 3. Gouni-Berthold I, Berthold HK. Policosanol clinical pharmacology and therapeutic significance of a new lipid-lowering agent. Am Heart J 2002;143356-365. 4. Arruzazabala ML, Carbajal D, Mas R, et al. Cholesterol-lowering effects of policosanol in rabbits. Biol Res 199427205-209. 5. Menendez R, Arruzazabala ML, Mas R, et al. Cholesterol-lowering effect of policosanol on rabbits with hypercholesterolemia induced by a wheat starch-casein diet. Br J Nutr 1997;77:923-932.

6. Menendez R, Femandez L, Del Rio A, et al. Policosanol inhibits cholesterol biosynthesis and enhances LDL processing in cultured human fibroblasts. Biol Res 1994;27199-203. 7. Menendez R, Amor AM, Gonzilez RM, et al. Effect of policosanol on the hepatic cholesterol biosynthesis of normocholesterolcmic rats. Biol Res 1996;29253-257. 8. Cruz Bustillo D, Mederos CM, Mas R, et al. Efecto hipocolesterol mico del Ateromixol (PPG) en el cerdo en ceba. Rev. CENIC Cien Biol1991;262-63. 9. Arruzazabala ML, Valdes S, Mas R, et al. Effect of policosanol succesive dose increases on platelet aggregation healthy volunteers. Pharmacol Res 1995;34:181-185. 10. Valdes S, Arruzazabala ML, Femandez L, et al. Effect of policosanol on platelet aggregation in healthy volunteers. Int J Clin Pharmacol Res 1996;1667-72.

DRUG INTERACTIONS

Pharmacology of Natural Medicines 11.Carbajal D, Arruzazabala ML, Valdes S, Mas R. Effect of policosanol on platelet aggregation and sem levels of arachidonic acid metabolites in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids 1998;58:61-64. 12. Noa M, Herrera M, Magraner J, Mas R. Effect of policosanol on isoprerdine-induced myocardial necrosis in rats. J Pharm Pharmacol 1998;46:282-285. 13.Carbajal D, Anuzazabala ML, Mas R, et al. Effects of policosanol on experimental thrombosis models. Prostaglandins Leuko Essent Fatty Acids 1994;50:249-251. 14. Arruzazabala ML, Molina V, Carbajal D, et al. Effect of policosanol on cerebral ischemia in Mongolian gerbils: role of prostacyclin and thromboxane A*. Prostaglandins Leuko Essent Fatty Acids 1993; 49:695-697. 15. Noa M, Mas R, de la Rosa MC, Magraner J. Effect of policosanol on lipofindin-induced artherosclerotic lesions in rats. J Pharm Pharmacol1995;47289-291. 16. Noa M, Mas R, Mesa R. Effect of policosanol in circulating endothelid cell in experimental models in Sprague-Dawley rats and in rabbits. J Pharm Pharmacol1997;49999-1002. 17. Noa M, Mas R, Mesa R. Effect of policosanol on intimal thickening in rabbit cuffed carotid artery. Int J Cardiol1998;67125-132. 18. Batista J, Stusser IL, Penichet M, Uguet E. Doppler-ultrasound pilot study of the effects of long-term policosanol therapy on carotidvertebral atherosclerosis. Curr Ther Res 1995;56906-914. 19. Fraga V, Menendez R, Amor AM, et al. Effect of policosanol on in vitro and in vivo rat liver microsomal lipid peroxidation. Arch Med Res 1997;28:355-360. 20. Menendez R, Mas R, Amor AM, et al. Effects of policosanol treatment on the susceptibility of low density lipoprotein (LDL) isolated from healthy volunteers to oxidative modification in vitro. Br J Clin Pharmacol2OOO;W255-262. 21. Soltero I, Fuenmayor I, Colmenares J. Ensayo doble ciego para la evalaucion del policosanol en el tratamiento de la hiperlipoproteinemia tip0 II. Arch Venezol Farmacol Terap 1993;1265-70. 22.Aneiros E, Calderon B, Mas R, et al. Effects of successive dose increases of policosanol on the lipid profile and tolerability of treatment. Curr Ther Res 1993;54:304-312. 23. Aneiros E, Calderon B, Mas R, et al. Effect of policosanol in lowering cholesterol levels in patients with type-II hypercholesterolemia. Curr Ther Res 1995;56:176-182. 24. Pons P, Rodriguez M, Mas R, et al. One-year efficacy and safety of policosanol in patients with type-II hypercholesterolemia. Curr Ther Res 1994;55:1084-1092. 25. Castano G, Mas R, Nodarse M, et al. One-year study of the efficacy and safety of policosanol (5 mg twice daily) in the treatment of type II hypercholesterolemia. Curr Ther Res 1995;56:296-304. 26. Canetti M, Morera M, Illnait J, et al. One year study on the effect of policosanol (5 mg-twice-a-day) on lipid profile in patients with type II hypercholesterolemia. Adv Ther 1995;12245-254. 27. Pons P, Rodriguez M, Robaina C, et al. Effects of successive dose increases of policosanol on lipid profile of patients with type-II hypercholesterolaemia and tolerability to treatment. Int J Clin Pharmacol Res 1994;1427-33. 28.Castano G, Mas R, Femandez L, et al. Effects of policosanol 20 versus 40 mg/day in the treatment of patients with type Il hypercholesterolemia: a &month double-blind study. Int J Clin Pharmacol Res 2001;21:43-57. 29. Canetti M, Morera M, Mas R, et al. A two year study on the efficacy and tolerability of policosanol in patients with type 11 hyperlipoproteinaemia. Int J Clin Pharmacol Res 1995;15:159-165. 30.Castano G, Menendez R, Mas R, et al. Effects of policosanol and lovastatin on lipid profile and lipid peroxidation in patients with dyslipidemia associated with type 2 diabetes mellitus. Int J Clin Pharmacol Res 2002;22:89-99.

31. Castano G, Mas R, Femandez L, et al. Effects of policosanol and lovastatin in patients with intermittent claudication: a double-blind comparative pilot study. Angiology 2003;54:25-38. 32. Castano G, Mas R, Femandez L, et al. Comparison of the efficacy and tolerability of policosanol with atorvastatin in elderly patients with type I1 hypercholesterolaemia. Drugs Aging 2003;20:153-163. 33.Benitez M, Romero C, Mas R, et al. A comparative study of policosanol vs pravastatin in patients with type-II hypercholesterolemia. Curr Ther Res 1997;58:859-867. 34.Ortensi G, Gladstein J, Vail H, Tesone PA. A comparative study of policosanol versus simvastatin in elderly patients with hypercholesterolemia. Curr Ther Res 1997;58:390-401. 35. Prat H, Roman 0,Pino E. Comparative effects of policosanol and two HMGCoA reductase inhibitors on type II hypercholesterolemia.Rev Med Chil 1999;127286-294. 36. Canetti M, Morera M, Illnait J, et al. Estudio comparativo de 10s efectos del policosanol y el gemfibrozil on pacientes con hipercolesterolemia primaria tip0 II. Rev CENIC Cien Biol1996;27&70. 37. Soltero I, Fuenmayor I, Colmenares J. Estudio comparativo doble ciego de la eficacia y tolerancia del policosanol vs. bezafibrato en pacientes con hiperlipidemia tip0 II. Arch Venezol de Farmacol Terap 1993;1271-76. 38. Pons P, Femandez L, Mas R, et al. Estudio comparativo de 10s efectos del policosanol y el bezafibrato en pacientes con hipercolesterolemia primaria tip0 II. Rev CENIC Cien Biol1996;2771-77. 39. Alcocer L, Femandez L, Campos E, Mas R. A comparative study of policosanol versus acipimox in patients with type I1 hypercholesterolemia. Int J Tissue React 1999;21:85-92. 40.Pons P, Illnait J, Mas R, et al. A comparative study of policosanol versus probucol in patients with hypercholesterolemia. Curr Ther Res 1997;58:26-35. 41. Torres 0, Agramonte AJ, Illnait J, et al. Treatment of hypercholesterolemia in NIDDM with policosanol. Diabetes Care 1995;18: 393-397. 42. Crespo N, Alvarez R, Mas R, et al. Effect of policosanol on patients with non-insulin-dependent diabetes mellitus and hypercholesterolemia: A pilot study. Curr Ther Res 1997;58:44-51. 43. Castano G, Tula L, Canetti M, et al. Effects of policosanol in hypertensive patients with type II hypercholesterolemia. Curr Ther Res 1996;57691-699. 44.Castano G, Mas R, Fernandez JC, et al. Effects of policosanol on older patients with hypertension and type 11 hypercholesterolaemia. Drugs R D 2002;3:159-172. 45. Pons P, Jimenez A, Rodriguez M, et al. Effects of policosanol in elderly hypercholesterolemic patients. Curr Ther Res 1993;53: 265-269. 46. Castano G, Canetti M, Morera M, et al. Efficacy and tolerability of policosanol in elderly patients with type-11 hypercholesterolemia: a 12 months study. Curr Ther Res 1995;56819-828. 47. Castano G, Mas R, Femandez JC, et al. Effects of policosanol in older patients with type II hypercholesterolemia and high coronary risk. J Gerontol A Biol Sci Med Sci 2001;56M186-M192. 48. Zardoya R, Tula L, Castano G, et al. Effects of policosanol on hypercholesterolemic patients with disturbances on serum biochemical indicators of hepatic function. Curr Ther Res 1996;57568-577. 49. Arruzazabala ML, Mas R, Molina V, et al. Effect of policosanol on platelet aggregation in type II hypercholesterolemic patients. Int J Xssue React 1998;20119-124. 50. Arruzazabala ML, Valdes S, Mas R, et al. Comparative study of policosanol, aspirin and the combination therapy policosanolaspirin on platelet aggregation in healthy volunteers. Pharmacol Res 1997;36:293-297. 51. Arruzazabala ML, Molina V, Mas R, et al. Antiplatelet effects of policosanol(20 and 40 mg/day) in healthy volunteers and dyslipidaemic patients. Clin Exp Pharmacol Physiol2002;29891-897.

52. Stusser R, Batista J, Padron R, et al. Long-term therapy with policosanolimproves treadmiu exercise-ECG testingperformance of coronary heart disease patients. Int J Clin Pharmacol Ther 1998;36:469473. 53. Castano G, Mas Ferreiro R, Femandez L, et al. A long-term study of policosanol in the treatment of intermittent claudication. Angiology 2001;52115-125. 54.Femandez L, Mas R, Illnait J, Femandez JC. Policosanol results of a postmarketing surveillance study of 27,879 patients. Curr Ther Res 1998595'717-7722. 55. Aleman CL, Mas R, Rod& L, et al.Toximlogia aguda del Ateromixol (PFG) en roedores. Rev CENIC Cien Bio11991;22:102-105. 56. Aleman CL, Mas R, Rodeiro I, et al. Acute, subchronic and chronic toxicology of policosanol in rats. Toxicol Letters 1992;Suppl2:248. 57. Rodriguez C, Mesa R, Mas R, et al. Study of policosanol oral chronic toxicity in male monkeys (Mucacu arcfoides). Food Chem Toxicol 1994;32565-575. 58. Mesa AR, Mas R, Noa M, et al. Toxicity of policosanol in Beagle dogs: one year study. Toxicol Lett 1994;73131-190.

59. Aleman CL, Mas R, Hernandez C, et al. A 12 months study of policosanol oral toxicity in Sprague-Dawley rats. Toxicol Lett 1994;70 77-87. 60.Aleman CL,Puig MN, Elias EC, et al. Carcinogenicityof policosanol in mice: an 18 month study. Food Chem Toxicol 199533: 573-578. 61. Aleman CL, Mas Femiro R, Noa Puig M, et al. Carcinogenicity of policosanol in Sprague Dawley rats: a 24 month study. Teratog Carcinog Mutag 1994;14239-249. 62. Rodriguez MD, Garcia H. Teratogenic and reproductive studies of policosanol in the rat and rabbit. Teratog Carcinog Mutag 1994; 14:107-113. 63. Rodriguez MD, Garcia H. Evaluation of pen- and post-natal toxicity of policosanol in rats. Teratog Carcinog Mutagen 1998;18:1-7. 64.Rodriguez MD, Sanchez M, Garcia H. Multigeneration reproduction study of policosanol in rats. Toxicol Lett 1997;90:97-106. 65.Carbajal D, Arnuazabala ML, Valdes S, Mas R Interaction policosanol-warfarin on bleeding time and thrombosis in rats. Phannacol Res 1998;38:89-91.

Prebiotics Jason A . Hawrelak, HNat (Hons 1, 1’hI)c CHAPTER CONTENTS Introduction 1183 Fructooligosaccharides 1183 Description 1183 Commercial Forms 1184 Clinical Applications 1185 Dosage 1187 Toxicity 1187

INTRODUCT10N Two main tools are available to beneficially alter the gastrointestinal tract (GIT) microflora-probiotics and prebiotics. The focus of this chapter is to review the beneficial actions and safety profile of the latter. A prebiotic is defined as “a nondigestible food ingredient that beneficially effects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the coIon.”l For a food ingredient to be classified as prebiotic, it must satisfy the following requirements: 1. Be neither digested nor absorbed in the stomach or small intestine.2 2.Act as a selective food source for one or a limited number of potentially beneficial commensal bacteria in the large intestine.2 3. Change the colonic microflora ecosystem toward a healthier composition.2 4.Induce luminal or systemic changes that improve the health of the host.3

Most emphasis at this stage has been on finding and studying food sources that are used by lactic acid-producing bacteria, a choice that is due to the health-promoting properties of these organisms? The best-known lactic acid-producing bacteria belong to the genera Lactobacillus and Bifdobac terium. Not all food ingredients that travel to the colon undigested are prebiotics. Only compounds that are selectively consumed by beneficial members of the microflora while being ignored by potentially pathogenic ones can truly be termed prebiotics. When prebiotics reach the colon, they are preferentially utilized by those organisms that have the capacity to hydrolyze their bonds.

Lactulose 1188 Commercial Forms 1188 Clinical Applications 1188 Dosage 1191 Toxicity 1191 Colonic Foods 1191

The metabolism of the prebiotic results in the increased growth and activity of the beneficial organisms, often at the expense of other components of the microflora.4 Food ingredients that make it to the colon undigested but lack the selectivity of fermentation are termed colonic foods; they are discussed in more depth at the end of this chapter. Numerous compounds have the potential to be called prebiotics. Table 117-1 lists those compounds and the type of microorganisms whose growth they p r o r n ~ t e . ~ - ~ However, the best-researched prebiotics are the fructooligosaccharides and lactulose, both of which are the focus of this chapter.

FRUCTOOLIGOSACCHARIDES Description Fructooligosaccharides (FOSs) are linear or branched chains of fructose and glucose molecule^.^ The number of fructose units contained in a compound determines the name of the FOS. Oligofructose is generally composed of between 2 and 7 units, whereas inulin is composed of up to 60.1°FOSs are found in varying percentages in foods and are present in more than 36,000 plant species, where they function primarily as storage carbohydrates.” FOSs are found in many common vegetables, including asparagus, onion, leek, garlic, artichoke, Jerusalem artichoke, and chicory root. But it is from chicory root (Cichorium intybus) that most of the commercially produced inulin and oligofructose is manufactured. Shortchain fructans, such as oligofructose, are produced from inulin through a process of partial enzymatic hydrolysis? 1183

Pharmacology of Natural Medicines Prebiotic substances and the organisms whose growth they promote Prebiotic compound

Food sources

Targeted microorganisms

Fructooligosaccharides

See TaMe 1 17-2

Bifidobacterium spp.

LaCtUlose

Ultra-heat-treated milk Unknown

Lactobacillus spp., Bifidobacterium spp.

Lactitol Beta-glucooligomers

Oats

Lactobacillus spp.

Raffinose Galactooligosaccharides

Legumes, beets Cow's milk, yoghurt; human milk

Lactobacillus spp., Bifidobacterium spp.

Xylooligosaccharides

Oats

Bifidobacterium spp.

Lactosucrose Galactosyl lactose

None Human milk

Bifidobacteriumspp.

Lactobacillus spp., Bifidobacterium spp.

Bifidobacterium spp.

Bifidobacteriumspp.

Data from references 5-8.

Commercial Forms There are two ways in which FOSs can be consumed, in supplements and in foods.

Fructooligosaccharide Supplements The most commonly employed method to p u d y and concentrate FOSs for supplement use via a hot water extraction of fresh chicory roots. This process results in inulin (a.k.a. Raftdine, a long-chain FOS) as the end product. Some manufacturers utilize enzymatic hydrolysis to produce oligofructose (a.k.a., Raftilose, a medium-chain FOS) from i n ~ . ' OOther manufacturers synthesize FOSs from sucrose by using the fungal enzyme fructosyltransferase (from Aspergdlus niger). This last process involves chemical synthesis of a new compound (called Neosugar or Actilight, a short-chain FOS) from two other natural compounds (fructose and glucose). The finished compound is similar to naturally obtained FOS, only smaller? FOSs are resistant to digestion in the upper GIT because of the beta-configuration of the bonds between the fructose units.Human digestive enzymes are specific in requiring alpha linkages; thus FOSs are classified as nondigestible oligosaccharides?

Foodstuff

Form

Asparagus

Raw Boiled

Banana

Raw Dried (raw) Raw kernels Cooked kernels

Barley Burdock

Root (raw)

Chicory

Root (raw) Roasted (as coffee) Leaves (raw)

Dandelion

Root (raw)

Garlic

Raw

Globe artichoke

Boiled

Jerusalem artichoke

Tubers (raw)

Leek

Raw

Onion

Raw Cooked

Rye Salsify

Flour (raw)

Wheat

Bran (raw) Flour (baked)

Yacon

Root (raw)

Food Sources of Fructooligosaccharides As previously mentioned, FOSs are common food ingredients. Individuals consuming the standard Western diet consume an average of 5.1 g FOSs per day.I2 However, this amount can easily be increased if foods rich in FOSs are consumed on a daily basis. Foods containing FOSS are listed in Table 117-2.12J3 Other Fos-Containing foods are honey,14beer, Chinese chives, and maple syrup.15 There is no particular advantage to the consumption of FOSs as supplements rather than in FOSrich foods. As long as the amount of FOSs consumed in a food form is similar to that used in clinical studies, it will promote

Root (raw)

Data from references 12 and 13.

g FOS per 100 g fresh weiaht

Average percentage of fresh weiaht (%)

2.0-3.0 1.4-2.0 0.3-0.7 0.9-2.0 0.5-1.O 0.1-0.2 12.0-17.0 15.2-20.5 35.747.6 12.0-15.0 7.9 9.8-16.0 2.0-6.8 16.0-20.0

2.5 1.7 0.5 1.5 0.75 0.15 14.5 17.5 41.7 13.5 7.9 12.9 4.4 18.0

3.0 1.1-7.5 0.8-5.3 0.5-1.O 4.2 1.040 1 .O-3.8 3.0-19.0

3.0 4.3 3.1 0.7 4.2 2.5 2.4 11.0

Prebiotics

identical effects, because all FOSs consumed reach the colon intact, whether ingested in whole foods or as supplements.

Clinical Applications

bifidobacteria have relatively high beta-fructosidase activity that is specific for the fructose bonds present in FOSS.~~

In Vivo Evidence of a Prebiotic Eflect In a human trial utilizing oligofructose (8 g/day over a 2-week period), Mitsuoka et all5also found a 0.9 log unit increase in bifidobacteria numbers with oligofructose consumption (p < 0.005). The trial also showed a decrease in enterobacteria numbers. Buddington et alZ reported a 0.8 log increase in bifidobacteria ( p < 0.03) using a smaller dosage level of Enhanced resistance to enteric pathogens, due to colooligofructose (4 g/day). Oligofructose was administered nization resistance provided by the increased growth of over a period of 25 days. There appeared to be no change lactic acid-producing bacterial6 in other microflora populations. Increased resistance to infections, due to the nonspeUtilizing fairly large doses of inulin, Kleeson et al’ cific stimulation of the immune systernl6 noted a decrease in Bucteroides numbers and an increase Modification of carcinogen metabolism16 in bifidobacteria levels over a 19-day trial. With 20 g/day Enhanced absorption of mineralsI6 dosage levels, bifidobacteria levels increased by 0.9 log Improved serum lipid parameters16 units, and with 40 g/day, by 1.3 log units (p < 0.05). Treatment of atopic eczema and prevention of atopy In an attempt to determine the optimal dose of development” oligofructose, in terms of maximizing bifidobacteria Increased intestinal mucin production and trophic numbers and minimizing side effects, Bouhnik et a121 effects on the colonic epithelium, secondary to the designed a trial that used five different dosage levels. The increased production of SCFAs18 oligofructose dosages used were 20 g/day, 10 g/day, 5 g/day, and 2.5 g/day, with 0 &day as the placebo. The This review focuses primarily on the ability of FOSs to duration of the trial was 7 days. The data indicated enhance bifidobacterial growth, mineral absorption, and that bifidobacteria counts did not change in subjects serum lipid parameters as well as on the possibility of receiving 0 g or 2.5 g/day of oligofructose, but that in using FOSs in the treatment and prevention of atopic those subjects ingesting 5, 10, or 20 g/day, counts were diseases. sigruficantly greater (p < 0.05) at day 8 than at baseline. Enhanced Growth of Bifidobacteria A significant correlation between the ingested dose In Vitro Evidence of a Prebiotic ESfect of oligofructose and fecal bifidobacterial counts was observed at day 8 (p < 0.01). In terms of side effects, all Gibson and Wang conducted the initial in vitro experigroups, including the placebo group, experienced mild ments on the fermentation of oligofructose and inulin. Anaerobic batch culture fermenters were inoculated abdominal symptoms such as bloating, excess flatus, borborygmi, and mild abdominal pain. In general, the with both types of FOSs and mixed fecal organisms. higher the dose of oligofructose, the more side effects The results indicated that both oligofructose and inulin experienced. The investigators concluded that 10 g/day are completely and quickly metabolized by the fecal fl~ra.’~,~~ was well-tolerated and that this dose is probably the optimal dose of oligofructose, as it leads to a significant This initial research was later followed up in order to increase in colonic bifidobacteria with minimal side ascertain which of the fecal microorganisms could utilize effects. FOSs as growth substrates. Data indicated that FOSs are efficient substrates for the majority of bifidobacteria In a study reported by Gibson et al,” both oligofrucstrains tested (except Bifidobucteriurn bifidum). In pure tose and inulin were tested to assess their effects on bificultures, many other organisms showed an ability to utidobacteria levels and the populations of other members lize FOSs as substrates, including Klebsiella pneurnoniue, of the intestinal microflora. Eight subjects participated in the 45-day trial in which they ate controlled diets. For Staphylococcus epidermis, Staphylococcus aureus, Bacteroides the first 15 days, all the subjects ate 15 g/day of sucrose. fragilis, Bacteroides ovutus, Bucteroides thetaiotaomicron, Bacteroides vulgatus, En terococcus faecalis, Enterococcus For the middle 15 days, the sucrose was substituted with faecium, Lactobacillus acidophilus, and Clostridium ~ p p . ~15 g of oligofructose. For the final 15 days, four of the participants were given 15 g/day of inulin. A marked However in mixed cultures,which mimic the real situation effect was noted in bifidobacteria numbers, which in the colon, bifidobacteria become the dominant microorganisms present, suggesting an ability to “out-compete” increased 0.7 log units with oligofructose (p < 0.01) and 0.9 log units with inulin (p < 0.001). There was also these other organisms for the available FOSs. Indeed The health benefits claimed for prebiotics stem mainly from their ability to increase numbers of beneficial organisms in the colon, to reduce numbers of potentially pathogenic microorganisms (PPMs), and to stimulate production of short-chain fatty acids (SCFAs). These health benefits are as follows:

Pharmacology of Natural Medicines ~

a sigruficant decrease in bacteroides (p < 0.01), clostridia (p < 0.05), and fusobacteria (p < 0.01) in the oligofructosefed subjects, whereas levels of gram-positive cocci decreased in the inulin-fed group (p c 0.001). Inulin administration also increased lactobacilli numbers, although not sigruficantly (p < 0.075). In both groups, bifidobacteria became the numerically predominant species in the feces (Figure 117-1).24*25

Enhanced Mineral Absorption Studies utilizing animal models have demonstrated that microfloral degradation of FOSs sigruficantly increases calcium and magnesium absorption.26-28 Human studies have also shown that FOS consumption improves calcium abs0rption.2~~~ The proposed mechanism by which mineral absorption is enhanced by FOSs is the action of protonated SCFAs. Protonated SCFAs are absorbed across the apical membrane of colonocytes by direct diffusion. Owing to the low pK, values of the SCFA in relation to the intracellular pH, the SCFA dissociates once it has entered the cell. This results in the release of a hydrogen ion. The hydrogen ion is subsequently secreted from the cell in return for a cation, which may be a magnesium or calcium ion. The hydrogen ion is then available to protonate another SCFA and enable it to diffuse into the cellz9Other mechanisms may also be involved, however, such as the decrease in colonic pH that results in greater solubility of calcium, higher colonic venous blood flow, enlarged colonic villi, and enhanced expression of

calbindin-D9k (the active calcium transport These effects are more pronounced in the colon and some are calcium-specific, explaining why calcium absorption is increased even though there is very little impact on the absorption of other minerals (e.g., iron and ~ i n c ) . ~

Lipid-Lowering Effects Animal studies have demonstrated that the consumption of FOSs lowers serum triacylglycerol and total and very-low-density lipoprotein (VLDL) cholesterol levels.3e36Human trials have produced mixed results, with one study showing improved lipid profiles after FOS consumption (specifically, higher fasting insulin levels and plasma triacylglycerol levels)34and others finding no significant effect^?^,^ The differences in results may be explained by the varying duration of treatment in these trials. The positive result was found in an 8-week-long trial, and the two trials with negative results were shorter (20 and 28 days). Thus long-term consumption of FOSs may beneficially affect dyslipidemia, although the effects appear to be fairly modest. Further trials in hyperlipidemic individuals are needed to clanfy the role of FOSs in the management of lipid disorders.

Improved Bioavailability of Phytoestrogens An interesting animal (rat) study has found that concurrent consumption of FOSs and the soy-isoflavones

Flgure 117-1 The prebiotk concept: The effects of sucrose, oligofructose and inulin on the intestinal ecosystem. Pie diagrams illustrate how the microflora can develop during the feeding of sucrose and the prebiotics oligofructose and inulin (From Gibson GR. Br J Nutr 1998;80:S209-S212. Used with permission).

Prebiotics genistein and daidzein significantly improved the bioavailability of these compounds. The relative absorption of genistein was ~ 2 0 %higher in FOS-fed rats than in controls. In addition, the presence of both phytoestrogens in serum was maintained for longer in FOSfed rats than in controls, suggesting that FOSs enhanced colonic absorption of these c0mpounds.3~ This result may be especially relevant to women who have just finished antibiotic therapy, in whom the metabolism and subsequent absorption of phytoestrogens appears to be impaired.40Bifidobacteria have been demonstrated to possess beta-glucosidase activity and FOS administration has resulted in enhanced betaglucosidase activity in animal models41 in addition to So, FOS improved phytoestrogen bioa~ailability.~~ consumption not only aids in the reestablishment of a healthy GIT microflora; its consumption also increases colonic beta-glucosidase activity, resulting in enhanced deglycosylation and, thus, increased colonic concentrations of the medicinally active aglycones. Hence, FOSs increase both the metabolism and the absorption of phytoestrogens.

Treatment of Atopic Eczema and Prevention of Atopy Development A number of studies have found an aberrant composition of the GIT microflora in infants who later experience food allergies and atopic More specifically, the development of atopic eczema has been correlated with higher colonic concentrations of Bacferoides spp., Clostridiu spp., and E. coli and a decreased concentration of bifidobacteria. This change in microbial composition is theorized to deprive the developing immune system from counter-regulatorysignals against responses mediated by helper type 2 T (Th2) cells and, hence, to promote Th2-type immunity?5 Infantile atopic eczema is characterized by a Th2-dominated immune response as well as excessive intestinal inflammation and aberrant macromolecular absorption across the intestinal mucosa.These latter characteristics may also be caused by the dysbiotic condition. Bacteroides, clostidia and E. coli all have the potential to trigger inflammatory responses in the gut and can release toxins that can impair intestinal permeability, leading to increased exposure to potential antigens.& Supplementation with FOSs has been to demonstrated to reduce colonic concentrations of both Bacteroides and clostridia as well as to promote a bifidobacteria-dominated colonic Hence FOSs use may bring the aberrant intestinal flora back into balance, thereby improving gut barrier function. The promotion of an intestinal flora dominated by grampositive bacteria may also promote a shift towards Thl immunity via an enhanced production of interleukin-12 and interferon-y.%

Two other studies have demonstrated the ability of B$dobacteriurn spp. (Bifidobucteriurn lactis strain Bb12) to alleviate the symptoms of infantile atopic e ~ z e m a . 4 ~ 5 ~ Thus, there is the potential for FOSs to be used in the treatment of atopic eczema, because stimulation of the growth of endogenous strains of bifidobacteria may produce similar results. FOS treatment has not yet been studied but it could prove to be very effective.

Dosage Studies have shown a bifidogenic effect in dosages of 4 to 40 g/day of FOSs. The optimum dosage, in terms of side effect profile and increases in bifidobacteria concentration, is considered to be 10 g/day. The physician should start with a lower dose and slowly increase it to reduce chances of adverse GIT reactions. Dosages smaller than 3 g/day are unlikely to cause significant alterations in the GIT microecology.

Toxicity FOSs are components of many common foods. No genotoxic, carcinogenic, mutagenic, teratogenic, or toxicologic effects are associated with the ingestion of any FOS.1652 Oligofructose and inulin are officially recognized as natural food ingredients in most European countries and have a self-affirmed GRAS (generally regarded as safe) status in the United States? A 2000 published case study described an instance of anaphylaxis attributed to inulin found in vegetables and processed foods. This was later confirmed with skin-prick testing and blinded food-provocation testing.53 This allergy does appear to be extremely rare, however, considering the widespread consumption of FOScontaining foods. The only side effects noted with administration of FOSs are mild digestive symptoms, such as flatulence, borborygmi, abdominal bloating, and abdominal discomfort. However these effects are dose-dependent and occur less regularly with smaller doses. Over time, these symptoms diminish as the intestinal flora adjusts to the greater amount of substrate available." However, some individuals may continue to experience mild abdominal bloating and discomfort even with continued use. Some concerns have been put forth in the literature regarding the ability of K. pneurnoniae to utilize FOS as a growth sub~trate.%5~ FOS has indeed been shown to stimulate the growth of K. pneurnoniae in Petri dishes; however, this occurred only when Klebsiella was grown in isolation, with no other competing organisms present. In mixed-culture experiments, in which KZebsieZZa was grown in the presence of many other human GIT microorganisms, this growth stimulation did not O C C U T . ~ ~ In these situations, which more closely resemble the environment of the human GIT (where more than

Pharmacology of Natural Medicines

500 species of bacteria compete for available growth substrates)%,FOS did not stimulate the growth of Klebsiella? In addition, no human or animal experiment has ever reported the Klebsiella concentration in the GIT to rise after FOS consumption.

LACTULOSE Lactulose is a semisynthetic disaccharide composed of the monosaccharides fructose and galactose. It was first synthesized from lactose in 1929 by Montgomery and Huds0n.5~The human digestive system lacks the ability to break down lactulose into its component hexose and pentose moieties. Hence, lactulose is neither catabolized nor absorbed in the small intestine. Once lactulose reaches the large intestine, it is fermented by the normal intestinal microflora. Fermentation is the process through which the normal intestinal microflora catabolizes carbohydrates in order to obtain energy for growth and maintenance of cellular functions. The end products of lactulose fermentation include SCFAs, lactic acid, and the gases hydrogen and carbon dioxide.% In vitro experiments have demonstrated that overall SCFA production is increased twofold to threefold by the addition of lactulose, and acetate synthesis fourfold to si~fold.5~*~ Within the large intestine, these SCFAs are avidly absorbed by colonocytes and used as a source of energy, either locally or systemically. The production of SCFAs also results in the acidification of the colonic contents.% Brown et a161have demonstrated that a daily dose of 30 to 40 g of lactulose reduces the pH of the proximal colon from 6.0 to 4.85.

Commercial Forms Lactulose is available in two forms, syrup and crystalline powder. Lactulose syrup generally contains between 50% and 67Y0 ladulose (in addition to some lactose and galactose), whereas the crystalline powder is composed of 99% lactulose. The only food source of lactulose thus far identified is ultra-heat-treated milk, although lactulose is present only in insignificant amounts in this substance?

Clinical Applications Lactulose has a wide variety of clinical applications, including: Promoting growth of lactobacilli and bifidobacteria Decreasing growth of intestinal pathogens Constipation Preventing colon cancer Liver disease Endotoxemia Preventing urinary tract infections

Promoting Growth of Lactobacilli and Bifidobacteria In Vitro Evidence of a Prebiotic Elypect Lactulose can be fermented by only a limited number of intestinal microorganisms. These microorganisms are Lactobacillus spp., Bifidobacterium spp., and Enterococcus spp. Studies have found that these three types of microorganisms readily metabolize lactulose, producing mainly lactic and acetic acids as end products. In these same experiments, E. coli, Proteus spp., Salmonella spp., and Shigella spp. were unable to utilize lactulose as a growth substrate.62 In vitro experiments conducted by Kontula et alG demonstrated the growth of some species of lactic acid-producing bacteria on lactulose. Lactobacillus species acidophilus, rhumnosus, and lactis ssp lactis, Enterococcus species faecalis and hirae, and various Streptococcus species were shown to be able to utilize lactulose as a growth substrate. In another in vitro study, It0 et alM found that the addition of lactulose to fecal samples resulted in a sigruficant alteration in the fecal microbial population. The growth of Clostridium dificicile, Bacteroides spp., Enterobacteriaceae, and Bifidobacterium spp. was significantly suppressed in the lactulose samples compared with controls, and lactobacilli became the dominant component of the fecal flora. The suppressed growth of the former organisms appears to be caused by the decrease in fecal pH caused by the metabolism of lactulose. The end products of ladulose metabolism-lactic acid and SCFAs-raise the hydrogen ion concentration in the intestinal lumen and hence lower the fecal pH. This decrease in pH appears to inhibit the metabolism and growth of various intestinal microorganisms, including the PPMs C. dificile and Bacteroides spp.@ The suppressive effect of lactulose on the growth of Bifidobacteriurn spp. in this last experiment appears to conflict with earlier data. However, the investigators believe that this inconsistency can be explained by the environmental pH in the fecal incubation system used in the study. Brown et a16 have reported that the pH in the proximal colon drops to a maximum of 4.85 after lactulose administration.61In the It0 in vitro study, the pH was measured at below 4.0.Vince et a16 have previously reported the growth of Bifidobucterium spp. to be suppressed when such acidic conditions develop. Thus this effect would not occur in vivo, where the pH is more alkaline. In Vivo Evidence of a Prebiotic Eflect In one of the original studies utilizing lactulose to change the fecal flora, MacGillivray et a1%assessed the effects of lactulose feeding on infants. All infants were formula fed and younger than 4 months old. After a feeding period of 2 days, the lactulose-containing formula

Prebiotics produced a preponderance of Lactobacillus bifidus (now known as B. bifidum) in the stools of 88% of the infants. In 66% of the infants, B. bifidum dominated the fecal flora at concentrationsgreater than 90%. None of these infants had a bifidobacteria-dominated flora at baseline. Terada et aF7reported that 3 &day of lactulose taken over a 2-week period altered intestinal microflora and fecal bacterial metabolism in adults. The study was conducted in 8 healthy volunteers. During the intake of lactulose, the number of bifidobacteria increased significantly (p < 0.001), as did the lactobacilli population (p < 0.05), whereas the number of Bacteroidaceae and clostridia decreased (p < 0.05) compared with baseline values. Bifidobacteria became the numerically dominant microorganism in the fecal flora after 14 days of lactulose administration. The fecal metabolites skatol, indole, and phenols were also significantly reduced with lactulose intake ( p < 0.05). Fecal betaglucuronidase, azoreductase, and nitroreductase activities also decreased significantly (p < 0.05) after 14 days of treatment. These latter results indicate reduced metabolism of putrefactive (protein-fermenting) organisms of the microflora. The mean fecal pH also dropped from 7.0 to 6.4. Ballongue et a P conducted an in vivo study to assess the effects of lactulose on the intestinal microbial ecosystem. In a double-blind, randomized, placebo-controlled trial, they measured the effects of a daily dose of 20 g lactulose on the gastrointestinal microbiota. After 4 weeks of treatment, populations of Bucteroides, Clostridium, coliforms, and Eubucterium had decreased by 4.1, 2.3, 1.8, and 3.0 log units, respectively, and populations of Bifidobucterium, Lactobucillus, and Streptococcus had increased by 3.0, 1.9, and 1.2 log units, respectively, in comparison with placebo; all the differences were statistically sigruficant (p < 0.01). The fecal pH also fell from a baseline of 6.9 to 5.8 by the end of the treatment period (p < 0.01). Acetic acid production was increased 33%, and lactic acid production by 30% (p < 0.01) by lactulose administration.

Decreasing Growth of Potentially Pathogenic Microorganisms Research suggests that lactulose not only enhances the growth of beneficial members of the GIT microflora but also inhibits the growth of potential intestinal pathogens. Studies have demonstrated that lactulose consumption can decrease colonic concentrations of clostridia, Bucteroides spp., and coliformsM as well as eradicate carrier states involving SulrnoneIlu spp.69*70 The ability of lactulose to increase numbers of lactobacilli and bifidobacteria and to diminish numbers of gram-negative bacteria is believed to be due to two mechanisms. The first is lactulose’s ability to act directly as a food source for lactobacilliand bifidobacteria

organisms while being only weakly metabolized by gram-negative organism^.^' The second mechanism is the change in colonic pH caused by the end products of lactulose metabolism-lactic acid and SCFAs. The coupled effect of SCFA production and pH decrease has been shown to inhibit the growth of gram-negative bacteria. The diminished pH resulting from lactulose administration has been shown to raise the total concentration of the undissociated forms of SCFAS.~These lipophilic acids can penetrate the microbial cell membrane and, at the higher intracellular pH, dissociate to produce hydrogen ions. The hydrogen ions interfere with essential metabolic functions, such as substrate translocation and oxidative phosphorylation, and hence inhibit the growth of gram-negative microbes.n In vitro experimentshave also demonstrated the ability of lactulose to inhibit the growth of Cundidu ulbicuns. A continuous-flow culture was used as a model of the human GIT ecosystem. Within 24 hours after the input of 0.25% lactulose, C. ulbicuns numbers were reduced by 97%. The reduction in Cundidu numbers was believed to be caused by the increase in the growth of lactic acidproducing bacteria and the overall drop in pH.73

Constipation Lactulose is used in conventional medicine mainly for its laxative effects. It works primarily as an osmotic laxative, but the greater production of SCFAs may also play a role.58t74 Ingestion of lactulose has been found to cause statistically sigruficant rises in the frequency, weight, volume, and water content of stools and to produce stools of softer consistency compared with both baseline and placebo.”

Preventing Colon Cancer Lactulose may protect against the development of colon cancer via a number of different mechanisms, four of which are discussed here. First, lactulose administration has been found to decrease the production of secondary bile acids in the intestinal tract (secondary bile acids have been postulated to be promoters of colonic carcinogenesis). This effect is thought to be mediated by the reduction in luminal pH caused by lactulose fermentati~n.~~ Second, lactulose also has the ability to decrease the metabolism of PPMs. This action appears to be directly related to lactulose’s ability to reduce colonic pH. The low pH suppresses overall metabolism of these organisms, which can be indirectly measured by the drop in fecal enzymatic activity by the microorganisms. In an in vivo study, Ballongue et alMdemonstrated a statistically significant decrease in the specific activity of a number of bacterial enzymes that are believed to be involved in the genesis of colon cancer. Activity of azoreductase was lowered by 45%, that of 7-alpha-dehydroxylase by 40%,

Pharmacology of Natural Medicines that of beta-glucuronidaseby 38%,that of nitroreductase by 36%, and that of urease by 27% (all, p < 0.01). Facultative anaerobes like coliforms and anaerobes like Clost ridiurn and Bacteroides normally produce betaglucuronidase, 7 - d p h d & y d 1 ~ ~ and ~1n ~i~h d , uctase. The decreased activity of these enzymes correlates with the reduced numbers of Bacteroides, Clostridiurn, and colifonns found in this clinical trial after administration of lactulose. Third, lactulose appears to inhibit the formation of ammonia within the intestinal tract.n Ammonia has been shown to alter the morphology and intermediary metabolism of intestinal cells as well as to increase DNA synthesis in and reduce the lifespan of mucosal cells.78It is also considered to be more toxic to healthy mucosal cells than to transformed cells, and thus, ammonia may potentially select for neoplastic gr0wth.7~Thus, any inhibition of ammonia production should be of benefit in the prevention of colon tumorigenesis. Additionally, a randomized, clinical trial conducted by Roncucci et alm demonstrated the ability of lactulose to prevent the growth of resected colorectal polyps. Lactulose administration (20 g/day) reduced the recurrence rates of colonic polyps by 66% (p < 0.02) compared with controls.

Hepatic Encephalopathy Hepatic encephalopathy is often found as a complication of liver cirrhosis. It is considered the totality of nervous system manifestations of liver failure. Symptoms include tremors, mental confusion, memory loss, and personality changes. The exact cause of hepatic encephalopathy is not known. However, an accumulation of neurotoxins (particularly ammonia) in the cerebral circulation is commonly believed to be the main causative factor.61 A number of studies have found lactulose to be effective in the management of this condition?”@ Lactulose is believed to work via a number of different mechanisms. First, lactulose fermentation results in the production of SCFAs and a subsequent decrease in colonic pH. This causes the protonation of potentially toxic ammonia (produced via the fermentation of proteins and blood in the intestinal lumen) to produce ammonium ions, which are unable to diffuse through to the portal circulation. Hence, systemic and cerebral ammonia levels de~rease.8~ Second, lactulose administration in cirrhotic individuals results in the beneficial modification of the microflora, so that non-proteinfermenting organisms (e.g., bifidobacteria) dominate the colonic flora, thereby reducing ammonia production in the ~ o l o n . ~Third, f i ~ the low colonic pH secondary to lactulose fermentation prevents the putrefaction of amino acids, proteins, and blood within the colon, reducing the luminal production of ammonia.=

Endotoxemia Endotoxins are lipopolysaccharide constituents of the outer membranes of gram-negative bacteria. Gramnegative bacteria continuously shed components of their outer cell membranes, resulting in the release of an enormous quantity of endotoxin. Gram-negative bacteria compose a sigruficant proportion of the intestinal microflora (e.g., Bacferoides spp., Fusobacteriurn spp., and Enteroba~teriaceae)~~~~~; thus, this membrane shedding results in release of significant quantities of endotoxin into the intestinal lumen. In healthy individuals, luminal endotoxin causes minimal systemic effects. However, in individuals with a compromised intestinal barrier or suboptimal liver function, this intestinal endotoxin can have pathologic consequences?l Liehr et a192 demonstrated that lactulose possesses antiendotoxin activity. When rats were fed lactulose over a 4 or 8 days before intravenous administration of galactosamine, the liver damage that normally develops was prevented. Because galactosamine-induced liver necrosis and inflammation are mediated by systemic endotoxemia of intestinal origin, the prevention of liver inflammation and necrosis after lactulose consumption suggests an antiendotoxin effect. This effect was most likely mediated by an alteration of the intestinal microecology, which indirectly diminished the intestinal pool of endotoxin. However the researchers also suggest a direct antiendotoxin effect, because intravenous administration of lactulose also prevents galactosamineinduced hepatitis. This work was followed by a prospective, controlled trial assessing the use of lactulose in endotoxemia secondary to obstructivejaundice. Oral lactulose (30 ml/6 hours) was given to 12 patients for 3 days before surgery, and another 12 patients were used as controls. Lactulose administration sigruficantly reduced the incidence of endotoxemia in the portal blood during the operation and in the systemic blood after the operation (both, p < 0.05). Interestingly, lactulose appear to both decrease the luminal pool of endotoxin and directly prevent endotoxin absorpti0n.9~

Preventing Urinary Tract Infections Two human studies have demonstrated the efficacy of lactulose therapy in the prevention of urinary tract infections. McCutcheon and F ~ l t o nconducted ~~ a retrospective study with 45 elderly, long-term hospital patients as subjects. They found that daily lactulose therapy for 6 months (30 ml lactulose syrup per day) led to a sigruficant reduction in rate of urinary tract infections (UTIs) compared with controls (p < 0.025). Sixteen of the 17 lactulose-treated patients (94%) remained infection free over the 6 months, compared with only 16 of the 28 control subjects (57%) (p < 0.005). In addition, there were significant reductions in the number of antibiotic

Prebiotics

prescriptions ( p < 0.05) and in the number of patients receiving antibiotics ( p < 0.005) in the lactulose group.” In the second study, Mack and colleagues (cited in enrolled 75 elderly, hospitalized patients in a randomized, placebo-controlled trial. Thrty-eight patients received the placebo, and 58 lactulose therapy. Only 12% of the lactulose group experienced UTIs during the period of follow-up, compared with 32% in the control group (p < 0.01). Thus lactulose consumption demonstrates sigruiicant protection against the development of UTIs. The intestinal microflora appears to act as a reservoir for urinary tract pathogens. Microorganisms such as E . coZi, E. faecaZis, E . faecium, and K. pneumoniae are all common urinary tract pathogens, and these organisms are also commonly found in the GIT. The organisms can escape the confines of the large bowel and, in susceptible individuals, colonize the vagina, periurethral area, and distal urethra. From these areas they can ascend into the bladder. Thus, interventions that can inhibit the growth of these organisms in the GIT should result in decreased numbers organisms available to colonize the genitourinary tract.89This is likely to be the mechanism by which lactulose therapy prevents UTIs. Ingestion of lactulose acidifies the large bowel and sigruficantly increases the production of SCFA.61*68 At a low pH, these SCFAs (particularly butyrate) inhibit the growth and metabolism of enterococci and E. coZi, substantially reducing their overall populations in the large bowels9and decreasing the intestinal reservoir of urinary tract pathogens.

constipation the recommended dose is 15 to 40 g/day.75,96 For the management of liver disease, higher dosages have usually been employed (-35 g/day).%

Toxicity Therapeuticuse of lactulose is considered to be extremely safe, with adverse reactions generally being mild and few. Side effects consist of vomiting, nausea, diarrhea, and abdominal However, these reactions tend to occur only with single doses larger than 60 g, which appears to be the maximum load of lactulose that the intestinal flora is able to metabolize to SCFAs at one time. When the bacterial fermentation capacity is exceeded, osmotic diarrhea, abdominal cramping, and nausea may result. These symptoms are most likely caused by the interference with net fluid absorption in the colon owing to the osmotic effect of malabsorbed and intact sugars?* Nonetheless, flatulence, abdominal bloating, and discomfort are common symptoms at the start of lactulose therapy. Gastrointestinal symptoms diminish, however, as the colonic microflora adapts to the greater amount of fermentable substrate.97

COLONIC FOODS

Colonzcfoods are defined as ”foods entering the colon and serving as substrates for the endogenous colonic bacteria, thus indirectly providing the host with energy, metabolic substrates and essential micronutients.”85By definition, then, colonic foods escape digestion and absorption in the Dosage upper GIT to reach the colon intact. Here members of the colonic microflora ferment the foods to produce SCFAs, Doses of lactulose as low as 3 g/day have been shown to cause beneficial alterations in the intestinal mi~roflora.~’ hydrogen, methane, and carbon dioxide. Through the production of SCFAs, the ingestion of colonic foods plays However, higher doses (e.g., 10 g/bid) appear to proa pivotal role in the health of the host.74 duce more substantial changes.@For the treatment of

.*

~

Other foods that may produce beneficial changes in the intestinal microflora

Food or food-component

Type of study

Observed changes

Oat bran

In vitro

Increased growth of Lactobacillus rhamnosus, Lactobacillus plantarum, and Lactococcus lactis1O0

Rat feeding study

Increased growth of lactobacilliand bifidobacteria; decreased numbers of coliformsIo1

Carrot

Human feeding study

Increased growth of bifidobacteriaIo2

Brown rice

Human feeding study

Increased numbers of Bifidobacterium adolescentis and Enterococcus faecalis; decreased counts of bacteroides, Eubacterium aerofaciens, Escherichia coli, and Clostridium spp.Io3

Tea polyphenols

Pig feeding study

Chicken feeding study

Increased numbers of lactobacilli;decreased counts of bacteroides and lecithin-positive clostridia; decreased fecal concentrations of ammonia, phenol, cresol, and skato1104 Enhanced growth of lactobacilli; reduced bacteroides numbersIo5

Human flora-associated rat feeding study

Increased growth of lactobacilli, bifidobacteria, and staphylococci; decreased counts of enterobacteria”

Resistant starch

Pharmacology of Natural Medicines

Colonic foods lack the specificity of fermentation that prebiotics possess. Thus their ingestion promotes the growth and/or metabolic activity of a number of different bacterial species within the large bowel, including species that are potentially harmful. Colonic foods include resistant starch, plant cell wall polysaccharides (e.g.,cellulose),hemicelluloses, pectins, and gums.@ Commonly used fibers, such as slippery elm, pectin, psyllium husks, and p a r gum, should all be considered colonic foods, not prebiotics,because they are utilized by a number of different bacterial species in the bowel.

1.Roberfroid MB. Prebiotics and synbiotics: concepts and nutritional properties. Br J Nutr 1998;80:S197-S202. 2.Collins MD, Gibson GR. Probiotics, prebiotics, and synbiotics: approaches for modulating the microbial ecology of the gut. Am J Clin Nutr 1999;691052!5-1057s. 3.Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995;125:1401-1412. 4. Goldin BR, Gorbach SL. Prebiotics: A review of their effects on the intestinal flora and health benefits. Gastroenterol Int 1998;ll (SUppll):l-3. 5. Van Loo J, CummingsJ, Delzenne N, et al. F~nctionalfood properties of non-digestible oligosaccharides: a consensus report from the ENDO project (DGW AIRIIcT94-1095). Br J Nutr 1999;81:121-132. 6. Hudson MJ, Marsh PD. Carbohydrate metabolism in the colon. In Gibson GR, Macfarlane GT, eds. Human colonic bacteria: role in nutrition, physiology, and pathology. Boca Raton, W. CRC Press, 1995. 7.Teramoto F, Rokutan K, Kawakami Y, et al. Effect of 4G-beta-cgalactosylsucrose (lactosucrose) on fecal microflora in patients with chronic inflammatory bowel disease. J Gastroenterol1996;31:33-39. 8. Teuri U, Korpela R. Galacto-oligosaccharidesrelieve constipation in elderly people. Ann Nutr Metab 1998;42.319-327. 9.Roberfroid MB, Delzenne NM. Dietary fructans. Ann Rev Nutr 1998;18117-143. 10. Roberfroid MB, Van Loo JA, Gibson GR. The bifidogenic nature of chicory inulin and its hydrolysis products. J Nutr 1998;12811-19. 11.Nmess KR. Inulin and oligofructose: what are they? J Nutr 1999;129140251406s. 12. Moshfegh AJ, Friday JE, Goldman JF', Ahuja JK. Presence of inulin and oligofructose in the diets of Americans. J Nutr 1999;129 1407S1411S. 13. Van Loo J, Coussement P, De Leenheer L, et al. On the presence of inulin and oligofructose as natural ingredients in the Western diet. Crit Rev Food Sci Nutr 1995;35:525-552. 14. Swallow KW, Low NH.Analysis and quantitation of the carbohydrates in honey using high-performance liquid chromatography. J Agric Food Chem 1990;38:1828-1832. 15. Mitsuoka T, Hidaka H, Eida T. Effect of fructooligosaccharides on intestinal microflora. Nahrung 1987;31:427-436. 16.Macfarlane GT, Cummings JH. Probiotics and prebiotics: can regulating the activities of the intestinal bacteria benefit health? BMJ 1999318:999-1003. 17. Laiho K, Ouwehand A, Salminen S, Isolauri E. Inventing probiotic functional foods for patients with allergic disease. Ann Allergy Asthma Immuno12002;89(Suppl1):75-82. 18. Latella G. Effects of SCFA on human colonocytes. Gastroenterol Int 1998;11(Suppl 1):76-79.

For example, guar gum is metabolized by Bucteroides spp. ~ is fermented by and Rurninococcus S P P . , ~pectin Bucteroides spp., Bifidobucteriurn spp., Eubucteriurn spp., and Clostridium spp.,* and psyllium husks are fermented solely by Bucteroides ~ p p . 9 ~ Some colonic foods, however, have demonstrated the ability to promote the growth of beneficial species of bacteria, although their effects are not as specific as with prebiotics. Foods and food constituents that promote the growth of beneficial bacteria are listed in Table 117-3.1m106

19. Wang X, Gibson GR. Effects of the in vitro fermentation of oligofructose and inulin by bacteria growing in the human large intestine. J Appl Bacteriol1993;75373-380. 20. Gibson GR, Wang X. Bifidogenic properties of different types of fructose containing oligosaccharides. Food Microbiol1994;11:491-498. 21. Bouhnik Y,Vahedi K, Achour L, et al. Short-chain fructmligosaccharide administration dose-dependently increases fecal bifidobacteria in healthy humans. J Nutr 1999;129113-116. 22.Buddington RK, Williams CH, Chen SC, Witherly SA. Dietary supplement of neosugar alters the fecal flora and decreases activities of some reductive enzymes in human subjects. Am J Clin Nutr 1996;63:709-716. 23. Kleessen B, Sykura B, Zunft HJ, Blaut M. Effects of inulin and lactose on fecal microflora, microbial activity, and bowel habit in elderly constipated persons. Am J Clin Nutr 1997;65:1397-1402. 24. Gibson GR, Beatty ER, Wang X, CummingsJH. Selectivestimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology 1995;108:975-982. 25. Gibson GR. Dietary modulation of the human gut microflora using prebiotics. Br J Nutr 1998;80:S209-S212. 26.Ohta A, Ohtsuki M, Baba S, et al. Calcium and magnesium absorption from the colon and rectum are increased in rats fed fructooligosaccharides.J Nutr 1995;1252417-2424. 27. Younes H, Coudray C, Bellanger J, et al. Effects of two fermentable carbohydrates(inulin and resistant starch) and their combination on calcium and magnesium balance in rats. Br J Nutr 2001;86479-485. 28.Takahara S, Morohashi T, Sano T, et al. Fructooligosaccharide consumption enhances femoral bone volume and mineral concentrations in rats. J Nutr 2O00;1301792-1795. 29.Trinidad Tp, Wolever TM, Thompson LU. Effect of acetate and propionate on calcium absorption from the rectum and distal colon of humans. Am J Clin Nutr 1996;63:574-578. 30.van den Heuvel EG, Muys T, van Dokkum W, Schaafsma G. Oligofructosestimulates calcium absorption in adolescents.Am J Clin Nutr 1999;69:544-548. 31. Griffin IJ, Davila I'M, Abrams SA. Non-digestible oligosaccharides and calcium absorption in girls with adequate calcium intakes. Br J Nutr 2002;87(Suppl2):S187-S191. 32. Scholz-AhrensKE, SchaafsmaG, van den Heuvel EG, SChreZenmeir J. Effects of prebiotics on mineral metabolism. Am J Clin Nutr 2001; 733459S-464s. 33. Coudray C, Bellanger J, Castiglia-DelavaudC, et al. Effect of soluble or partly soluble dietary fibres supplementation on absorption and balance of calcium, magnesium, iron and zinc in healthy young men. Eur J Clin Nutr 199751:375-380. 34.Jackson KG, Taylor GR, Clohessy AM, Williams CM. The effect of the daily intake of inulin on fasting lipid, insulinand glucose concentrations in middle-aged men and women. Br J Nutr 1999;8223-30.

Prebiotics 35.Kok N, Roberfroid M, Robert A, Delzenne N. Involvement of lipogenesis in the lower VLDL secretion induced by oligofructose in rats. Br J Nutr 1996;76881-890. 36. Fiordaliso M, Kok N, Desager JP, et al. Dietary oligofructose lowers triglycerides, phospholipids and cholesterol in serum and very low density lipoproteins of rats. Lipids 1995;30163-167. 37.Alles MS, de Roos NM, Bakx JC, et al. Consumption of fructooligosaccharides does not favorably affect blood glucose and serum lipid concentrations in patients with type 2 diabetes. Am J Clin Nutr 1999;69:64-69. 38. Pedersen A, Sandstrom 8, van Amelsvoort JM. The effect of ingestion of inulin on blood lipids and gastrointestinal symptoms in healthy females. Br J Nutr 1997;78:215-222. 39. Uehara M, Ohta A, Sakai K, et al. Dietary fructooligosaccharides modify intestinal bioavailability of a single dose of genistein and daidzein and affect their urinary excretion and kinetics in blood of rats. J Nutr 2001;131:787-795. 40. Kilkkinen A, Pietinen P, Klaukka T, et al. Use of oral antimicrobials decreases serum enterolactone concentration. Am J Epidemiol2002; 155:472477. 41.Rowland IR, Rumney CJ, Coutts JT, Lievense LC. Effect of Bifidobacteriurn longurn and inulin on gut bacterial metabolism and carcinogen-induced aberrant crypt foci in rats. Carcinogenesis 1998;19:281-285. 42. Ohta A, Uehara M, Sakai K, et al. A combination of dietary fructooligosaccharides and isoflavone conjugates increases femoral bone mineral density and equol production in ovariectomized mice. J Nutr 2002;132:2048-2054. 43. Bjorksten B, Sepp E, Jdge K, et al. Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol 2001;108516-520. 4.4.Kalliomaki M, Kirjavainen P, Eerola E, et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol2001;107129-134. 45. Kqavainen PV, b o l a T, Salminen SJ, Isolauri E. Aberrant composition of gut microbiota of allergic infants: a target of bifidobacterial therapy at weaning? Gut 2002;51:51-55. 46. Eigenmann PA, Calza AM. Diagnosis of IgE-mediated food allergy among Swiss children with atopic dermatitis. Pediatr Allergy Lmmunol2000;11:95-100. 47.Majamaa H, Laine S, Mettinen A. Eosinophil protein X and eosinophil cationic protein as indicators of intestinal inflammation in infants with atopic eczema and food allergy. Clin Exp Allergy 1999;29:1502-1506. 48. Van Der Velden VH, Laan MI', Baert MR, et al. Selective development of a strong Th2 cytokine profile in high-risk children who develop atopy: risk factors and regulatory role of IFN-y, IL-4and IL-10. Clin Exp Allergy 2001;31:997-1006. 49. Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology 1995;108:975-982. 50. Kujavainen PV, Apostolou E, Arvola T, et al. Characterizing the composition of intestinal microflora as a prospective treatment target in infant allergic disease. E M S Immunol Med Microbiol2001;321-7. 51. Isolauri E, b o l a T, Sutas Y, et al. Probiotics in the management of atopic eczema. Clin Exp Allergy 2O00;30:1604-1610. 52. Roberfroid MB. Chicory fructooligosaccharides and the gastrointestinal tract. Nutrition 2000;16677-679. 53. Gay-Crosier F, Schreiber G, Hauser C. Anaphylaxis from inulin in vegetables and processed food. N Engl J Med 2000;342:1372. 54. Trenev N. Probiotics: Nature's internal healers. Garden City Park, W. Avery Publishing, 1998126127. 55. Miller AL. The pathogenesis, clinical implications, and treatment of intestinal hyperpermeability. Altern Med Rev 1997;2:330-345. 56. Moore WE, Holdeman LV Human fecal flora: the normal flora of 20 Japanese-Hawaiians. Appl Microbiol 1974;27961-979.

57. Montgomery E, Hudson CS. Transformation of lactose to a new disaccharide, lactoketose. Science 1929;69:556-557. 58. Clausen MR, Mortensen PB. Lactulose, disaccharides and colonic flora. Clinical consequences. Drugs 1997;53:930-942. 59. Mortensen PB, Rasmussen HS, Holtug K. Lactulose detoxifies in vitro short-chain fatty acid production in colonic contents induced by blood implications for hepatic coma. Gastroenterology 1988; 94~750-754. 60.Mortensen PB, Rasmussen HS, Holtug K. Short-chain fatty acid production from mono- and disaccharides in a fecal incubation system: implications for colonic fermentation of dietary fiber in humans. J Nutr 1988;118321-325. 61. Brown RL, Gibson JA, Sladen GE, et al. Effects of lactulose and other laxatives on ileal and colonic pH as measured by a radiotelemetry device. Gut 1974;15:999-1004. 62. Liao W, Cui XS, Jin XY, Floren CH. Lactulose-a potential drug for the treatment of inflammatory bowel disease. Med Hypotheses 1994; 43:234-238. 63. Kontula P, Suihko ML, Von Wright A, Mattila-Sandholm T. The effect of lactose derivatives on intestinal lactic acid bacteria. J Dairy Sci 1999;82:249-256. 64.It0 Y, Moriwaki H, Muto Y, et al. Effect of lactulose on short-chain fatty acids and lactate production and on the growth of faecal flora, with special reference to Clostridiurn dzficile. J Med Microbiol 1997;46:80-84. 65. Vince A, Killingley M, Wrong OM. Effect of lactulose on ammonia production in a fecal incubation system. Gastroenterology 1978;74544-549. 66. MacGillivray PC, Finlay HVL, Binns TB. Use of lactulose to create a preponderance of lactobacilli in the intestine of bottle-fed infants. Scott Med J 1959;4182-189. 67. Terada A, Hara H, Kataoka M, Mitsuoka T. Effect of lactulose on the composition and metabolic activity of the human faecal flora. Microb Ecol Health Dis 1992;5:43-50. 68. BallongueJ, SchumannC, Quignon P. Effects of ladulose and lactitol on colonic microflora and enzymatic activity. Scand J Gastroenterol Suppl1997;222:4144. 69. Knothe H, Knapp G, Meyer M, et al. [Therapy of salmonella enteritis with special reference to lactulose] [abstract]. Infection 1980; 8(Suppl3):S294S298. 70. Hoffmann K. [Treatment of healthy salmonella carriers with lactulose beta-galactosido-fructose] [abstract]. Dtsch Med Wochensch 1975;100:1429-1431. 71. Salminen S, Salminen E. Lactulose, lactic acid bacteria, intestinal microecology and mucosal protection. Scand J Gastroenterol Suppl 1997;222:45-48. 72. Naidu AS, Bidlack WR,Clemens RA. Probiotic spectra of lactic acid bacteria (LAB). Crit Rev Food Sci Nutr 1999;39:13-126. 73. Bernhardt H, h o k e M. Mycological aspects of gastrointestinal microflora. Scand J Gastroenterol Suppl1997;222102-106. 74. Topping DL. Short-chain fatty acids produced by intestinal bacteria. Asia Pac J Clin Nutr 1996;5:15-19. 75. Bass P, Dennis S. The laxative effects of lactulose in normal and constipated subjects. J Clin Gastroenterol1981;3(Suppl 1):23-28. 76. Nagengast FM, Hectors MP, Buys WA, van Tongeren JH. Inhibition of secondary bile acid formation in the large intestine by lactulose in healthy subjects of two different age groups. Eur J Clin Invest 1988;1856-61. 77. Bird SP, Hewitt D, Ratcliffe 8, Gurr MI. Effects of lactulose and lactitol on protein digestion and metabolism in conventional and germ free animal models: relevance of the results to their use in the treatment of portosystemic encephalopathy. Gut 1990;31: 1403-1406. 78. Macfarlane GT, Gibson SA. Metabolic activities of the normal colonic flora. In Gibson SA, ed. Human health the contribution of microorganisms. London: Springer-Verlag,1994.

79. Madarlane S, Madarlane GT. Proteolysis and amino acid fermentation. In Gibson GR, Madarlane GT, eds. Human colonic bacteria: role in nutrition, physiology, and pathology. Boca Raton, n:CRC Press, 1995. 80.Roncuca L, Di Donato P, Carati L, et al. Antioxidant vitamins or lactulose for the prevention of the rrcurrrnce of colorectal adenomas. Coloredal Cancer Study Group of the University of Modena and the Health Care District 16. Dis Colon Redurn 1993;36227-234. 81. Porth C, ed. Pathophysiology: concepts of altered health states, ed 5. Philadelphia: Lippincott, 1998764-765. 82. Horsmans Y, Solbreux PM, Daenens C, et al. Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy. Aliment Pharmacol Ther 1997;11:165-170. 83. Watanabe A, Sakai T, Sat0 S, et al. Clinical efficacy of ladulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 1997;261410-1414. 84. Dhiman RK, Sawhney MS,Chawla YK, et al. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci 2OOO;451549-1552. 85.Gibson GR, Roberfroid MB. Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics. J Nutr 1995;125:1401-1412. 86. Riggio 0, Varriale M, Testore GP, et al. Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients. J Clin Gastroenterol1990;12433-436. 87. Murawaki Y, Kobayashi M, Koda M, Kawasakia H. Effects of lactulose on intestinal bacterial flora and fecal organic acids in patients with liver cirrhosis. Hepatol Res 2OOO;1756-64. 88. Mortensen PB, Holtug K, Bonnen H, Clausen MR. The degradation of amino acids, proteins, and blood to shortchain fatty acids in colon is prevented by lactulose. Gastroenterology 1990;98:353-360. 89. Tannock GW. The bowel mimflora: an important source of urinary tract pathogens. World J Urol1999;17339-344. 90.salminen S, Isolauri E, Onnela T. Gut flora in normal and disordered states. Chemotherapy 1995;41(Suppll):5-15. 91. Houdijk AF',Meijer C, Cuesta MA, et al. Perioperative anti-endotoxin strategies.Scand J Gastroenterol Suppl 1997;222:93-97. 92. Liehr H, Englisch G, Rasenack U. L a c t u l o e a drug with antiendotoxin effect. Hepatogastroenterology 1980;27356-360.

93. Pain JA, Bailey ME. Experimental and clinical study of lactulose in obstructivejaundice. Br J Surg 1986;73:775-778. 94. McCutcheon J, Fulton JD. Lowered prevalence of infection with lactulose therapy in patients in long-term hospital care. J Hosp Infect 1989;1381-86. 95. Conn HO. A clinical hepatologist's predictionsabout non-absorbed carbohydrates for the early twenty-first century. Scand J GastroenterolSuppl 1997;222:88-92. 96.Sanders JF. Lactulose syrup assessed in a double-blind study of elderly constipated patients. J Am Geriatr Soc 1978;26236-239. 97. Flourie B, Briet F, Florent C, et al. Can diarrhea induced by lactulose be reduced by prolonged ingestion of lactulose? Am J Clin Nutr 1993;58:369-375. 98. Myers AA, Leedle JAZ. Carbohydrate metabolism in the human colon. In Hentges DJ, ed. Human intestinal microflora in health and disease.New York Academic Press, 1983. 99. Bemalier A, Dore J, Durand M. Biochemistry of fermentation. In Gibson GR, Roberfroid M, eds. Colonic microbiota, nutrition and health. Dordrecht: KLuwer Academic Publishers, 1999. 100.Kontula P, Von Wright A, Mattila-Sandholm T. Oat bran P-glucoand xylo-oligosaccharides as fermentativesubstrates for lactic acid bacteria. Int J Food Microbiol1998;45:163-169. 101.Ryhanen EL. Studies on probiotic bacterial supplementationin rats fed different diets with special reference to dietary fiber. Finnish J Dajr Sci 1996;52131-136. 102.Tamura Z. Nutriology of bifidobacteria. Bifidobaderia Microflora 1983;2:3-16. 103.Benno Y, Endo K, Miyoshi H, et al. Effect of rice fiber on human fecal microflora. Microbiol Immunol1989;33435-440. 104.Hara H, Orita N, Hatano S, et al. Effect of tea polyphenols on fecal flora and fecal metabolic products of pigs. J Vet Med Sci 1995; 5745-49. 105.Terada A, Hara H, Nakajyo S, et al. Effect of supplements of tea polyphenols on the caecal flora and caecal metabolites of chicks. Microb Ecol Health Dis 1993;63-9. 106. Silvi S, Rumney CJ, Cresci A, Rowland IR. Resistant starch modifies gut microflora and microbial metabolism in human flora-associated rats inoculated with faeces from Italian and UK donors. J Appl Microbiol 1999;86:521-530.

Probiotics Jason A. Hawrelak, BNat (Hons), PhDc CHAPTER CONTENTS Introduction 1195 Description 1196 Proposed Mechanisms of Action

1196

Probiotics Characteristics 1197 Desirable Properties of Probiotics 1 197 Probiotics in Common Use 1197 Issues in Probiotic Nomenclature 1198 The Importance of Strain 1198 Commercial Forms 1199 Fermented Foods 1 199 Supplements 1200 Clinical Applications 1200 Promotion of Proper Intestinal Environment 1201 Stabilization and Recolonization of Gastrointestinal Tract Flora after Antibiotic Therapy 1201 Urinary Tract Infection 1202 Vaginal Yeast Infections and Bacterial Vaginosis 1203 Prevention of Atopic Disease 1203

Atopic Eczema 1204 Cancer 1204 Irritable Bowel Syndrome 1204 Inflammatory Bowel Disease 1205 Ulcerative Colitis 1205 Crohn’s Disease 1205 Traveler’s Diarrhea 1206 Lactose Intolerance 1206 Stimulation of Gastrointestinal Tract and Systemic Immunity 1207 Using the Right Strain

1207

Dosage 1207 Supplements 1207 Yogurts 1209 Fermented Vegetables

1209

Promoting Growth of Lactobacilli and Bifidobacteria 1209 Oligosaccharides and Disaccharides 1209 Spirulina 1209 Toxicity

1209

Drug Interactions 1209

specific supplements containing freeze-dried bacteria. The microorganisms found in these products are usually lactobacilli and bifidobacteria.4 The term probiotic is derived from the Greek and literally Humans have been consuming probiotics for many means “for life.” It was first coined in 1965by Lilley and thousands of years, and fermented foods have been, and Stillwell’ to describe substances secreted by one microstill are, of great importance to the diets of most of the organism that stimulate the growth of another. In 1974, world’s people. Microbial cultures have been used to Parkel.2 modified this definition to ”organisms and subproduce beer, wine, yogurt, tempeh, sauerkraut, olives, stances which contribute to intestinal microbial balance.” cheese, and many other fermented foods.3Thus the symA more comprehensive definition has been put forth by biotic relationship between humankind and probiotic Naidu et a1,3 that is, ”microbial dietary adjuvants that microorganisms has a long history of important nutribeneficially affect the host physiology by modulating tional and therapeutic benefits for humans. mucosal and systemic immunity,as well as improving nutritional and microbial balance in the intestinal t r a ~ t . ” ~ Currently there is renewed interest in the field of fermented foods and probiotics. This interest has been stimuIn broad terms, this last definition includes fermented lated by the explosion of research in thisarea. This chapter foods such as yogurt, sauerkraut, and kefir as well as

INTRODUCTION

1195

Pharmacology of Natural Medicines focuses on the health benefits and therapeutic uses of probiotic-containing foods and supplements.

DESCRIPTION At the tum of the century, Metchnikoff5 asserted that yogurt is the elixir of life. He theorized that putrefactive bacteria in the large intestine produce toxins that invite disease and shorten life. He believed that the eating of yogurt would cause lactobacilli to become dominant in the colon and displace the putrefactive bacteria. For years, these claims of healthful effects from fermented foods were considered unscientific folklore. However, a substantial and growing body of scientific evidence has now demonstrated that lactobacilli, bifidobacteria, and fermented foods play a significant role in human health. The genus Lactobacillus is characterized by considerable heterogeneity. Bacteria are classified as lactobacilli if they are gram-positive, nonsporing, and rod-shaped organisms that produce lactic acid as the major end product of carbohydrate fermentation. Lactobacilli appear to be fairly unique in that they have been isolated from a number of diverse environments, such as fermented vegetables and dairy foods, as well as the human gastrointestinal tract (GIT) and vagina? On the other hand, bifidobacteria are not found in natural fermentative processes, but are native to the GIT and ~ a g i n a Bifidobacteria .~ are also gram-positive, nonsporing bacteria, but they are Y-shaped instead of rod-shaped, and their major fermentative end product is acetic acid.8 Intestinal colonization by lactobacilli and bifidobacteria begins during the birthing process. Prior to birth, the GIT of the neonate is completely sterile. During delivery, the newborn is inoculated with microorganisms from the birth canal and the mother’s fecal flora as well as from organisms in the environment. In the first week, the organisms that are best suited to the intestinal environment become established. Initially there is often a predominance of Escherichia coli, enterococci, and streptococci. A diet of breast milk creates a colonic environment that favors the growth of a simple flora of bifidobacteria and a few other anaerobes. Breast milk contains many bifidogenic oligo~accharides~ as well as living bacteria. Amazingly, breast milk from healthy women can contain up to lo9 bacteria/L, including various strains of lactobacilli and bifidobacteria.lOJ In formula-fed infants the microbiota is more complex (resemblingthe adult flora), containing far fewer bifidobacteria and more Bacteroides spp., clostridia, and anaerobic streptococci. The introduction of solid food to the breast-fed infant causes major changes in the microflora. A rapid rise in the numbers of enterococci and enterobacteria is followed by increases in Bacteroides spp. anaerobic streptococci, and clostridia. As the amount of solid food increases in the diet, the bacterial

Lactobacillus Species reuteri crispatus acidophilus jensenii gasseri plantarum casei rharnnosus paracasei ruminis Bifidobacterium Species adolescentis infantis longum bifidum breve catenulaturn pseudocatenulatum angulatum ruminantium dentium Data from references 11 and 15-19.

flora of formula-fed and breast-fed infants approaches that of adu1ts.l2-l4Common species of lactobacilli and bifidobacteria found in the infant and adult human GIT are listed in Box 118-1.11J5-19

PROPOSED MECHANISMS OF ACTION The exact mechanisms by which probiotics accomplish their beneficial actions have not been well documented. However, several postulated mechanisms explain many of the favorable effects. One such mechanism is competition for adhesion sites. Many pathogenic organisms must associate with the GIT epithelium in order to colonize effectively. However, some strains of bifidobacteria and lactobacilli can adhere to the epithelium and act as “colonization barriers” by preventing pathogens from adhering to the mucosa.20 This effect has been demonstrated with Lactobacillus rhumnosus strain GG and Lactobacillus plantarurn 299v. Both of these organisms have shown the ability to inhibit attachment of E . coli to human colon cells.21 Another possible mechanism of action is the modification of the microbial flora through the synthesis of antimicrobial compounds. Many types of lactobacilli and bifidobacteria produce bacteriocins or other antimicrobial compounds. Bacferiocins are defined as ”compounds produced by bacteria that have a biologically active protein

Probiotics

Other biologically moiety and a bactericidal active compounds produced by lactic acid-producing bacteria (LAB) are hydrogen peroxide (H202),diacetyl, and short-chain fatty acids (SCFAs). The release of these compounds by probiotic organisms results in a beneficial modification of the microflora.23However, not all strains of lactobacilli or bifidobacteria produce antimicrobial compounds, and some produce compounds that are fairly nonspecific in their activity, so that beneficial bacteria as well as pathogenic organisms may be negatively affected. It has also been observed that probiotics can stimulate the immune response. This immune response may take the form of increased secretion of immunoglobulin (Ig) elevated numbers of natural killer cells, or enhanced phagocytic activity of macrophages.25Increased secretion of IgA may reduce the numbers of pathogenic organisms in the gut, thus improving the composition of the microflora.2°,26 Probiotics may also compete for nutrients that would otherwise be utilized by path0gens.2~This situation occurs with Clostridiurn dificile, a potentially pathogenic organism that depends on monosaccharides for its growth. Probiotic organisms in sufficient numbers can utilize most of the available monosaccharides, resulting in the inhibition of C . dificile.=

PROBIOTIC CHARACTERISTICS Probiotic organisms require certain characteristics to enable them to exert maximum therapeutic effects. These qualities are summarized in Table 118-1F9

Desirable Properties of Probiotics Of these characteristics of probiotics, the following are considered almost essential for a probiotic to have therapeutic effects: (1)gastric acid and bile salt stability, (2) an ability to adhere to the intestinal mucosa, and (3) an ability to colonize the intestinal tract. Another vital characteristic is the ability to produce antimicrobial compounds and directly antagonize more pathogenic organisms.3oUnfortunately, many commercially available probiotic supplements and yogurts contain organisms that do not exhibit these vital characteristics. A probiotic strain that does not exhibit these characteristics, it will be nowhere near as effective as those that do. Thus some specific strains of bacteria will be more effective probiotics than others.

Probiotics in Common Use Many different microorganisms are currently used as probiotics. Box 118-2 lists commonly used probiotic spe~ies.2~3~~~ To enhance the reader’s understanding of how bacteria are named and classified, the following summary may be helpful. Genus is the first name of a bacterium (e.g., Lactobacillus). It is somewhat general and refers to a grouping of organisms based on similarity of qualities, such as physical characteristics, metabolic needs, and metabolic end products. Species is a bacterium’s second name (e.g., acidophilus). It is a much more narrow classification based on shared common characteristics that distinguish them from other species. Strain is an even more specific classification that divides members of the

The desirable characteristics of effective probiotic organisms Probiotic characteristic

Functional benefit

Human origin

Human origin should translate to ability to survive conditions in the human gastrointestinal tract (GIT) as well as the possibility of species-specific health effects.

Gastric acid and bile salt stability

Survival through stomach and small intestine

Adherence to intestinal mucosa

Essential for immune cell modulation and competitive inhibition of pathogens

Colonization of intestinal tract

Multiplicationin the intestines suggests that daily ingestion may not be needed; immune cell modulation.

Safety in food and documented clinical safety

Adverse effects absent or minimal; accurate identification (genus, species, strain)

Production of antimicrobial compounds

Normalization of GIT flora; suppressed growth of pathogens

Antagonism against pathogenic organisms

Prevention of adhesion and toxin production by pathogens

Clinically documented and validated health effects

Clinicians can be confident of therapeutic effects; dose-response data for minimum effective dosage in different formulations is known.

Increased shelf-life and stability during processing

All of the preceding properties should be maintained during storage and processing.

Adapted from Mattila-Sandholm T, Salminen S. GastroenterologyInternational 1998;ll(Suppl 1):8-16.

Pharmacology of Natural Medicines ~~

familiaris. Within this one species is great diversity in size, shape, strength, and other physical characteristicsranging from the Irish wolfhound to the Chihuahua. A similar division occurs within species of bacteria. Lactobacilus species Bacillus Species Within each species of bacteria there is a multitude of acidophilus johnsonii coagulans strains. Some probiotic strains are resilient and strong, plantarum brevis able to survive passage through the upper GIT and rhamnosus casei Streptococcus Species paracasei lactis inhibit pathogenic bacteria, and others are weak and thermophilus fermentum delbrueckii cannot survive the upper GIT or kill pathogenic bacteria. reuteri Also important to note is that just because one strain of Enterococcus Species bacteria in a given species has a proven action does not Blffdobacterium Species faecium mean that another strain will as well, even if they are breve adolescentis closely related. Furthermore, actions found in one strain Sacchammyces Species infantis animalis of L. rhamnosus cannot be extrapolated to a strain of longum lactis cerevisiae L. acidophilus or L. plantarum. Actions and qualities are bifidum thermophihm fundamentally strain specific.39 Therefore strains of bacteria within the same species can have significantly Data from references 29,31,and 32. different actions, proper ties, and characteristics. Unfortunately, this strain specificity is not well known, leading to inaccurate extrapolations from the literature. For example, some supplement manufacturers same species into subgroups on the basis of several quote a study that utilized L. rhumnosus strain GG and properties that these bacteria have in common that distinguish them from other members of the species then say that their probiotic supplement containing a strain of L. acidophilus or another strain of L. rhamnosus (e.g.,strain LA5).33 will do the same. This is quite incorrect. Unless the feaIssues in Probiotic Nomenclature ture is proven, one cannot assume that a given strain of L. acidophilus, B. bifidum, or any other species of lactic The reader should note changes in nomenclature, some acid bacteria will survive transit through the upper recent and some fairly antiquated, so as to make better GIT, let alone colonize the intestines or have specific sense of the probiotic literature; they are as follows: therapeutic actions. The species might, but unless they are proved to have such features, it is impossible to The species Lactobacillus bulguricus is now referred to as know. Two recent studies have demonstrated this strain Lactobacillus delbrueckii ssp. bulgaricus.34 specificity. Lactobacillus bifidus (also known as "bifidus") was One trial assessed the efficacy of two strains of renamed Bifuobucterium bifidum more than 30 years L. rhamnosus in the treatment of viral gastroenteritis. One ago, but the improper nomenclature continues to be strain was L. rhamnosus strain GG (LGG), the other was widely used.% a strain found in a supplemental product (Lactophilus). Many strains of bacteria that were once classified as LGG accelerated recovery from the diarrhea, whereas Lactobacillus casei have been reclassified as strains of the closely related strain did not.40 Lactobacillus rhamnosus (e.g., L. rhamnosus GG) or Additional in vitro research using two closely related Lactobacillus paracasei (e.g., L. paracusei Shirota strain).35 strains of B. bifidum (CIDCA 537 and 5310) found that Strains of Lactobacillus sporogenes have been renamed one strain (CIDCA 5310) inhibited enterocyte invasion Bacillus coagulans (they are not true lactobacilli because by Salmonella arizonae, whereas the other had no effect!' they form spores).% The results of both of these studies demonstrate the Bacterial strains that were once classified as Lactobacillus principle of strain specificity-that is, different bacterial acidophilus (often referred to as "acidophilus") have now strains within the same species can have sigruficantly been divided into six species: L. acidophilus, Lactobacillus different actions and therapeutic effects. gusswi, Lactobacillus amylovorus, Lactobacillus gallinarum, Thus clinicians are urged to use well-researched proLactobacillus johnsonii, and Lactobacillus ~ r i s p a t u s . ~ ~ biotic strains whenever possible. By choosing wellStrains of Sacchurornyces boulardii are now definitively researched strains one can be assured of using probiotics regarded as a distinct group within the species that have documented gastric acid and bile tolerance, can Saccharomyces cermisiae.37,3a adhere to the intestinal mucosa, can temporarily colonize The Importance of Strain the intestinal tract, and have proven therapeutic actions, thus increasing the probability of achieving good clinical Strains of bacteria can be likened to different breeds of dogs. All dogs belong to the genus Canis and the species outcomes. ~

~

~~

~

Probiotics

COMMERCIAL FORMS There are two main forms in which probiotic organisms can be ingested, fermented foods and supplements. Fermented foods can be of both dairy and vegetable origin, the most commonly known of each being yogurt and sauerkraut, respectively. Probiotic supplements consist of freeze-dried (lyophilized) bacteria in powder, capsule, or tablet form. Regardless of the form in which the microorganisms are consumed, products containing probiotic organisms must provide live organisms in sufficient numbers to exert therapeutic effects in order to have clinical efficacy. Both types of fermented foods and supplements do so.

Fermented Foods Fermented Dairy-Yogurt The origin of fermented dairy products is somewhat obscure, but their consumption is believed to date back to at least 5000 BC." Sour milks have always been popular throughout Europe, Asia, and Africa as nutritious, long-lasting foodstuffs. Fermented milks were also considered medicine, ancient physicians like Hippocrates, Galen, and Avicenna advocating their use for the treatment of gastrointestinal ills.43 Early in the twentieth century, Nobel prize laureate Elie Metchnikoff popularized the idea that fermented milk products could beneficially alter the microflora of the GIT. He attributed the long life of Bulgarian peasants to their consumption of soured milk, which he believed to arrest the abnormal putrefaction of proteins within the bowel.5 Metchnikoff later researched the bacteria found in this Bulgarian milk-Bacillus bulguricus (now known as Lactobacillus delbrueckii subspecies bulguricus) and a type of cocci (now known as Streptococcus thermophil~s)!~ He used these cultures in the manufacture of a type of sour milk he launched in Paris at the beginning of the twentieth century? These same species of bacteria are still used today in the manufacture of commercial yogurts. These two bacterial species (L. delbrueckii ssp. bulguricus and S. therrnophilus) are responsible for the taste, consistency, and smell that we associate with yogurt.44It is now known, however, that these species lack the ability to survive in the human GIT. Hence, yogurt manufacturers now routinely add additional probiotic species of bacteria to yogurt in an attempt to enhance its therapeutic effects (e.g., Lactobacillus acidophilus and Bifidobacterium bifdu rn) .* The therapeutic efficacy of a specific yogurt depends substantially on the characteristics of the strains of bacteria that it contains as well as on the number of viable bacteria present at the point of consumption. A therapeutic yogurt contains bacterial strains with the desired characteristics outlined in Table 118-1, and these strains

should be in sufficient numbers to exert therapeutic effects once consumed (i.e., >lo6 bacteria/ml of each bacterial strain)?5 Recent market-basket surveys have shown that some yogurts do achieve and maintain this level of bacterial viability throughout their shelf life, and furthermore, these same brands of yogurt often use bacterial strains with the desired probiotic characteristics.% A number of studies have attested to the therapeutic efficacy and ability of yogurt and fermented milks to successfully deliver probiotic bacteria to the human GIT.47-55 Yogurt appears to act as an ideal transport medium for probiotic bacteria, because it has been shown to enhance the survival of bacteria through the upper GIT.45 In fact, one study found that 10s bacteria given in a milk-base demonstrated greater fecal recovery after oral administration than 1O1O organisms given as a freeze-dried powder. Thus sigruficantly smaller numbers of probiotic bacteria can be given in yogurt than in supplements to achieve similar numbers of viable organisms in the lower GIT.%

Fermented Vegetables-Sauerkraut and Kimchi Fermented plant foods have always been an important component of the human diet and are still common food items throughout the world, from sauerkraut in Eastern Europe to kimchi in Southeast Asia. Traditionally prepared, both of these foods contain large amounts of probiotic bacteria. Strains of L. plantarurn are involved in the h a l stages of fermentation in both kimchi and sauerkraut, and they typically reach populations of >1@ bacteria/ml by the end-stages of f e r m e n t a t i ~ n ~ and ~ . ~thus ~ are present in sufficient quantities to have therapeutic effects when consumed. Additionally, research has found that many of the L. plantarurn strains isolated from fermented foods can survive exposure to gastric acid and bile salts, thereby indicating an ability to survive transit through the upper GIT. These same strains have also been found able to adhere to intestinal epithelial cells, thus fulfilling three of the main criteria needed by desirable probiotic 0rganisms.5~Kimchi and sauerkraut can be used as therapeutic tools much like probiotic supplements and yogurts. However, the characteristics of the bacterial strains found in these fermented foods will not be known, so their therapeutic effects will not be as certain. Some strains of L. plantarurn isolated from fermented foods also use a mannose-specific mechanism to adhere to human intestinal cells. Many pathogenic bacteria and parasites (e.g., enterotoxigenic E . coli, Shigellu spp., Vibrio cholerue, Salmonella spp., and Giurdiu lurnbliu) also utilize a mannose-specific binding mechanism.60,61 Hence strains of L. plan tarurn compete directly with these microorganisms for a limited number of binding sites along the

Pharmacology of Natural Medicines

human GIT. The consumption of traditionally prepared kimchi and sauerkraut may thus play a role in the prevention and treatment of gastroenteritis caused by these pathogens.

Supplements The quality of probiotic supplements depends on two main factors, (1) the characteristics of the strains contained in the supplement and (2) adequate viability, so that sufficientnumbers of bacteria are viable at the point of consumption. Bacterial strains used in probiotic supplements should ideally demonstrate all the characteristics outlined in Table 118-1,but as a minimum should at least survive transit through the stomach and proximal small intestine. Viability at consumption depends on a number of factors, such as proper manufacturing and the "hardiness" of the strain, as well as packaging and storage of the product in the right amount of moisture and at the correct temperature. Many strains of lactobacilli and bifidobacteria do not respond well to freezedrying (lyophilization), spray drying, or conventional frozen storage, and too high a temperature during packaging or storage can dramatically reduce viability. Typically, unless the product has been shown to be stable, refrigeration is necessary during storage and ideally during transport. Some products may not have to be refrigerated until after their container has been opened, however. Some manufacturers utilize enteric coatings on their tablets and capsules to improve survival through the acidic medium of the stomach. Recent research suggests that this practice does indeed enhance survival through the upper although enteric coatings are not necessary if the strain has demonstrated satisfactory tolerance to gastric acid. A number of excellent companies provide highquality probiotic products, but it is difficult to sort through all of manufacturer's claims of superiority. Additionally, market-basket surveys have found that some supplements contain potentially pathogenic contaminantsta but the majority fails to contain the species and quantity of bacteria listed on the label.@In fact, a 1990 study concluded, "Most of the lactobacilli-containing products currently available either do not contain the Lactobacillus species advertised and/or contain other bacteria of questionable benefit."* Another study evaluated 16 commercial probiotic products for actual microbial content. Four contained L. acidophilus as stated on the label, but 11 were found to be contaminated with pathogens." Clearly, the clinicians need documentation of strain characteristics, product quality/viability, and microbiologic content of a product before prescribing it for their patients.

CLINICAL APPLICATIONS The intestinal flora plays a major role in the health of the h 0 ~ t . The l~~ beneficial ~~ effects of the intestinal flora are (1) stimulation of the immune system, (2) synthesis of vitamins (B group and K), (3)enhanced GIT motility and function, (4) improved digestion and nutrient absorption, (5)relief of gas-induced abdominal distention, (6) inhibition of pathogens (colonizationresistance), (7) metabolism of important plant compounds/drugs, and (8) the production of SCFAs and p o l y a m i n e ~ . ~Because ~ , ' ~ , ~ of the important role of lactobacilli and bifidobacteria within the human GIT microflora, and thence to human health, probiotic supplements can be used to promote overall good health. There are, however, several specific uses for probiotics (Box 118-3).432,69-n

Treatment of intestinal Disorders Constipation Lactose intolerance Prevention and treatment of gastrointestinaltract (GIT) infections Flatulence Diarrhea: infantile, antibiotic-associated,traveler's Inflammatory bowel disease Irritable bowel syndrome Intestinal hyperpermeability Other Conditions and Uses Treatment of hypercholesterolemia Prevention and treatment of vaginal infections Prevention and treatment of urinary tract infections Treatment of hepatic encephalopathy Prevention of alcohol-inducedliver disease Stimulation of gastrointestinaland systemic immunity Prevention of cancer Improvement in digestion Prevention of atopic disease Alleviation of atopic eczema Treatment of food allergies Recolonization of GIT and vagina after antibiotic use Stabilization of GIT flora Data from references 4, 32, and 69-72.

The primary areas of probiotic use discussed here are: Promotion of proper intestinal environment Stabilization and recolonization of GIT flora after antibiotic therapy For irritable bowel syndrome (IBS) For inflammatory bowel disease For traveler's diarrhea For lactose intolerance For cancer prevention For urinary tract infections

Probiotics

For vaginal yeast infections Prevention of atopic disease For atopic eczema Stimulation of gastrointestinal and systemic immunity

Promotion of Proper Intestinal Environment Lactobacilli and bifidobacteria have long been known to play important roles in the prevention of, and defense against, diseases, particularly those of the GIT and vagina. As part of the ”normal flora,” they inhibit the growth of other organisms through competition for nutrients, alteration of pH and oxygen tension to levels less favorable to pathogens, prevention of attachment of pathogens by physically covering attachment sites, and production of limiting factors such as antimicrobial Lactobacilli and bifidobacteria produce a variety of factors that inhibit or antagonize other microorganisms. These include metabolic end products, such as organic acids (lactic and acetic acid), carbon dioxide, and hydrogen peroxide, as well as other antimicrobial compounds, such as ba~teriocins.’~-~* It should be noted, however, that the ability to produce bacteriocins, hydrogen peroxide, and other antimicrobial compounds is extremely strain-dependent. Some of the antimicrobial activity of lactobacilli has been shown to be due to their production of hydrogen peroxide.78However, this reaction requires folic acid and riboflavin; if they are in short supply, H202production will be reduced. The earliest reported therapeutic uses of lactobacilli in the 1920s suggested that their proliferation in the gut was associated with a concomitant decrease in potentially harmful coliform bacteria. This effect has since However, it is believed that many of been the earlier commercial products were less reliable than those used in later published clinical trials because of inappropriate strains and problems in production, storage, and distribution to consumers?l Later research has demonstrated a possible role of probiotics in the management of both Helicobacter pylori and G. lamblia infections. Epidemiologic research has found an inverse association between fermented milk intake and peptic ulcer disease, suggesting a protective effect from lactobacilli in the Additionally, in vitro research has found that L. acidophilus DDS1, L. acidophilus NAS, L. delbrueckii ssp bulgaricus LB-51,83 L. acidophilus LB,84 and L. johnsonii La-1 can inhibit the growth of H. pylori.85 Michetti et alss followed up on the original in vitro work with L. johnsonii La-1 to assess whether such growth inhibition occurred in vivo. Twenty individuals with

documented H. pylori infection consumed 200 ml/day of L. johnsonii Supernatant.After 3 days, urea breath tests documented signrficantly decreased H . pyZori growth and activity. This decrease in activity remained for 6 weeks after administration of the probiotic.8s This promising result gave rise to a randomized, double-blind, placebo-controlled trial. Fifty-three subjects consumed either 180 ml twice daily of acidified milk (containing>lo7 L. johnsonii La-1 per ml) or placebo for 3 weeks. During the last 2 weeks, all subjects received clarithromycin (500 mg bid). After the 3-week time period, the La-1 group showed significant reductions in H. pylori density, of 34.2%in the antrum and of 39.2%in the corpus, compared with baseline ( p = 0.02 and p = 0.04, respectively), and there were no significant changes in the placebo group. Additionally, the La-1 group had a significant decrease in gastric inflammation in the antrum ( p = 0.02) and in the activity of inflammation in the antrum ( p = 0.01) and corpus ( p = 0.02), but the placebo group had no significant changes.86Thus L. johnsonii La-1 may play an adjunct role in the management of H. pylori-related gastritis and peptic ulcer disease. L. johnsonii La-1 has also been shown to inhibit the growth of G. lamblia trophozoites (the adult form of the parasite). L. johnsonii La-1 has demonstrated the ability to produce a combination of substances that inhibits growth of G. larnblia in vitro. Substances found in La-1 supernatant impaired the ability of Giardia to replicate and encyst. These products also caused dramatic alterations in the morphology of trophozoites. Thus consumption of L. johnsonii La-1 may help arrest the proliferation of Giardia and prevent encystation,consequently breaking the lifecycle of the para~ite.8~

Stabilization and Recolonization of GastrointestinalTract Flora after Antibiotic Therapy Antibiotic use is the most common and significant cause of major alterations in the normal GIT microbiota.88The potential for an antimicrobial agent to influence the gut microflora is related to its spectrum of activity, pharmacokinetics, and length of administration.’O In regard to an agent’s spectrum of activity, an antimicrobial agent that is active against both gram-positive and gram-negative organisms has a greater impact on the intestinal flora.88In terms of pharmacokinetics, the rate of intestinal absorption plays a fundamental role, but whether the drug is excreted in active form in either the bile or saliva is also important. Both of these pharmacokinetic factors determine the drug’s ultimate concentration in the intestinal lumen and, hence, the severity of the microfloral alteration.88 In general, oral antimicrobials that are well absorbed in the small intestine have minor affect on the colonic

Pharmacology of Natural Medicines flora, whereas agents that are poorly absorbed can cause sigrulicant changes. Parenteral administration of antimicrobial agents is not free of these consequences, because some agents can be secreted in the bile or saliva or from the intestinal mucosa and thus can still cause considerable alterations in the colonic flora?l The dosage of the agent as well as the length of its administration also determine the magnitude of the impact on the intestinal flora. In general, the greater the dosage and the longer its administration, the larger the effect on the microflora.gO If an antimicrobial agent does severely affect the microflora, negative repercussions on the host's health can result. These repercussions include the overgrowth of already present microorganisms, such as fungi and C. dificile,92 the establishment of new, resistant pathogenic bacteria that can colonize other areas of the a decrease in the production of SCFAs, which can lead to electrolyte imbalances and and a greater susceptibility to intestinal and genitourinary pathogens owing to the decrease in colonization re~istance.9~ Probiotic supplementation can attenuate the impact of antibiotics on the GIT environment. A number of probiotic strains have proven effective in the prevention and treatment of antibiotic-associated diarrhea, including S. cerevisiae (Hansen CBS 5926),95,96 L. rlmmnosus GG,51*97,98 and L. acidophilus LA5.99These results demonstrate the ability of probiotics to stabilize the GIT microflora during antibiotic administration. Probiotics may also produce or enhance endogenous production of SCFAs, a feature that may also explain their antidiarrheal activity during antibiotic therapy. O0 Additionally, some probiotic strains have proven efficacious in the treatment and prevention of C. dificile overgrowth after antibiotic use. C. dificile superinfection is considered the most common cause of antibioticassociated diarrhea, and severe infections can result in pseudomembranous colitis and even death. Probiotic agents such as L. rhamnosus GG101J02, L. plarzfariinz 299v,lo3 have been shown and S. cerevisiae (Hansen CBS 5926)1M,105 to play important roles in the prevention and treatment of C. dzficiZe infection. L. acidophilus LA5@JMand L. rhanznosus GG'O' and have also demonstrated anti-Cundidu activity and thus may play a role in the prevention and treatment of antibioticinduced candidal overgrowth in the GIT and vagina. Although it is commonly believed that probiotics are not effective if taken during antibiotic therapy, the research actually supports the use of probiotics during antibiotic administrati~n.~~,~~,~~J~~ Reductions of friendly bacteria and/or superinfection with antibiotic-resistant flora may be prevented by administering probiotics products during antibiotic therapy. Probiotics should, however, be taken as far away in time from the antibiotic doses as possible.

Urinary Tract Infection Lactobacilli play a significant role in the prevention of urinary tract infections (UTIs). The normal urogenital microflora is dominated by lactobacilli. Strains of L. crispatus and Lactobacillus jensenii usually predominate in this environment, and most of these strains appear to produce H202.1D9 Hydrogen peroxide plays an important microbial-balancing role in the urogenital region, and its production helps maintain a healthy lactobacillipredominant flora. Unfortunately, factors such as antibiotic and spermicide use lead to the disruption of this flora and a predisposition to UTIS.~*OJ~' Recent research has found an inverse association between vaginal E. coli colonization and the presence of H202-positive lactobacilli within the vagina. In fact, women who did not have H202-positivelactobacilli in their vaginal flora were 650% more likely to have vaginal E. coli colonization. Because E. coli colonization of the vagina appears to be the critical initial step in the pathogenesis of both acute and recurrent UTIs, reestablishing a flora dominated by H202-producinglactobacilli should help prevent UTIs.l12 A number of studies have also demonstrated the efficacy of some strains of lactobacilli in preventing UTIs. Reid et a1113conducted a placebo-controlled trial assessing the effects of lactobacillus suppositories on the recurrence of UTIs after administration of antibiotics. The suppositories contained 1.6 x lo9 colony-forming units (CFU), consisting of L. rhamnosus GR-1 and Lactobacillus ferrnenf u m B-54. Thirty-one participants applied either the placebo or lactobacilli suppositories twice weekly for 2 weeks and then once a month for 2 months. Treatment with the lactobacillus suppositories resulted in 45% fewer UTI recurrences than the placebo. In addition, no side effects or candidal superinfections occurred in the lactobacillus-treated group. The researchers theorized that more frequent administration would produce even greater re~u1ts.l~~ A study conducted by Bruce et a P 4 also investigated the activity of L. rhanznosus GR-1 and L. ferrnentum 8-54 suppositories on UTI recurrence. Ten women with a history of recurrent UTIs took part in the study. Participants administered one suppository containing more than 1.6 x lo9 freeze-dried lactobacilli each week for 12 months. Results indicated a substantial reduction in the infection rate (66.3%)with no side effects. Additional research using L. rhamnosus GR-1 and L.ferrnentum RC-14 found that oral consumption of these strains resulted in vaginal colonization within 7 days. In some cases, colonization persisted for 10 weeks after administration. Oral administration of these probiotics also resulted in an improvement in vaginal flora (as measured by the Nugent scoring system). Thus some strains of orally administered lactobacilli can survive

Probiotics

douche twice a day with a lactobacilli solution containing los live organisms per ml. However, the right strains must be used (see the important criteria previously listed for Vns). Hydrogen peroxide-producing lactobacilli are present in the majority of normal vaginas but are absent in women suffering from chronic v a g i n o ~ i s . ' ~The ~ J ~pro~ duction of H202by lactobacilli is toxic to pathogens such Not all women's vaginas are as Gardnerella v~ginalis.'~~ colonized by the right strains of lactobacilli, however. One study evaluated the lactobacilli population in 275 women in the second trimester of pregnancy by obtaining vaginal culture specimens to detect H202production status as well as the presence of pathologic organisms. Women colonized by H2O2-positivelactobacilli were less likely to have bacterial vaginosis, symptomatic candidiasis, and vaginal colonization by G. vaginalis, Bacteroides spp., Peptostreptococcus spp., Mycoplasrna horninis, Adherence to uroepithelial and vaginal cells Ureaplasma urealyticum, and viridans streptococci.132The Colonization of the vagina women who did not have any vaginal lactobacilli were Inhibition of urogenital pathogen growth and/or also more likely to have Chlamydia trachomatis. The attachment researchers also reported that most commercially availProduction of hydrogen peroxide able products contain either lactobacilli that do not If the probiotic preparation is to be orally consumed, produce H202or Lactobacillus strains derived from dairy the strains must have gastric acid and bile salt foods, which are unable to bind to vaginal epithelial stability cells. Although intravaginal application of probiotics Bacterial strains that exhibit these characteristics will be appears to be the preferred therapy for vaginal infections, more effective in the treatment and prevention of UTIs even simple consumption of appropriate yogurts appears than those that do not. Hence, selection of strains with beneficial. For example, one study of 33 patients with these characteristics is e~sential."~ recurrent Candida vaginitis found a threefold decrease in Vaginal Yeast Infections infections when the patients consumed 8 ounces/day of and Bacterial Vaginosis yogurt containing H202-producingL. acidophilus (strain LA5) for a period of 6 months. The mean number of Many strains of lactobacilli have been shown to retard infections per 6 months was 2.54 in the control group the growth of Candida albicans, the major yeast involved and 0.38 in the yogurt-treated group. Candida colonizain vaginal yeast i n f e ~ t i o n s . * ~ JClinical ~ ~ J ' ~ studies have tion occurred with a mean of 3.23 per 6 months in the suggested that the ingestion or introduction of yogurt or control group and of 0.84 per 6 months in the yogurt lactobacilli into the vagina can assist in clearing up and group. Lactobacilli concentrationsin the vagina rose as a preventing recurrent vaginal yeast infections as well as result of yogurt ingestion, suggesting that L. acidophilus bacterial vaginosis.48J20-122 LA5 colonized the The normal urogenital microflora is dominated by A later trial evaluated the capability of orally adminlactobacilli, the function of which is to maintain an environment that limits the growth of potentially pathogenic istered probiotic strains to reestablish eubiosis in women with bacterial vaginosis. Ten women with a recent microorganisms. Lactobacilli do this through the maintenance of an acidic environment (via the fermentation history of urogenital infections consumed L. rhamnosus of vaginal glycogen to lactic acid) and the production of GR-1 and L.femzmturn RC-14 in a skim milk base. Within 1 week the bacterial strains were recovered from the H202.112,123 It was previously believed that the vaginal vagina in all 10 subjects. After 14 days of treatment, six flora was dominated by strains of L. a~idophiZus'~~J~; however, research has found that L. mspatus and L. jmsenii of the subjects who had had abnormal vaginal flora at baseline were found to have normal lactobacilliare the predominant vaginal lactobacilli.lWJz6 dominated Antibiotic use has been shown to suppress the growth of vaginal lactobacilli and raise the pH of the vagina as Prevention of Atopic Disease well as increase the growth of yeast, E. coli, and other Two recent groundbreaking studies have demonstrated gram-negative b a ~ t e r i a . Reestablishment ~~~J~~ of normal the ability of probiotics to prevent the development of vaginal lactobacilli can be aided by having the woman transit through the GIT, colonize the vagina, and beneficially alter the microecology of the genitourinary tract.'15 On the other hand, Baerheim et reported that vaginal application of an unknown strain of L. rhamnosus (Gynophilus)failed to decrease the incidence of UTIs over a 6-month period compared with placebo. Interestingly, twice-weekly application of Gynophilus did not affect the periurethral lactobacilli population, suggesting that this strain was unable to adhere to and colonize the urogenital environment. Additional in vitro research demonstrated that the bacterial strain found in Gynophilus was unable to inhibit the growth of E. coli.116 Thus this research highlights the need to use bacterial strains with the specific characteristics needed for success in urogenital applications. The critical properties needed for a bacterial strain in urogenital applications are as follows:

atopic disease in infants. In a randomized, double-blind, placebo-controlled trial, either placebo or L. rhamnosus GG was administered prenatally (for the last month of pregnancy) to mothers who had at least one first-degree relative (or partner) with allergic rhinitis, asthma, or atopic eczema and then postnatally (for 6 months) to their infants. When the infants were 2 years old, the frequency of atopic eczema in the probiotic group was half that of the placebo group (relative risk [RR] 0.51; 95% confidence interval [CI] 0.32-0.84; p = 0.008).133 The second study reported similar results. In this randomized, double-blind, placebo-controlled trial, either L. rkamnosus GG or a placebo was administered to 159 mothers who were at high risk of giving birth to an atopic child, for the last month of pregnancy and then for the 3 months after birth. At the end of a 2 years, the rates of chronic relapsing atopic eczema in the children were compared in the two groups. Maternal intake of probiotics was associated with a 2/3 reduction in the prevalence of atopic eczema in comparison with placebo (RR 0.32; 95% CI 0.12-0.85; p = 0.0098). In addition, the concentration of transforming growth factor-beta2 (TGF-P2; a key immunoregulatory factor involved in the induction of oral tolerance and IgA production) was significantly greater in the breast milk of the probiotic group than that of the control group ( p = 0.018). This latter finding is highly sigruficant because hgher concentrationsof TGF-P? in breast milk and colostrum have been correlated with an infant's ability to produce specific IgA antibodies against dietary antigens and to prevent development of atopic disease during breast feeding.'%

Atopic Eczema Atopic eczema is a common, chronically relapsing skin disorder particularly prevalent in infancy and childhood. It is characterized by hypersensitivity reactions to environmental allergens. In children, the relationship between environmental allergens, such as dietary antigens, and exacerbation of symptoms is especially apparent. The pathophysiology of atopic eczema consists of excessive intestinal inflammation, aberrant macromolecular absorption across the intestinal mucosa, and an immune response dominated by type 2 helper T (Th2) cells.135-138 Probiotics have the potential to moderate all three of these underlying pathophysiologic processes. For instance, L. rkamnosiis GG has demonstrated a capacity to decrease interleukin-4production,'3ysuppress lymphocyte proliferation,'" increase intestinal IgA secretion,"" enhance allergen degradation by the intestinal mucosa,142 normalize increased intestinal permeability, and alleviate intestinal inflammation.143 All of these actions promote a shift toward type 2 helper T (Thl)cell immune responses and improve macromolecule handling in the gut. A recent clinical trial assessed the potential of Bifdobacterium lactis Bb12 and L. rkamnosus GG in the

management of infantile atopic eczema. After &weeks administration, B. lactis Bb12 reduced the SCORAD score (a measure of the extent and severity of atopic eczema symptoms) by loo%, and L. rhamnosus GG reduced the score by 9470, as compared to baseline. The improvement in symptoms in both treatment groups was significantly greater than in the control group (p = O.Ol)."

Cancer A series of population studies have suggested that the consumption of high levels of cultured milk products may reduce the risk of colon L. delbrueckii ssp. bulgaricirs strain LB-51, a strain of the primary lactobacilli used in traditional yogurt, has demonstrated potent antitumor activity.14*Feeding colostrum fermented with L. acidopkilus D D S l and milk fermented with L. acidophilus (strain Delvo Pro LA-1) has been reported to result in a reduction in tumor proliferation in animal s t ~ d i e s . ' ~ ~ , ' ~ ~ In human studies, ingestion of L. acidophilus NCFM,151 L. rlmmnosus GG,49and L. paracasei Shirota50has resulted in reduced activity of bacterial enzymes associated with the formation of cancer-causing compounds in the gut. The beneficial effects of lactobacilli against cancer appear to extend well beyond the colon. In a double-blind trial conducted in 138 patients surgically treated for bladder cancer, the patients were divided into three groups: (A) those with primary multiple tumors, (B) those with recurrent single tumors, and (C) those with recurrent multiple tumors. In each group, patients were randomly allocated to receive either the oral L. paracasei strain Shirota (LPS) or placebo. LPS showed a better effect than placebo in preventing cancer recurrences in groups A and B. However, no significant effect was noted in group C.152 Probiotic preparations are also of value in patients with cancer who were undergoing either chemotherapy or radiation therapy involving the gastrointestinal tract. In one study, 24 patients scheduled for internal and external irradiation of the pelvic area for gynecologic cancers were selected for a controlled study to test the prevention of intestinal side effects by administration of L. acidopkilus. The test group received 150 ml/day of a fermented milk product supplying them with live L. acidophilus (strain NCFB-1748) in a 6.5% lactulose substrate. Lactobacilli administration resulted in the prevention of radiotherapy-associated diarrhea.153

Irritable Bowel Syndrome Probiotics appear to have a promising role in the management of IBS. Studies and case series conducted in the 1950s and 1960s repeatedly demonstrated the beneficial effects of probiotic administration on IBS symptoms.'"" This initial research has been followed by more rigorous examination in later clinical trials. Bazzocchi et al7I performed an open study assessing the effects of a probiotic preparation on the course of IBS. They used a freeze-dried probiotic preparation called

Probiotics

VSL# 3, which contained 5 x 10” cells/g of three strains of bifidobacteria (B. longurn Y10, B. infanfis Y1, and B. breve Y8), four strains of lactobacilli (L. acidophilus, L. casei, L. delbrueckii ssp bulguricus, and L.plantarum) and one strain of Streptococcus salivarius ssp. t h o p h i l u s . Forty-two patients who satisfied the Rome I criteria for diagnosis of IBS received 3 g of the preparation per day for 1month. At the end of the trial, only 19%of the study participants still fulfilled all the criteria for IBS (p < 0.01). Fecal concentrations of bifidobacteria, lactobacilli, and S. salivarius all sigruhcantly rose from baseline values ( p < 0.01). In addition, two experimental objective measurements-intestinal contractile response and visceral response to mechanical colonic stimulationwere significantly reduced (p < 0.04).” Thus this probiotic preparation appears to improve both objective and subjective measures of IBS symptomatology. A second randomized, placebo-controlledtrial was conto investigate the effects of ducted by Noebaek et L. plantarurn 299v on IBS. The subjects were 60 patients with IBS as defined by the Rome I criteria, who were randomly divided into two groups. One group received 400 ml/day of a rose hip drink containing 5 x lo7CFU/ml of L. plantarurn 299v, and the other group received a plain rose hip drink comparable in texture, color, and taste. Administration lasted 4 weeks. No adverse effects were reported in either group. Rectal biopsies confirmed the growth of L. plantumm 299v in the intestinal mucosa of the treated group. Abdominal pain was sigruficantlyand rapidly reduced in the treated group (p < 0.01), as was flatulence (p < 0.05). At 12-month follow-up, patients who had received L. plantarurn maintained their improvement in overall GIT function compared with the placebo

Inflammatory Bowel Disease

Ulcerative Colitis Venturi et aP9 performed an open trial assessing the effects of a multiple-strain probiotic preparation (VSL# 3; for specific contents see the IBS discussion) in patients with ulcerative colitis. Twenty patients who were allergic or intolerant to 5-aminosalicylic acid (5-ASA) were treated with VSL# 3 for 12 months. Fecal concentrations of lactobacilli and bifidobacteria rose significantly from baseline values by the 20th day of treatment (p < 0.05). At the end of the 12 months, 15 of the 20 participants remained in remi~sion?~ a finding that compares favorably with rates of remission observed during long-term mesalazine therapy.*&Thus long-term administration of VSL# 3 may protect against relapse in quiescent ulcerative colitis. Rembacken et a P 7performed a randomized, doubleblind trial with 116 subjects to compare the efficacy of mesalazine and a nonpathogenic strain of E . coli (strain Nissle 1917) in the prevention of relapse of ulcerative colitis. All subjects were initially treated with an initial course of antibiotics (oral gentamicin for 7 days) and corticosteroids until remission of the active disease was induced. Fifty-nine subjects were then allocated to mesalazine treatment and 57 to E. coli administration. In the mesalazine group, 73% of subjects experienced a relapse within 12 months, whereas in the E . coli group, only 67% did so. The mean duration of remission was 206 days in the mesalazine group and 221 days in the E. coli group. Statistical analysis indicated that the two treatments were equivalent. These results suggest that daily treatment with E . coli (Nissle 1917)is as efficacious as mesalazine in maintaining remission in patients with ulcerative ~ 0 l i t i s . l ~ ~

Crohn’s Disease Intestinal dysbiosis may be one of the etiologic factors In a randomized, double-blind, placebo-controlled trial, involved in the pathogenesis of both ulcerative colitis and 20 subjects who had Crohn’s disease and were suffering Crohn’s disease. According to Campieri and Gionchetti,l= from diarrhea and moderate GI complaints (as measured “the onset of inflammation may be associated with an by the BEST Crohn’s Disease Activity Index) were imbalance in the intestinal microflora with relative pretreated with S. cereuisiue (Hansen CBS 5926) for 2 weeks dominance of ’aggressive’ bacteria and an insufficient concentration of ’protective’species.”158In support of this in combination with basic treatment (either salazosulfapyridine or 5-ASA). Treatment resulted in a significant theory, research has found that patients with ulcerative colitis have lower colonic concentrations of la~tobacilli,’~~reduction in the frequency of bowel movements have higher colonization by sulfate-reducingbacteria,lm (p < 0.01) and the BEST index ( p < 0.05) in comparison with baseline. After this initial period, participants were and may also have pathogenic strains of E . coli in greater assigned to either the placebo group or the verum (i.e., concentrations than healthy controls.*61Patients with active agent) group, and both groups took their respecCrohn’s disease have been found to have decreased tive medications for 7 weeks. At the end of the trial, parnumbers of bifidobacteria162and elevated numbers of ticipants in the verum group had a further reduction in Bacteroides spp in their feces as well as to have pathogenic strains of E . coli in greater amounts than healthy populastool frequency and BEST index, whereas in the placebo group, the two parameters returned to baseline levels. tions.161 In addition, research conducted in animal Hence, this strain of S. cerevisiue appears of benefit in the models of inflammatory bowel disease has achieved sucmanagement of Crohn’s disease and can be given concessful outcomes with administration of probiotics, and currently with orthodox treatment to improve clinical human research has also demonstrated some level of outcomes.

Pharmacology of Natural Medicines The efficacy of L. rharnnosus GG in Crohn’s disease was evaluated in a small, open study. Four children with mildly to moderately active Crohn’s disease were given L. rhumnosus GG enterocoated tablets (each tablet contained > 10’O viable bacteria) twice daily for 6 months. Clinical improvement was noted 1 week after the commencement of therapy. After 4 weeks, the Pediatric Crohn’s Disease Activity Index (PCDAI) scores were 73% lower than at baseline, an improvement that was sustained throughout the study period. Intestinal permeability improved in similar fashion (in particular, paracellular permeability). Thus L. rhamnosus GG administration appeared to improve both clinical symptoms and gut barrier function in children with Crohn’s d i s e a ~ 2 . l ~ ~ These promising results contrast sharply with the findings from a double-blind, placebo-controlled trial that assessed the efficacy of L. rhumnosus GG in preventing relapses of Crohn’s disease. Before trial commencement, all study participants underwent extensive intestinal resections to remove all diseased intestinal tissue. Fortyfive subjects were then assigned to either the placebo group or the L. rhamnosus GG group (LGG). After 12 months, clinical and endoscopic remission rates were equivalent in the two groups, suggesting that LGG had no beneficial effect in this cohort of patients.”O Interestingly, a clinical trail using mesalazine in a cohort of patients with Crohn’s disease who had just undergone surgical resection also did not demonstrate significant benefit of the medication over pla~ebo.’~’ Thus this subgroup of cases of Crohn‘s disease may be fairly nonresponsive to therapeutic intervention, which may explain why LGG administration had no significant benefits.

Traveler’s Diarrhea Probiotics are routinely recommended by nutritionally oriented doctors to their patients who travel to developing countries. However, one published report casts doubt on this practice. A randomized, double-blind, placebocontrolled trial was conducted on 282 British soldiers deployed to Belize. They received two capsules containing L. fermenturn (strain KLD), L. acidophilus (unknown strain), or a placebo daily for 3 weeks. L.fermentum KLD was a human isolate, able to adhere to intestinal cells and inhibit pathogenic bacteria, and was acid and bile tolerant; hence, it displayed many of the characteristics of a successful probiotic strain. No information was provided regarding the characteristics of the L. acidophilus strain. Each capsule contained 10” CFU of bacteria. No protection from traveler’s diarrhea was provided by either strain.In This was a surprising result, given the characteristics of L. ferrnentum KLD, indicating that in vitro antimicrobial activity against intestinal pathogens does not always translate into in vivo results. However, other research using L. rhamnosus GG demonstrated better results. Eight-hundred and twenty

Finnish travelers holidaying in two locations in Turkey completed the trial. Subjects received either L. rhamnosus GG powder (daily dose 2 x lo9 CFU) or placebo. Interestingly, subjects who traveled to one distinct location in Turkey had a modest, yet statistically significant benefit, whereas travelers to the other location did not receive significant protection. This result suggests that L. rhamnosus GG protects against the development of traveler’s diarrhea in some locations but will have little effect in others.’73 Strains of L. plan tarum may have greater benefit in the prevention of traveler’s diarrhea. The main causative organisms of this disorder are enterotoxigenic E . co2i (= 40% of cases), Salmonella spp., Entamoeba histolytica, and G. l~mblia.’~~ E. coli, Salmonella sp., and G. lamblia all use a mannose-specific mechanism to adhere to enterocytes.60,61 Many, but not all, strains of L. plantarum also use a mannose-specificadherence mechanism (including strains isolated from traditional fermented foods, like sauerkraut and Nigerian ogi). This characteristic appears to be rather unique, as no other species of lactobacilli or bifidobacteria adhere to human enterocytes in this manner. Direct competition for a limited number of mannosespecific adhesion sites between strains of L. plantarum and enteropathogens may limit the ability of the pathogens to bind to the intestinal mucosa, which is a necessary prerequisite to infection.6oAs yet, however, no clinical trials have been conducted using strains of L. plantarum.

Lactose Intolerance Lactose intolerance is a fairly common condition, affecting up to 70% of the world’s adults,’75although its prevalence is far lower in communities from Northern European descent (15% to 25%).’76It is caused by a deficiency of the enzyme lactase, which is usually located on the brush border of the small intestine. In the absence of lactase, lactose remains in the gut and osmotically draws water into the intestines. When lactose reaches the large intestine, it is avidly fermented by the colonic microflora into SCFAs, lactic acid, C02, and hydrogen gas. These processes result in the symptoms of lactose intolerance-bloating, diarrhea, flatulence, and abdominal discomfort.’” A number of studies have shown that lactose in ”living” yogurt is better tolerated by lactose-intolerant individuals than lactose in other dairy food^."^-'^^ This difference is primarily due to the activity of microbial beta-galactosidase, which breaks down lactose in vivo. However, yogurt consumption also significantly slows gastrointestinal transit compared with . unfermented dairy foods. This delay in gastrointestinal transit also contributes to the improvement in lactose tolerance.lT Most, if not all, strains of the typical yogurt-producing bacteria (L. delbrueckii ssp. bulgaricus and S. thermophilus) appear to possess sigruficantbeta-galactosidase a~itivity.’~~

Probiotics development of atopy if consumed during pregnancy and the early months of b r e a ~ t f e e d i n g . l Other ~ ~ J ~ strains of L. rharnnosus cannot be assumed to act in a similar manner. The clinician who chooses to use the exact strain that had the effects in clinical trials can be confident of similar results. Using another closely-related strain may or may not have any effects.Whenever possible, use the exact strain used in the research, because other strains, even closely related ones, may not have the same effects. Even a strain that has a proven effect in one area may not be the best strain for another application. For instance, L. rharnnosus GG has been shown to be useful in the treatment of infantile eczema,’2 but it does not appear to be of any benefit in the treatment of U T I S . ’ ~This ~ situation is somewhat analogous to the use of specific breeds of dog for specific jobs. For instance, if a guard dog is needed, a German Shepherd or Rottweiler would be far more useful than a Labrador or Scottish terrier. That is not to say that a Labrador is not a “good” or useful breed of Stimulation of Gastrointestinal Tract dog; it is merely that Labradors may not be the best and Systemic Immunity breed available for this task. All probiotic strains similarly have areas of strengths and weaknesses. As more A number of probiotic strains have demonstrated an abilresearch is conducted on each strain, it will become ity to enhance indices of both gastrointestinal and sysclearer which strains are best suited for specific health temic immune function in humans. Administration of conditions. Unfortunately, much of the earlier probiotic L. joknsonii La1251mand L. rharnnosus GG1411@resulted in research failed to delineate the bacterial strain used, so enhanced gut IgA response to antigens. Phagocytic activthe findings are hard to place in the context of later ity of peripheral blood leukocytes has been increased research. by consumption of L. johnsonii La1,183J85-187 B. lactis Table 118-2193-236 outlines the most appropriate probiBb12,183J87 L. rhurnnosus HNO01,188B. Zacfis HN019,189J90 otic strains available for some common health condiand L. rharnnosus GG.191B. Zucfis HN019 also improves natural killer cell tumor-killing a c t i ~ i t y ’ ~and J ~ ~ tions. If it is not possible to locate and utilize the specific strains delineated in this table, the best option is to use enhances phagocyte-mediated bactericidal activity.lE9 an alternative bacterial strain that possesses the characOne double-blind, placebo-controlled trial was teristics listed in Table 118-1. designed to assess whether this enhancement of immune indices translated to decreased rates of infection and/or severity of infection. Five-hundred seventy-one children DOSAGE enrolled in daycare took part in the trial. Children were randomly assigned to drink L. rharnnosus G G The dosage of probiotic foods and supplements is based solely on the number of live organisms present in the containing milk (LGG) or probiotic-free milk (PFM) as product. Successful results have been attained in clinical the control. After 7 months, the LGG group were found trials using between lo7 and 10” viable bacteria per to have significantly fewer days of absence from daycare day.47,71,216 Interestingly, it appears that 100 times less due to illness (4.9 [95% CI 4.4-5.51 versus 5.8 [95% CI viable bacteria need to be given in a dairy medium than 5.3-6.41 days, 16% difference;p = 0.03) than the PFM group. in a freeze-dried supplement to achieve similar numbers There were also relative reductions of 17”/0in the number of live bacteria in the lower Dairy appears to of children suffering from complications from respiratory work as an ideal transport medium for the bacteria, infections and lower respiratory tract infections (p = 0.05), and of 19%in antibiotic use in the LGG group (p = 0.03).47 enhancing their survival through the upper GIT?5 When consumed in a yogurt medium, most of the bacteria survive transit through the stomach to the small intestine. In the proximal small intestine, they are exposed to large quantities of bile salts. However, bacterial strains from these two species are typically intolerant to bile salts, and exposure to these salts results in cell death and lysis. Microbial beta-galactosidase is an intracellular enzyme, so cell lysis results in the liberation of this enzyme into the intestinal lumen, where it can function to digest lactose. Microbial beta-galactosidase has been shown to be metabolically active in the middle and distal small intestine, contributing to the digestion of lactose before it reaches the large intestine, where its fermentation causes symptoms.1n In addition to the yogurt-producing bacteria, two specific probiotic strains have demonstrated their usefulness in the management of lactose intolerance, L. ucidophilus NCFM178J81 and L. johnsonii La1.1E2

USING THE RIGHT STRAIN To achieve successful and reproducible clinical outcomes, it is imperative to use the exact probiotic strain that has been proven to have the specific therapeutic action that is desired. For example, two trials have demonstrated that L. rhurnnosus GG can prevent the

Supplements

Supplements are best consumed with meals in order to take advantage of the greater alkalinity of the gastric environment (which equates to greater bacterial survival).237 A dosage of lo8 bacteria per sitting is often mentioned in the probiotic literature as the minimum quantity of bacteria needed to produce therapeutic e f f e ~ t s . ~ ~ , ~ ~ ~

Therapeutic application

Most appropriate probiotic strain@)

Reference(@

Hypercholesterolemia

Lactobacillus plantarum 299v, Bacillus coagulans ATCC # 31284, Lactobacillus acidophilus L1

53, 193-195

Prevention of atopy

Lactobacillus rhamnosus GG

133, 134

Eczema

L. rhamnosus GG, Bifidobacterium lactis Bbl2, Lactobacillusparacasei Shirota

72, 142, 143, 196-198

Food allergies

L. rhamnosus GG, B. lactis Bb12, L. paracasei Shirota

70, 72, 139, 140, 142, 143, 191, 197-199

Nonsteroidal antiinflammatory drug use/erosive gastritis

L. rhamnosus GG

200

Antibiotic use (during and afler)

L. rhamnosus GG, Saccharomyces cerevisiae (Hansen CBS 5926), L. acidophilus LA5, L. plantarum 299v

51, 95-99, 101, 103, 201-204

Lowered immunity

L. rhamnosus GG, B. lactis HN019 (DRlO), Lactobacillusjohnsonii La1, L. rhamnosus HNOOl (DR20), L. acidophilus LA5

47, 183, 187-190, 205-209

Intestinal hyperpermeability

L. rhamnosus GG, S. cerevisiae (Hansen CBS 5926)

142, 143,210,211

Gastroenteritis

L. rhamnosus GG, Lactobacillus reuteri MM53, L. paracasei CRL431, L. acidophilus CRL730, L. johnsonii La1, B. lactis Bb12, L. plantarum 299v, L. paracasei Shirota

21, 54,55, 184, 212-219

Giardia infection

L. johnsonii La1, L. plantarurn 299v. L. rhamnosus GG

21, 60, 87

Intestinal dysbiosis

L. rhamnosus GG, L. johnsonii La1, L. plantarum 299v, L. paracasei Shirota, L. acidophilus LA5

50, 52, 101, 202, 220-224

Irritable bowel syndrome

L. plantarum 299v, VSL# 3

71, 157, 225

Traveler's diarrhea

L. rhamnosus GG, 6.lactis Bb12, L. acidophilus LA5, S. cerevisiae (Hansen CBS 5926), L. plantarum 299v

21, 173, 186, 218, 226

Lactose intolerance

L. acidophilus NCFM, L. johnsonii La1, L. acidophilus LA5

178, 181, 182,227,228

Peptic ulcer diseasehonerosive gastritis

L. johnsonii La1, L. acidophilus LB, L. acidophilus strain NAS, L. acidophilus DDS-1, L. rhamnosus GG

47. 83-86

Crohn's disease

L. rhamnosus GG, S.cerevisiae (Hansen CBS 5926)

141,168,169,229

Ulcerative colitis

Escherichia coli strain Nissle 1917, VSL# 3, L. plantarum 299

69, 167, 230-232

Prevention of colon cancer

L. rhamnosus GG, L. acidophilus NCFM, L. paracasei Shirota, L. acidophilus DDS-1, L. acidophilus Delvo Pro LA1, Lactobacillus delbrueckii ssp. bulgaricus strain LB-51

49, 148-151

Urinary tract infection

L. rhamnosus GR-1, Lactobacillus fermenturn 6-54, L. fermentum RC-14. L. acidophilus NCFM

111, 113-115, 117, 233-235

Vaginal candidiasis (thrush)

L. acidophilus LA5, L. acidophilus strain NAS, L. rhamnosus GG, L. rhamnosus GR-1, L. fermentum RC-14

48, 106, 107, 119, 122,236

Probiotic strains are listed in decreasing order of appropriateness. For instance, strains listed first generally have the most evidence supporting their use in that condition. (Note: This table highlights only those strains widely discussed in the peer-reviewed literature.)

Also, a handful of studies have demonstrated therapeutic effects utilizing lo7 to lo8 viable bacteria per dose.47,216,239 However, most of the successful probiotic research has utilized more than lo9 bacteria per dose. The minimum concentration of probiotic bacteria needed to achieve therapeutic effects appears to be somewhat strain dependent, in that for some strains (e.g., L. reuteri MM53), lo7bacteria is a sufficient quantity to produce beneficial effects,2I6but for other strains, lo9 viable bacteria is needed (e.g., L. rharnnosus GG, if given as lyophilized b a ~ t e r i a )This . ~ ~ situation, unfortunately, makes it hard to give firm dosage recommendations;

the minimum effective dosage appears to differ by strain. Thus it is best practice to ensure that supplements contain bacteria in concentrations greater than lo9bacteria per dose, unless research has demonstrated that the specific strain contained in the supplement is effective in smaller amounts. Therefore, the dosage of viable bacteria given in supplemental forms should generally be lo9 to 10" bacteria per dose. If a formulation contains multiple strains, each strain must be present in amounts higher than lo9, because smaller doses of living bacteria may not produce therapeutic effects.

Probiotics

Yogurts The minimum dosage of viable bacteria needed in a dairy medium is lo8 per dose. Therapeutic yogurts contain more than lo6 viable bacteria per mL, so a 100-g serving (= '/2 cup) will provide sufficient probiotic bacteria for therapeutic effe~ts.2~~ Unfortunately, many so-called acidophilus and/or bifidus yogurts do not Only yogurt brands that contain this minimum are guaranteed to contain this level of viable bacteria, or those that have done so in market-basket surveys, should be utilized. A serving of yogurt containing less than lo8 viable bacteria is unlikely to have any medicinal effects beyond its inherent nutritional content. A 100-g serving of yogurt contains only 3.1 to 3.5 g of lactose,"' well below the threshold level for people with lactose intolerance. Hence lactose-intolerant individuals should be able to consume the minimum amount of yogurt without ill effe~ts.2~~

Fermented Vegetables Traditionally prepared fermented vegetables generally contain more than lo8 living bacteria per gram, so 10 grams is the minimum dosage r e q ~ i r e d . ~ ~ B For applications in the mouth, esophagus, and stomach, supplement powders, therapeutic yogurts, or fermented vegetables are the best forms of administration, as administration in these forms will allow the probiotic bacteria to come into direct contact with the areas where they are needed. For applications in the small and large intestine, however, there is no advantage of one form of administration over another (assuming an adequate dose is prescribed).

oligosaccharides. For further details, please refer to Chapter 117.

Spirulina Another possible way to improve the intestinal ecology is through the consumption of spirulina. Although no human studies appear to have been published, intriguing veterinary research has shown that providing horses with spirulina stimulates the growth of lactobacilli in the cecum. The researchers suggest that this result may be due to the mucopolysaccharides in ~ p i r u l i n a . ~ ~ ~

TOXICITY Lactobacilli have been consumed in large numbers throughout recorded history. The fermentation of foodstuffs is one of the oldest known uses of biotechnology, and even today fermented foods and beverages constitute 20% to 40% of the human food supply worldwide. Thus lactobacilli have a long history of safe use.3 In a 1999 article, Naidu et aP reviewed the safety profile of lactobacilli and bifidobacteria. No adverse effects or events were reported by any of the 7526 subjects who participated in the 143 human trials r e ~ i e w e d . ~ A number of cases of fungemia from the oral administration of S. cermisiae (aka S. boulardii)have been reported in the literature. These cases have occurred almost exclusively in immunocompromised or critically ill individuals. Thus, administration of strains of S. cereuisiae should be given only to immunocompetent i n d i ~ i d u a l s ? ~ , ~ ~ ~

DRUG INTERACTIONS

A number of different sugars can stimulate the growth of endogenous strains of lactobacilli and bifidobacteria, including fructooligosaccharides,lactulose, and soybean

Lactobacilli and bifidobacteria are negatively affected by alcohol and antibiotic^.^^,^^^ Although there is no evidence that L. acidophilus interferes with the activity of most antibiotics, some strains affect the metabolism of sulfasalazine, chloramphenicol palmitate, and phthalylsulfathiazole?48Concurrent administration of S. cerevisiae (Hansen CBS 5926) with monoamine oxidase inhibitors may increase blood pressure.249

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PROMOTING GROWTH OF LACTOBACILLI AND BlFlDOBACTERlA Oligosaccharides and Disaccharides

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204. Cremonini F, Di Car0 S, Covino M, et al. Effect of different probiotic preparations on anti-Helicobacter pylori therapy-related side effects: a parallel group, triple blind, placebo-controlled study. Am J Gastroenterol2002;972744-2749. 205. Perdigon G, Nader de Macias ME, Alvarez S, et al. Enhancement of immune response in mice fed with Streptococcus therrnophilus and Lncfobncillus acidophilus. J Dairy Sci 1987;70:919-926. 206. Tejada-Simon MV, Lee JH, Ustunol Z, Pestka JJ. Ingestion of yogurt containing Lnctobncillus acidophilus and BiFdobacteriurn to potentiate immunoglobulin A responses to cholera toxin in mice. J Dairy Sci 1999;82:649-660. 207. Hatcher GE, Lambrecht RS.Augmentation of macrophage phagocytic activity by cell-free extracts of selected lactic acid-producing bacteria. J Dairy Sci 1993;762485-2492. 208. Marteau P, Vaerman JP, Dehennin JP,et al. Effects of intrajejunal perfusion and chronic ingestion of Lactobacillus johnsonii strain La1 on serum concentrations and jejunal secretions of immunoglobulins and serum proteins in healthy humans. Gastroenterol Clin Biol 1997;21:293-298. 209. Gill HS, Rutherford KJ, Prasad J, Gopal PK. Enhancement of natural and acquired immunity by Lactobacillus rhamnosus (HNOOl), Lnctobncillrts acidophilus (HN017) and Bifdobacteriurn lactis (HN019). Br J Nutr 2000;83:167-176. 210. Jahn HU, Ullrich R, Schneider T, et al. Immunological and trophical effects of Sncchnromyces boulardii on the small intestine in healthy human volunteers. Digestion 1996;5795-104. 211. Buts JP, De Keyser N, De Raedemaeker L. Saccharornyces boulardii enhances rat intestinal enzyme expression by endoluminal release of polyamines. Pediatr Res 1994;36:522-527. 212. Isolauri E, Juntunen M, Rautanen T, et al. A human Lactobacillus strain (Lactobacillus casei strain GG) promotes recovery from acute diarrhea in children. Pediatrics 1991;88:90-97. 213.Shomikova AV, Isolauri E, Burkanova L, et al. A trial in the Karelian Republic of oral rehydration and Lactobacillus GG for treatment of acute diarrhoea. Acta Pediatr 1997;86460-465. 214. Isolauri E, Kaila M, Mykkanen H, et al. Oral bacteriotherapy for viral gastroenteritis. Dig Dis Sci 1994;39:2595-2600. 215. Saavedra JM, Bauman NA, Oung I, et al. Feeding of Bifdobacterium bifdrtm and Streptococcus therrnophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet 1994344:1046-1049. 216. Shomikova AV, Casas IA, Mykkanen H, et al. Bacteriotherapy with Lactobncillrrs reirtrri in rotavirus gastroenteritis. Pediatr Infect Dis J 1997;16:1103-1107. 217. Sugita T, Togowa M. Efficacy of Lactobacillus preparation Biolactis powder in children with rotavirus enteritis. Jpn J Pediatr 1994;47213-220. 218. Michail S, Abemathy F. Lactobacillus plantarurn reduces the in vitro secretory response of intestinal epithelial cells to enteropathogenic Escherichin coli infection.J Pediatr Gastroenterol Nutr 2002;35:350-355. 219.Ogawa M, Shimizu K, Nomoto K, et al. Protective effect of Lactobacillus casei strain Shirota on Shiga toxin-producing Eschrrichin coli 0157:H7 infection on infant rabbits. Infect Immun 2001;69:1101-1108. 220.Silva M, Jacobus NV, Deneke C, Gorbach SL. Antimicrobial substance from a human Lactobacillus strain. Antimicrob Agents Chemother 1987;31:1231-1233. 221.Bemet-Camard MF, Lievin V, Brassart D, et al. The human Lnctobncillus ncidophilus strain LA1 secretes a nonbacteriocin antibacterial substance(s) active in vitro and in vivo. Appl Environ Microbiol 1997;63:2747-2753. 222.Bernet MF, Brassart D, Neeser JR, Servin AL. Lactobacillus acidophilus LA1 binds to cultured human intestinal cell lines and inhibits cell attachment and cell invasion by enterovirulent bacteria. Gut 1994;35:483-489.

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Procyanidolic Oligomers Michael T. Murray, ND JosephE. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1217 Chemical Composition 1217

Clinical Applications 1219 Venous and Capillary Disorders 1219 Visual and Function and Retinopathy 1219 Atherosclerosis 1219

History and Folk Use 1217 Dosage 1219 Pharmacology 1218 Protection of Collagen 1218 Antioxidant and Free Radical Scavenging Activity 1218

GENERAL DESCRIPTION The proanthocyanidins (also referred to as "procyanidins") are one of the most beneficial groups of plant flavonoids. The most active proanthocyanidins are those bound to other proanthocyanidins. Collectively, mixtures of proanthocyanidin dimers, trimers, tetramers, and larger molecules are referred to as procyanidolic oligorners (PCOs).'J Although PCOs exist in many plants as well as red wine, commerciallyavailable sources of PCOs include extracts from grape seed skin (Vitex v i n f i a ) and the bark of the maritime (Landes)pine.'$ This chapter reviews the benefits of PCOs from grape seeds and pine bark.

CHEMICAL COMPOSITION Grape seed and pine bark PCO extracts are well defined chemically.Grape seed extracts are available that contain 92% to 95%PCOs, whereas the PCO content of pine bark extracts varies from 80% to 85%. Proanthocyanidin B2 is shown in Figure 119-1.

HISTORY AND FOLK USE In 1534, French explorer Jacques Cartier led an expedition up the Saint Lawrence River in what would become North America. Trapped by ice, Cartier and his crew were forced to survive on a ration of salted meat and biscuits. Cartier's crew began to exhibit signs and symptoms of scurvy, the cause of which was unknown at that time. Fortunately for Cartier and the surviving members

Toxicity

1220

Drug Interactions 1220

of his crew, they met a Native American who advised them to make a tea from the bark and needles of pine trees. As a result, Cartier and his men survived. More than 400 years later, Professor Jacques Masquelier of the University of Bordeaux, France, read the book Cartier wrote detailing his expedition. Intrigued by Cartier's story, Masquelier and others concluded that pine bark must contain some vitamin C as well as bioflavonoids, which can exert vitamin C-like effects. Masquelier termed the active components of the pine bark pycnogenols.'J This term was used to describe an entire complex of proanthocyanidin complexes found in a variety of plants, including pine bark, grape seeds, lemon tree bark, peanuts, cranberries, and citrus peels. The term pycnogenol has been replaced in the scientific community by the terms proanthocyanidis,oligorneric prounthocyanidin complex (OPC),and PCO. In the United States, Pycnogenol is a registered trademark of Horphag Ltd of Guernsey, UK, and refers to the PCO extracted from the bark of the French maritime pine. Masquelier patented the method of extracting PCOs from pine bark in France in 1951, and from grape seeds in 1970. The PCO extract from grape seed emerged as the preferred source on the basis of research conducted between 1951 and 1971 as well as intensive research from 1972 to 1978.' The 1970s research was conducted with the goal of gaining approval for PCO as a medicinal agent by the French equivalent of the U.S. Food and Drug Administration (FDA). During this time, detailed analytical, toxicity, pharmacologic, and clinical studies were performed on PCOs derived from grape seeds. 1217

Increase intracellular vitamin C levels Decrease capillary permeability and fragility Scavenge oxidants and free radicals Inhibit destruction of collagen Data from references 1 and 2.

I

OH Figum 119-1 Proanthocyanidin B2

PCOs from both grape seeds and pine bark have been marketed in France for decades, where they have been promoted to improve retinopathies, venous insufficiency, and vascular fragility.

PHARMACOLOGY

Trap hydroxyl free radicals Trap lipid peroxides and free radicals Markedly delay the onset of lipid peroxidation Chelate free iron molecules, thereby preventing iron-induced lipid peroxidation Inhibit production of free radicals by noncompetitively inhibiting xanthine oxidase Inhibit the damaging effects of the enzymes (e.g., hyaluronidase, elastase, collagenase) that can degrade connective tissue structures

Extracts of PCOs have demonstrated a wide range of activity, as listed in Box 119-1.

Protection of Collagen Collagen, the most abundant protein of the body, is responsible for maintaining the integrity of ground substance as well as the integrity of tendons, ligaments, and cartilage. Collagen is also the support structure of the dermis and blood vessels. PCOs are remarkable in their effects of supporting collagen structures and preventing collagen destruction. They affect collagen metabolism in several ways. They have the unique ability to cross-link collagen fibers, resulting in reinforcement of the natural cross-linking of collagen that forms the so-called collagen matrix of connective tissue.45 They also protect against free radical damage with their potent antioxidant and free radical scavenging action, and they inhibit enzymatic cleavage of collagen by enzymes secreted by leukocytes during inflammation and microbes during infection.6~~ PCOs also prevent the release and synthesis of compounds that promote inflammation and allergies such as histamine, serine proteases, prostaglandins, and leuk0trienes.'2,~,~

Antioxidant and Free Radical Scavenging Activity Perhaps the most celebrated effects of PCOs in the United States are their potent antioxidant and free radical scavenging activity. Free radical damage has been linked to the aging process and virtually every chronic degenerative disease, including heart disease, arthritis, and cancer. Fats and cholesterol are particularly

susceptible to free radical damage. When damaged, fats and cholesterol form toxic derivatives known as lipid peroxides and cholesterol epoxides, respectively. The antioxidant and free radical-scavenging effects of PCOs were discovered by Masquelier in 1986.' One study evaluated the free radical-scavenging activity of PCOs and determined their inhibitory effects on xanthine oxidase (a primary generator of oxygenderived free radicals) and the lysosomal enzyme system (which governs the release of enzymes that can damage the connective tissue framework acting as a protective sheath around capillary walls).' This research, summarized in Box 119-2, provides a detailed explanation of the vascular protective action of PCOs and a strong rationale for their use in vascular disease. In experimental models, the antioxidant activity of PCOs is much greater (approximately 50 times) than that of vitamin C and vitamin E. From a cellular perspective, one of the most advantageous features of PCOs' free radical scavenging activity is that, because of their chemical structure, they are incorporated into cell membranes. This physical characteristic, along with their ability to protect against both water- and fat-soluble free radicals, provides significant cellular protection against damage by free radicals. The researchers concluded their discussion with the following comment: "These findings, together [with]those of other investigators, provide a strong rationale for using these compounds in the therapeutic management of microvascular disorder^."^

Procyanidolic Oligomers

CLINICAL APPLICATIONS Venous and Capillary Disorders The primary clinical applications of PCOs are in the treatment of the following conditions: Venous and capillary disorders including venous insufficiency Varicose veins Capillary fragility Disorders of the retina, including diabetic retinopathy and macular degeneration Good clinical studies have shown positive results in the treatment of these c~nditions.'J@*~ PCO extracts have also been helpful in improving sperm quality and function (see discussion of male infertility) and melasma, presumably as a result of their antioxidant effect^.'^,'^

Visual Function and Retinopathy Increased intake of PCO is likely to benefit almost everyone. This suggestion is perhaps best illustrated by research evaluating the effects of grape seed PCOs extract on visual function in healthy subjects.2°,21In the studies, 100 normal volunteers with no retinal disorder received either 200 mg/day of PCOs or placebo for 5 or 6 weeks. The group receiving PCOs demonstrated significant improvement in visual performance in dark and after-glare tests compared with the placebo group. PCO extracts have also been shown to be of benefit in treating retinopathies, especially diabetic retinopathy. In one study, 40 patients with diabetes, atherosclerosis, and other vascular diseases involving the retina were randomly treated with placebo or PCO extract (50 mg x 3/day for 2 months). The results demonstrated a beneficial effect of PCOs on the progression of retinopathy. In patients without any treatment (placebo)the retinopathy progressively worsened during the trial and the visual acuity significantly decreased; on the contrary, the PCOtreated patients showed no deterioration of retinal function, and a sigruficant recovery of visual acuity was also obtained. The fluorangiography showed an improvement of retinal vascularization and a reduced endothelial permeability and leakage in the PCO group, but not in the placebo-treated patients. The ophthalmoscopy and the electroretinogram also confirmed the beneficial effects of PCOs. In addition to the PCOs exerting free radicalscavenging, antiinflammatory, and capillary protective activities, it has been suggested that Pycnogenol may bind to the blood vessel wall proteins and mucopolysaccharides and produce a capillary "sealing" effect, leading to a reductions in capillary permeability and edema f~rmation.'~

Atherosclerosis There are now numerous studies demonstrating that an individual's level of antioxidants may be a more significant factor in determining the risk of heart disease than cholesterol levels. Antioxidants prevent both the oxidation of cholesterol and its carrier proteins and the initial damage to the artery that ultimately leads to the process of atherosclerosis.Several studies have shown the protective effects of red wine against heart disease and stroke through protection against low-density lipoprotein (LDL) oxidation.22 The active components in the wine are thought to be proanthocyanidins.Also, a study of 805 men beginning in 1985 and published in 1993demonstrated an inverse correlation between flavonoid intake and death due to heart atta~k.2~ Clinical studies have shown that PCO extract supplementation enhances the oxygen radical absorbance capacity (ORAC) in plasma throughout the supplementation peri0d.2~'~ In one double-blind study, the effect of a standardized formulation of a PCO extract bound to phosphatidylcholine (Leucoselect-Phytosome)was determined on susceptibility of LDL to oxidation in a group of heavy smokers. Among oxidative indices, the concentration of thiobarbituric acid-reactive substances (TBARS) was sigruficantly reduced in subjects taking the PCO extract, and the lag phase prolonged, compared with the values in subjects taking placebo as well as with baseline values. In addition to preventing damage to LDL and the lining of the artery, PCO extracts have been shown to lower blood cholesterol levels and shrink the size of cholesterol deposits in arteries in animal and human s t ~ d i e s . ' , ~Additional ~J~ mechanisms of PCOs useful in preventing atherosclerosis include inhibition of platelet aggregation and inhibition of angiotensin-I-converting e n ~ y m e . Presumably, ~~J~ PCO extracts may exert similar benefits in humans. PCO extracts appear to be helpful in improving endothelial function in patients with hypertension. In one double-blind study in 58 patients with hypertension who received supplementation with 100 mg PCOs over a period of 12 weeks, endothelin-1 concentrations were significantly lower, and concentrations of 6-keto prostaglandin F1, in plasma significantly higher, in the PCO group than in the placebo group, and the PCOs helped reduce the effective dose of the calcium antagonist nifedipine in a statistically significant manner.16 PCO extracts, although in a supplement form, should be regarded as a necessary food in the prevention and treatment of atherosclerosis.

DOSAGE As antioxidant support, a daily dose of 50 mg of either the grape seed or pine bark extract is suitable.

For comparison, it is now estimated that the average daily intake of total flavonoids in the United States is about 25 mg. An intake greater than 30 mg offers a simificant reduction in risk for cardiovascular mGrtality.23 When PCO extracts are being used for therapeutic purposes, the daily dosage should be increased to150 to 300 mg.

1. Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther 2002;40:158-168. 2. Schwitters 8, Masquelier J. OPC in practice: biflavanols and their application. Rome: Alfa Omega, 1993. 3. Masquelier J. [Procyanidolic oligomers.] J Parfums Cosmetiques Aromes 1990;95:89-97. 4. Masquelier J, Dumon MC, Dumas J. [Stabilization of collagen by procyanidolic oligomers.] Acta Therap 1981;7101-105. 5. lixier JM, Godeau G, Robert AM. Evidence by in vivo and in vitro studies that binding of pymogenols to elastin affects its rate of degradation by elastases. Biochem Pharmacol1984;333933-3939. 6. Meunier MT, Duroux E, Bastide P. Free-radical scavenger activity of procyanidolic oligomers and anthocyanosides with respect to superoxide anion and lipid peroxidation. Plant Med Phytother 1989; 4~267-274. 7. Maffei Facino R, Carini M, Aldini G, et al. Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis viniferu. A mechanism for their capillary protective action. Arneimitteforschung 1994;44:592-601. 8. Sharma SC,Sharma S, Gulati OP. Pycnogenol inhibits the release of histamine from mast cells. Phytother Res 2003;1766-69. 9.Cho KJ, Yun CH,Packer L, Chung AS. Inhibition mechanisms of biotlavonoids extracted from the bark of Pinus maritima on the expression of proinflammatory cytokjnes.Ann N Y Acad Sci 2001,928:141-156. 10. Henriet JI? Veno-lymphatic insufficiency:4,729 patients undergoing hormonal and procyanidol oligomer therapy. Phlebologie 1993; %313-325. 11. Baruch J. Effect of Endotelon in postoperative edema: results of a doubleblind study versus placebo in 32 female patients. Ann Chir Plast Esthet 1984;29393-395. 12. Lagrue G, Oliver-Martin F, Grillot A. A study of the effects of procyanidol oligomers on capillary resistance in hypertension and in certain nephropathies. Sem Hop 1981;571399-1401. 13. Petrassi C, Mastromarho A, Spartera C. Pycnogenol in chronic venous insufficiency. Phytomedicine 2OOO;7383-388. 14. Soyeux A, Segiun JP, Le Devehat C, Bertrand A. Endotelon: diabetic retinopathy and hemorheology (preliminary study). Bull Soc Ophtalmol Fr 1987;871441-1444. 15. Proto F, et al. Electrophysical study of Vitis viniferu procyanoside oligomers effects on retinal function in myopic subjects. Ann Ott Clin Ocul 1988;11485-93.

TOXICITY PCO extracts are without known side effects.

DRUG INTERACTIONS There are no documented drug interactions for the procyanidins.

16. Liu X, Wei J, Tan F, et al. Pycnogenol@,French maritime pine bark extract, improves endothelial function of hypertensive patients. Life Sci 2004;74:855-862. 17. Spadea L, Balestrazzi E. Treatment of vascular retinopathies with Pycnogenol. Phytother Res 2001;15:219-223. 18. Roseff SJ. Improvement in sperm quality and function with French maritime pine tree bark extract. J Reprod Med 2002;47 821-824. 19. Ni Z, Mu Y, Gulati 0. Treatment of melasma with Pycnogenol. Phytother Res 2002;16567-571. 20. Corbe C, Boissin JP, Siou A. [Light vision and chorioretinalcirculation: study of the effect of procyanidolic oligomers (Endotelon).] J Fr Ophtalmol 1988;11:453-460. 21. Boissin JP, Corbe C, Siou A. Chorioretinal circulation and dazzling: use of procyanidol oligomers. Bull Soc Ophtalmol Fr 1988;88: 173174,177-179, 22. Frankel EN, Kanner J, German JB, et al. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet 1993;341:454-457. 23. Hertog MG, Feskens EJ, H o h a n PC, et al. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993;3421007-1011. 24. Devaraj S, Vega-Lopez S, Kaul N, et al. Supplementation with a pine bark extract rich in polyphenols increases plasma antioxidant capacity and alters the plasma lipoprotein profile. Lipids 2002;37 931-934. 25.Vigna GB, Costantini F, Aldini G, et al. Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers. Metabolism 2003;52 1250-1257. 26. Nuttall SL, Kendall MJ, Bombardelli E, Morazzoni P.An evaluation of the antioxidant activity of a standardized grape seed extract, Leucoselect. J Clin Pharm Ther 1998;23:385-389. 27. Wegrowski J, Robert AM, Moczar M. The effect of procyanidolic oligomers on the composition of normal and hypercholesterolemic rabbit aortas. Biochem Pharmacol1984;333491-3497. 28. Chang WC, Hsu FT.. Inhibition of platelet aggregation and arachidonate metabolism in platelets by procyanidins. Prostagland Leukot Essent Fatty Acids 1989;38181-188. 29. Meunier MT, V i e F, Jonadet M. Inhibition of angiotensin I converting enzyme by flavanolic compounds: in vitro and in vivo studies. Planta Med 1987;54:12-15.

Pygeum africmum (Bitter Almond) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS General Description 1221

Male Infertility and Impotence 1224 Pygeum versus Serenoa 1224

Chemical Composition 1221 Dosage 1224 History and Folk Use 1221 Toxicology 1224 Pharmacology 1221 Ferulic Acid Esters 1222 Other Components 1222

Drug Interactions 1224

Clinical Applications 1222 Prostate Disorders 1222

Pygeum ufricunum (family: Rosaceae) Synonym: Prunus ufricunum Common names: bitter almond, red stinkwood

GENERAL DESCRIPTION Pygeum ufricunum is an evergreen tree native to Africa that can grow to a height of 120 to 150 feet. It has pendulous branches with thick, oblong, leatherlike, mat-colored leaves and creamy white flowers. The fruit (drupe)resembles a cherry when ripe. The dark brown to gray bark of the trunk is the part used for medicinal purposes.

CHEMICAL COMPOSITION The major active components of the bark are as follows: Lipid-soluble pentacyclic triterpenes Sterolic triterpenes Fatty acids Esters of ferulic acid (Figure 120-1) The pentacyclic triterpenic components are ursolic acid (Figure 120-2), oleanolic acid, crataegolic acid, and their derivatives. The sterolic fraction is composed mainly of beta-sitosterol and beta-sitosterone (Figure 120-3). The fatty acids range from C12 to C24 and the important ferulic acid esters are those bound to n-tetracosanol and n-doc~sanol.'~

HISTORY AND FOLK USE The powdered bark of P. ufricunum was used by the natives of tropical Africa as a treatment for urinary disorders. It was often given with palm oil or milk. Since about 1970, the bark has been entirely wild-collected, with the major exporters being Cameroon, Madagascar, Equatorial Guinea, and Kenya. Two companies, Groupe Fournier of France and Indena of Italy, produce 86% of the world's bark extract, both for their own products and for the free market. Worldwide exports of dried bark in 2000 were estimated at 1350 to 1525 metric tons per year, down from its peak of 3225 tons in 1997. Bark extracts (6370 to 7225 kg/year) are worth an estimated $4.36 million US.dollars per year. However, wild collection of the bark is no longer sustainable. Since 1995, P. ufricunum has been declared an endangered species. Alternatives to wild collection to meet future market demand include conservation practices, enrichment plantings, and smalland large-scale production. Currently, the species is at the beginning of a transition from an exclusively wild-collected species to that of a cultivated medicinal tree?

PHARMACOLOGY Pharmacologic screening of various extracts prepared with solvents of differing degrees of polarity indicated that the highest activity was found in lipophilic extracts.l 1221

0

11

H HC=C-C-OH

h OH Figure 120-1

Ferulic acid.

CH3 I

H3cA COOH

HO

Figure 120-2 Ursolic acid.

0

M Figure 120-3 Beta-sitosterone.

This finding is interesting in light of pygeum's historical administration in lipophilic media (palm oil or milk). Virtually all of the pharmacologic research has featured a pygeum extract standardized to contain 14% triterpenes including beta-sitosterol and 0.5% n-docosanol. This extract has been extensively studied in both experimental animal studies and clinical trials with humans. The primary target organ for pygeum's effects in men is the prostate. The three major active components of pygeum appear to exert different, yet complementary, effects in benign prostatic hyperplasia (BPH).In addition, pygeum has been shown to enhance the secretions of the prostate and bulbourethral glands, in terms of both quantity and quality.

Ferulic Acid Esters The esters of ferulic acid act primarily on the endocrine system. Studies in animals have shown docosanol to reduce levels of luteinizing hormone and testosterone while raising adrenal steroid secretion of both adrenal

androgens and cortico~teroids.~~~ Docosanol also significantly lowers serum prolactin levels. This reduction of prolactin is quite significant because prolactin increases both the uptake of testosterone and the synthesis of dihydrotestosterone within the prostate. The accumulation of testosterone within the prostate and its subsequent conversion to the more potent dihydrotestosterone is thought to be the major contributing factor to the hyperplasia of the prostatic cells observed in BPH.8 Although traces of docosanol are present in pygeum, the esterification with ferulic acid results in greater bioavailability and a c t i ~ i t y . ~ , ~ , ~ Ferulic acid esters and the sterol fraction of pygeum exert cholesterol-lowering action systemically as well as within the prostate? Breakdown products of cholesterol have been shown to accumulate in the prostate tissue affected with either BPH or cancer." These metabolites of cholesterol initiate degeneration of prostatic cells, which can promote prostatic enlargement. Drugs that lower cholesterol levels have been shown to have a favorable influence on BPH, preventing the accumulation of cholesterol in the prostatic cells and limiting subsequent formation of damaging cholesterol metabolites. The lowering of intraprostatic cholesterol content is an important aspect of the pharmacology of pygeum. The sterolic fraction is also endowed with competitive action against testosterone accumulation within the prostate. In addition, the sterols of pygeum have also been shown to reduce inflammation by preventing the intraprostatic formation of inflammatory prostaglandins?JO

Other Components Other components of pygeum are also important. For example, the pentacyclic triterpenes exhibit antiinflammatory effects within the prostatic epithelium and may be responsible for stimulation of the secretory cells of the prostate, seminal vesicles, and bulbourethral glands?-" Finally, the fatty acid components are similar to those of Serema repens (see Chapter 124) and may exert similar effects as well as improve the oral bioavailability of other components of the lipophilic extract.

CLINICAL APPLICATIONS Prostate Disorders The pharmacologic actions of the standardized pygeum extract support its use in prostate disorders, BPH in particular. Adding further support are the results of numerous clinical trials in more than 600 patients.12-M Consistently, these studies have demonstrated pygeum to effectively reduce the symptoms and clinical signs of BPH, especially in early cases. However, it must be pointed out that improvement is largely symptomatic, because the reductions in size of the prostate and in residual urine content of the bladder are modest. The results

Pygeum africanum (Bitter Almond)

Patients Showing Reduction (%) Study Open Trials Guillernin12 Lange & MureP Werneau et all4 Vi~llet~~ Lhez & LeguevagueI6 Thomas & RouffilangeI7 HuetI8 RornettilS Gallizia & Gallizia’O Durval2’ Pansadoro & BenincasaZ2 Double-BlindedTrials Maverz4

BongiZ5 Dorernieux et a126 Del Valio‘’ Colpi & Farinaz8 Donkervoort et alz9 Dufour et aPO Legromandi et aP1 Ranno et Frasseto et al3 Bassi et at3

Dosage (mg/day)

No. of days

100 100 100 75 75 75 50 100 100 100 75

30 30 45 60 90 50 30 50 60 90 90

100 75 100 100 150 150 100 100 200 200 200

60 60 60 60 45 90 45 45 60 60 60

No. of patients in study

Residual urine

Prostate volume

Dysuria

Nocturia

Frequency

25 25 27 20 52 33 55 25 19 23 35

80 72 60 64 69 60 85 72 90 72 94

80

80

NC

NC

NC

NC

80 72 71 64

60 50 77 30 47 20 120 104 39 20 40

77 88 85

-

NC NC

NC

NC

NC

NC

NC

NC

NC

57 85 72 85 72 94

57 85 72 70 72 94

NC

20 72 94

70 88

57 88

23 88

NC -

NC

48

NC -

-

76

NC

NC

NC

65

NC

NC

NC

-

70

NC

89 75

-

-

-

NC -

70

70

70

70

-

80 45 89 75

20 25

NC

70 80 78 89 75

80

NC

-

NC NC

-

88 NC

-

NC

-, not measured;NC,no change.

of the clinical trials on pygeum are given in Table 120-1. A discussion of some of the most important aspects of these studies follows. One of the major findings in evaluating the effectiveness of pygeum in BPH has been the high rate of response to placebo. This is well-demonstrated in one of the larger double-blind studiesm As in other double-blind studies, pygeum extract was shown to be statistically superior to placebo in reducing the major symptoms of BPH (nocturnal frequency, difficulty in starting micturition, and incomplete emptying of the bladder). However, there was a high percentage of responses to the placebo (Table 120-2). It seems that simply taking a capsule provides relief to many sufferers. Another study highlights the importance of doubleblind studies that feature both objective and subjective findings. In the study, both patients and physicians rated the placebo and pygeum extract to be effective in improving subjective symptoms, which were daytime frequency, nocturia, weak stream, after-dribbling, hesitation, and

Patients showing response to

SvmDtom

Placebo arouD

Pvaeurn arow

26/52= 50% 16/50= 33% 14/40= 35% 15/34= 44% 1 1/43= 26%

44/56= 78% 27/54= 50% 21/32= 66% 13/33= 39% 21/38= 55%

~

Nocturia Daytime frequency Incompletevoiding Dribbling Urine flow rate

Data from references 12-22 and 24-34.

interruption of fl0w.2~However, urodynamic variables (flow, frequency, and histogram) clearly demonstrated the superiority of pygeum over placebo. One of the shortcomings of some of the clinical research on pygeum is the lack, in many of the studies, of objective measures such as urine flow rate (ml/sec),

residual urine content, and prostate size. Studies that have used objective measurements have shown some good results. For example, in one open trial, 30 patients with BPH who were given 100 mg/day of the pygeum extract for 75 days demonstrated significant improvements in objective parameters: Maximum urine flow rate increased from 5.43 to 8.20 ml/sec and the residual urine volume dropped from 76 to 33 ml.=

Male Infertility and Impotence Pygeum may be effective in improving fertility when diminished prostatic secretion plays a significant role in the problem. Pygeum has been shown to increase prostatic secretions and improve the composition of the seminal Specifically,pygeum administration to men with decreased prostatic secretion has led to higher levels of total seminal fluid plus rises in alkaline phosphatase and protein levels. Pygeum appears to be most effective in cases in which the level of alkaline phosphatase activity is reduced (i.e., less than 400 IU/cm3) and there is no evidence of inflammation or infection (i.e., absence of white blood cells and immunoglobulin A [IgA]).The lack of IgA in the semen is a good predictor of clinical success. In one study, the patients with no IgA in the semen demonstrated an alkaline phosphatase increase from ~ ~ ~ subjects whose semen 265 to 485 I U / C ~In. contrast, contained IgA showed only a modest increase, from 213 to 281 IU/cm3. Pygeum extract has also shown an ability to improve the capacity to achieve an erection in patients with BPH or prostatitis, as determined by nocturnal penile tumescence in a double-blind clinical trial.% BPH and prostatitis are often associated with erectile dysfunction and other sexual disturbances. Presumably by improving the underlying condition, pygeum can improve sexual function.

Pygeum versus Serenoa

was better tolerated.39In addition, the improvement of objective parameters, especially urine flow rate and residual urine content, is better in the clinical studies of serenoa. However, there may be circumstances in which pygeum is more effective than serenoa. For example, serenoa has not been shown to have the effects on prostate secretion that pygeum has. Although the two extracts have somewhat overlapping mechanisms of actions, they can be used in combination.

DOSAGE The dosage of the lipophilic extract of P. africunurn standardized to contain 14% triterpenes including betasitosterol and 0.5% n-docosanol is 100 to 200 mg/day. Typically the dosage has been divided for twice-daily administration; however, results were similar in a double-blind study with 100 mg given once daily and 50 mg twice daily, indicating that taking pygeum once daily is equivalent to using divided doses.40The crude herb is not used.

TOXICOLOGY Tests for acute and chronic toxicity in the rat and mouse have shown that the standardized extract of P.ufricunum bark is nontoxic. Raising the dosage from 1to 6 g/kg in the mouse and from 1 to 8 g/kg in the rat caused no deaths within 48 hours. In chronic toxicity studies, giving the animals from 60 to 600 mg/kg for 11 months did not produce any negative effects. In the human clinical trials, the pygeum extract also demonstrated no sigruficant toxicity. The most common side effect is gastrointestinal irritation, resulting in symptoms ranging from nausea to severe stomach pains; however, the presence of these side effects rarely leads to discontinuation of therapy.

The standardized liposterolic extract of Serenou repens is another popular botanical treatment for BPH (see Chapter 124). In a double-blind study that compared pygeum extract with extract of serenoa, the serenoa extract produced a greater reduction of symptoms and

There are no documented drug interactions for l? africanum.

1. Long0 R, lira S. Steroidal and other components of Pygeum africanum bark. Farmaco 1983;38:28&292. 2.Martinelli EM, Seraglia R, Pifferi G. Characterization of Pygeum africanum bark extracts by HRGC with computer assistance. HRC & CC 1986;9106-110. 3. Pierini N, Citti F, Di Marzio S, et al. Identificationand determination of n-docosanol in the bark extract of Pygeum africanum and in patent medicines containing it. Boll Chim Farm 1982;121:27-34. 4. Uberti E, Martinelli EM, Pifferi G, Gagliardi L. HPLC analysis of n-docosyl ferulate in Pygeum afrzcanum extracts and pharmaceutical formulations.Fitoterapia 1990;61:342-347.

5. Stewart KM.The African cherry (Prunus africana): can lessons be learned from an over-exploited medicinal tree? J Ethnopharmacol 2003;893-13. 6. Muntzing J, Eneroth P, Gustafsson JA, Liljekvist J. Direct and indirect effects of docosanol (IK.2),the active principle in Tadenan, on the rat prostate. Invest Urol1979;17176-180. 7. Thieblot L. Preventive and curative action of a bark extract of an African plant, Pygeum afrzcanurn: experimental prostatic adenoma in the rat. Therapie 1971;26575-580. 8. Hinman F. Benign prostatic hyperplasia. New York Springer-Verlag, 1983.

DRUG INTERACTIONS

9. Bombardelli E. Methods, composition and compounds for the treatment of prostatic adenoma. EP Appl 8330491.3, June 10, 1985. 10. Marcoli M. Anti-inflammatory and antiedemigenic activity of extract of Pygeum africunum in the rat. New Trends Androl Sci 1985; 1239-93. 11. Latalski M. The ultrastructure of the epithelium of bulbomthral glands after administrationof the Tadenan preparation. Folia Morphol 19799:193-201. 12.Guillemin P. Clinical trials of V1326, or Tadenan, in prostatic adenoma. Med Prat 1970;386:75-76. 13. Lange J, Muret P. Clinical trial of V1326 in prostatic disease. Med 1970;11:2807-2811. 14. Wemeau L, Delmay J, Blankaert J. Tadenan in prostatic adenoma. Vie Medicale 1970;Jan:585-588. 15. Viollet G . Clinical experimentation of a new drug from prostatic adenoma. Vie Medicale 1970;June:3457-3458. 16.Lhez A, Leguevague G. Clinical trials of a new lipid-sterolic complex of vegetal origin in the treatment of prostatic adenoma. Vie Medicale 197O;Dec:5399-5404. 17.Thomas JP, Rouffilange F. [The action of Tadenan in prostatic adenoma]. Rev Int Serv 1970;43:43-45. 18. Huet JA. Prostatic disease in old age. Med Intern 1970;5:405-408. 19. Rometti A. [Medical treatment of prostatic adenoma]. Prov Med 1970;38:49-51. 20. Gallizia F, Gallizia G. Medical treatment of benign prostatic hypertrophy with a new phytotherapeutic principle. Recent Med 1972; 9:461-468. 21. Durval A. [On the use of a new drug in the therapy of prostatic adenoma: Tadenan. Clinical considerations on 23 cases]. Minerva Urol1970;22:106-111. 22. Pansadoro V, Benincasa A. Prostatic hypertrophy. Results obtained with Pygeum africunum extract. Minerva Med 1972;11:119-144. 23. Zurita IE,Pecorini M, Cuzzoni G. Treatment of prostatic hypertrophy with Pygeum africanum extract. Rev Bras Med 1984;41:364-366. 24. Maver A. Medical treatment of fibroadenomatous hypertrophy of the prostate with a new plant substance. Minerva Med 1972;63: 2126-2136. 25. Bongi G. Tadenan in the treatment of prostatic adenoma: anatomoclinical study. Minerva Urol 1972;24:129-139. 26. Doremieux J, Masson JC, Bollack C. [Prostatic hypertrophy, clinical effects and histological changes produced by a lipid complex extracted from Pygeum africanum]. J Med Strasbourg 1973;4253-257.

27. Del Valio B. Use of a new drug in the treatment of chronic prostatitis. Minerva Urol1974;26:81-94. 28. Colpi G, Farina U. [Study of the activity of chloroformic extract of Pygeum africunum bark in the treatment of urethral obstructive syndrome caused by non-cancerous prostapathy]. Urologia 1976;43: 441-448. 29. Donkervoort T, Sterling J, van Ness J, Donker PJ. A clinical and urodynamic study of Tadenan in the treatment of benign prostatic hypertrophy. Eur Urol1977;8218-225. 30. h f o u r B, Choquenet C, Revol M, et al. Controlled study of the effects of Pygeum africanum extract on the functional symptoms of prostatic adenoma. Ann Urol1984;18:193-195. 31. Legramandi C, Ricci-Barbini V, Fonte A. [The importance of Pygrum africunum in the treatment of chronic prostatitis void of bacteria]. Gazz Med Ital 1984;143:73-76. 32. Ranno S, Minaldi G, Viscusi G, et al. [Efficacy and tolerability in the treatment of prostatic adenoma with Tadenan 501. Progr Med 1986;42165-169. 33. Frasseto G, Bertoglio S, Mancuso S, et al. [Study of the efficacy and tolerability of Tadenan 50 in patients with prostatic hypertrophy]. Progr Med 1986;42:49-52. 34. Bassi P, Artibani W, De Luca V, et al. Standardized extract of Pygerrm uficunum in the treatment of benign prostatic hypertrophy: controlled clinical study vs. placebo. Minerva Urol1987;39:45-50. 35. Lucchetta G, Weill A, Becker N, et al. Reactivation of the secretion from the prostatic gland in cases of reduced fertility: biological study of seminal fluid modifications. Urol Int 1984;39222-224. 36. Menchini-Fabris GF, Giorgi P, Andreini F, et al. New perspectives on the use Pygeurn ufricunum in prosato-bladder pathology. Arch Int Urol Nefrol Androl1988;60.313-322. 37. Clavert A, Cranz C, Riffaud JP, et al. Effects of an extract of the bark of Pygeum ufricanum (V.1326) on prostatic secretions in the rat and man. Ann Urol1986;20341-343. 38. Carani C, Salvioli C, Scuteri A, et al. Urological and sexual evaluation of treatment of benign prostatic disease using Pygeum ufiicunum at high doses. Arch Ital Urol Nefrol Androl1991;63341-345. 39. Duvia R, Radice GP, Galdini R. Advances in the phytotherapy of prostatic hypertrophy. Med Praxis 1983;4:143-148. 40. Chatelain C, Autet W, Brackman F. Comparison of once and twice daily dosage forms of Pygeum africunum extract in patients with benign prostatic hyperplasia: a randomized, double-blind study, with long-term open label extension. Urology 1999;54473-478.

Ruscus aculeatus (Butcher’s Broom) Kathy Abascal, BS, JD, RH(AHG) Eric L. Yamell, ND, RH(AHG) CHAPTER CONTENTS General Description

1227

Chemical Composition History and Folk Use

1227 1227

Pharmacology 1227 Anticancer Effect 1227 Antielastase Effect 1227 Ahtihypoxic Effect 1228 Antiinflammatory Effect 1228 Antimicrobial Effect 1228 Fibirinolytic Effect 1228 Lymphatic Flow Effect 1228 Vasoconstrictive Effect 1228

Clinical Applications 1228 Chronic Venous Insufficiency 1228 Edema and Varicosities 1230 Hemorrhoids 1230 Diabetic Retinopathy 1230 Premenstrual Syndrome 1230 Soft Tissue Injuries 1230 Dosage 1230 Toxicology

1230

Drug Interactions

1230

Ruscus uculeutus (family: Liliaceae) Common names: butcher’s broom, box holly, knee holly, kneeholy, kneeholm, Jew’s myrtle, sweet broom, pettigree, Maeusedornwurzelstock (German)

coumarins, sparteine, tyramine, and glycolic See Figure 121-1.

GENERAL DESCRIPTION

In ancient Greece, butcher’s broom was used as a laxative and to treat kidney stones.6In European botanical medicine, a wine decoction of butcher’s broom was used as a diuretic to treat urinary obstructions, kidney stones and gravel. It was also used to regulate menses, ameliorate jaundice, and treat headaches. In South America, the roasted root was made into a beverage for prostate tumors.7

Ruscus aculeatus is an evergreen shrub native to Mediterranean Europe and Africa from the Azores islands to Iran in southwesternAsia.’ Butcher’s broom has tough, green, erect, striated stems that do not have bark. Its leaves are rigid and terminate in a single sharp spine. It has large berries that remain attached to the plant through the winter. The root is thick, typically 2 to 4 inches long with many woody rootlets growing on its lower surface. The root is the part used medicinally.

CHEMICAL COMPOSITION The primary active ingredients of butcher’s broom are the steroidal saponins ruscogenin and neoruscogenin (up to 6%). The plant also contains other steroidal sapogenins and saponins (such as ruscin and ruscoside), fatty acids (mainly tetracosanoic acid), sterols (including sitosterol, campesterol, stigmasterol), flavonoids,

HISTORY AND FOLK USE

PHARMACOLOGY Anticancer Effect Butcher’s broom saponins have a cytostatic effect on leukemia HL-60 cells in vitro.8

Antielastase Effect Ruscinogens isolated from butcher’s broom have a remarkable antielastase in ~ i t r oThe . ~ author noted that the concentration of ruscinogen that will reach the perivascular matrix of the subpapillary derma after

1227

Vasoconstrictive Effect

HO Figure 121-1 Ruscogenin.

topical application of the herb in vivo is greater than the concentration tested in this study.

Antihypoxic Effect Hypoxia-induced activation of endothelial cells may be a cause of venous disease. A proprietary extract of butcher’s broom known as Cyclo 3 fort dose-dependently protected human endothelial cells from induced hypoxia in vitro.”

Antiinflammatory Effect Butcher’s broom extract and its isolated steroidal saponins had an antiinflammatory effect in several animal models.’0 Injected intravenously, it inhibits the permeability-increasing effects of bradykinin, leukotriene B4, and histamine in hamster cheek pouch preparations.”

Antimicrobial Effect Butcher‘s broom showed a very low activity against Candida albicans.’2

Fibrinolytic Effect Thrombosis in chronic venous insufficiency is associated with reduced levels of tissue plasminogen activator in varicose veins. In a small study (20 patients), patients scheduled for vein stripping surgery were administered butcher’s broom (150 mg) and methylhesperidine chalcone (150 mg) or placebo 3 times daily for 14 days prior to ~urgery.’~ Segments of the great saphenous vein removed from patients in the active group had enhanced levels of tissue plasminogen activator and enhanced fibrinolytic activity compared to placebo.

Lymphatic Flow Effect Butcher’s broom dose-dependently enhanced the duration and flow intensity of the lymphatic vessels in dogs.14This effect did not change when the calcium channel antagonist nifedipine was injected, indicating that butcher’s broom’s lymphatic effect does not involve the opening of calcium channels but appears to act directly on peripheral lymphatics.

Topical administration of butcher’s broom extract in a hamster cheek preparation dose-dependently inhibited histamine-induced increases in ~ermeabi1ity.I~ This action was inhibited by the alpha-1 adrenoceptor antagonist prazosin and the calcium channel blocker diltiazem but was not affected by the alpha-2 adrenoceptor antagonist rauwolscine. This suggests that butcher’s broom’s vasoconstrictive effect is mediated by calcium and alpha-1 adrenergic receptors. Heat increases, and cold decreases, butcher’s broom’s ability to increase the release of norepinephrine from the ad re no receptor^.'^

CLINICAL APPLICATIONS There are few clinical studies on the effect of butcher’s broom alone. Instead, most of the clinical studies investigate a proprietary combination formula known as Cyclo 3 fort by Pierre Fabre Medicament, Paris, France, or Phlebodril by Pierre Fabre Pharma GmbH, Frieburg, Germany. These formulas combine butcher’s broom with trimethylhesperidin chalcone (a flavonoid precursor) and ascorbic acid. Butcher’s broom has an action independent of the other compounds in the formula, and some studies indicate that butcher’s broom used alone may have a stronger effect. Yet other studies indicate that the combination may have a synergistic effect. All discussions of butcher’s broom trials below therefore include the possibility that it was not butcher’s broom by itself that was active. Butcher’s broom is also paired with Melilotus spp. (sweet clover) in some topical preparations. There are no studies indicating whether butcher’s broom alone would achieve the same results.

Chronic Venous lnsufficiency Butcher’s broom is most commonly used to alleviate the symptoms of chronic venous insufficiency (CVI), including ankle edema, itching, tension, and cramping of the legs. Both animal and clinical studies support its effectiveness in CVI, and the German Commission E approved butcher’s broom as an adjunct treatment for this condition.’ There are seven clinical trials on the use of butcher’s broom combination extracts in CVI. These studies consistently found the herb to have a positive effect, and are summarized in Table 121-1.1”22All but two were randomized, double-blind trials; however, both the quality of the trials and the butcher’s broom preparations vary from trial to trial. Nonetheless, butcher’s broom’s ability to improve venous circulation is well accepted. In one large multi-center trial, 81.6% of treating physicians rated its efficacy as excellent and the remaining physicians rated it as good.20Butcher’s broom acts most strongly when

30

80

Kiesewetter et alls

Beltramino et aIz0 Open-label, randomized, multicenter

Random selection, uncontrolled

Placebo-controlled, double-blind

CW,Chronic venous insufficiency.

36

Randomized, double-blind, placebo-controlled

20

Haas et all8

Randomized, doubleblind, multicenter

Seydewitz et aIz2

141 +20 healthy volunteers

Rudofsky17

Double-blind,crossover, placebo-controlled, prospective

Randomized, double-blind, placebo-controlled

40

Cappelli et all6

TvDe

Le Devehat et aIz1 60 + 7 healthy volunteers

No. of DarticiDants

Studv

2 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily: Control 2 tablets of 500 mg hydroxyethyl rutoside daily 2 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily 3 capsules (150 mg ruscus, 150 mg trimethylhesperidin chalcone) daily

3 ruscus capsules twice daily for 5 weeks, then 2 capsules twice daily; amount of ruscus in capsules not stated

1 capsule (150 mg ruscus, 150 mg methylhesperidin chalcone) 3 times a day

2 capsules (450 mg ruscus extract) 3 times daily for 4 weeks, then 2 capsules 2 times daily for 8 weeks

2 capsules (16.5 mg ruscinogens, 75 mg hesperidin, 50 mg ascorbic acid) 3 times a day

Product

Stage IV varicosities w/stage I or stage II CVI, scheduled for vein stripping

CVI; blood samples drawn from foot before and after provoked venous stasis

CVI (heavy, tired, swollen or painful legs)

CVI

CVI stage I and II, scheduled for surgery

CVI

CVI, varicosities

Focus

cher’s broom in chronic vascular insufficiency (CVI)

Increase in enzyme activity in the proximal segment of the vein, distinctly higher incidence of subjective improvement of symptoms

Improved blood viscosity disturbances caused by venous stasis

Significant improvement in symptoms, reduction in limb circumference; physicians and patients had a more favorable opinion of ruscus than of rutoside

Reduced circumferences of lower legs and malleoli, subjective complaints; greater rheologic improvement in patients with advanced stages of CVI

Significantly increased fibrinolytic activity of removed great saphenous vein

Continuous decrease in foot and ankle volume, decrease in leg swelling, improved venous pumping

Itching, edema, and paresthesia improved greatly

Result

4 weeks

4 weeks

90 days

5 months

14 days

2 weeks’ washout followed by 12 weeks’ treatment

2 months withl 15-day washout and 2 months’ crossover

Duration

Pharmacology of Natural Medicines

circulation is impaired, but some researchers caution that it is less effective when the disease has compromised venous wall receptor activity.’*

Edema and Varicosities Butcher’s broom shows promise as a treatment for a wide variety of edemas and circulatory disturbances of the venous system. The results of these clinical trials are summarized in Table 121-2.B32 As mentioned above, these trials were on combination extracts with butcher’s broom as a major component. Many of the studies are small and some are poorly designed, but the overall picture supports the ability of butcher’s broom to reduce swelling and discomfort associated with primary and secondary edema. It has positive effects in pregnancyrelated venous insufficiency, varicosities, lymphedema, symptoms of swelling of ankles and breast tenderness in premenstrual syndrome, edema secondary to calcium channel antagonist therapy of hypertension, and swelling secondary to soft tissue injury.

Hemorrhoids The German Commission E has approved butcher’s broom as a treatment for hemorrhoids.’ In an open-label multi-center study of 124 patients with hemorrhoids, 69% of patients and 75% of the treating physicians rated the butcher’s broom combination extract Cyclo 3 fort as having good or excellent efficacy.33Ninety-two percent of physicians rated the treatment as safe and well tolerated. Significant positive effects were observed after 7 days of treatment. Though controlled trials are warranted, butcher’s broom may be a useful treatment for patients with hemorrhoids.

duration of 67 months.32The amount of butcher’s broom administered for 90 days was not stated. Eighty percent of the women in the active group reported a complete resolution of PMS symptoms of mastalgia and breast tension. Unexpectedly, butcher’s broom also had a dramatic effect on some of the psychological symptoms associated with PMS (e.g., complete resolution in 85% of the subjects of symptoms such as irritableness, “hairtrigger temper,” ”temporary alienation”). In vitro research indicates that butcher’s broom acts more efficiently in the presence of progesterone; butcher’s broom may be most effective during the luteal phase of a woman’s menstrual cycle.

Soft Tissue Injuries In a small study, butcher’s broom applied topically reduced swelling and pain caused by soft tissue sports injuries.2s Several in vitro studies show that butcher’s broom’s action is enhanced by heat, suggesting that it may be advantageous to apply heat to the site of the injury when using the herb.

DOSAGE Most clinical studies administered 150 mg butcher’s broom three times daily with meals. The German Commission E recommends extracts and preparations standardized to contain 7 to 11 mg total ruscogenin (sum of neoruscogenin and ruscogenin) per dose.’ A typical dose of tincture of the dried root is 1to 2 ml three times daily.35

Diabetic Retinopathy

TOXICOLOGY

Diabetic retinopathy can abruptly cause severe deterioration of vision, and it is estimated that the incidence of retinopathy may be as high as 80% in patients with longstanding, poorly controlled diabetes. In a study of 60 patients with non-insulin-dependent diabetes, butcher’s broom compared favorably with troxerutin.34 Butcher’s broom produced a 23% regression of negative changes in the fundus of the eye with no sign of progression. Troxerutin produced a somewhat larger regression (27.8%) but also had a greater (5.8%) progression rate. Butcher’s broom also decreased blood glucose and cholesterol levels and significantly increased high density lipoproteins in this preliminary study.

Butcher’s broom is generally considered very safe. It occasionally causes gastrointestinal distress, and in rare instances causes lymphatic ~ o l i t i s . ’ ,Thus ~ ~ , ~butcher‘s ~ broom should probably not be combined with nonsteroidal antiinflammatory drugs or other drugs linked with lymphatic colitis, and use should be discontinued if negative gastrointestinal symptoms are severe or persist. One author cautions against the use of butcher’s broom in pregnancy based on a lack of proof of safety3 While not definitive, preliminary animal and clinical studies cited above indicate that butcher’s broom does not have negative effects when used during pregnancy.

Premenstrual Syndrome

DRUG INTERACTIONS

Butcher’s broom sigruficantly reduced symptoms of breast tenderness in women with diagnosed premenstrual syndrome (PMS) in a randomized, placebo-controlled, double-blind study of 40 women with PMS of an average

In an in vitro study, adenosine, cocaine, phentolamine, prazosin, and verapamil reduced butcher’s broom’s vasoconstrictive effect.3*Acetylcholine and rauwolscine potentiated its vasoconstrictive action. No studies have

Double-blind, placebocontrolled

9

48

57

12

12

50

11

25 + 20 healthy controls

Bergz3

BohmeP

Cluzan et aIz6

Cossio et alz7

Jager et aI2*

Weindorf et atz9

Lagrue et aPO

Le Devehat et a P

Monteil-Seurin 40 and L a d ~ r e ~ ~

Open, uncontrolled

20

Baudet et al 24

Randomized, double-blind, placebocontrolled

Double-blind, placebocontrolled

Open, uncontrolled

2 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily

2 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily

150 mg hesperidin methylchalchone, 100 mg ascorbic acid) daily

3 capsules (150 mg ruscus,

3 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) 3 daily plus physiotherapy Drinkable ampules; 1st week: 180 mg ruscus and 900 mg hesperidin methylchalchone per day; weeks 2-8 120 mg ruscus and 600 mg hesperidin methylchalchone per day 3 capsules (150 mg ruscus, 150 mg hesperidin methylchalchone, 100 mg ascorbic acid) per day 450 mg ruscus, 450 mg hesperidin, 300 mg ascorbic acid daily

Placebocontrolled, double-blind Uncontrolled

4 g ruscus cream (1.6 g ruscus and 1.6 g melilot per 100 g) 3 times daily

Compression stocking, kinesitherapy, and melilot and ruscus cream (4 to 6 g creadday)

2 capsules of ruscus extractlday (amt. not stated) from week 21 to 24 of pregnancy

Melilot and ruscus cream (4 to 6 g creamJday)

Product

Placebocontrolled

Placebocontrolled

Uncontrolled

Placebocontrolled

18

Bergz3

Type

participants

Study

No. of

Premenstrual syndrome symptoms for at least 60 months (breast tension, pelvic heaviness, “menstrual psychopathic disorder,” ankle edema)

Venous insufficiency characterized by varicose veins; blood samples drawn before and after provoked venous stasis

Edema secondary to calcium antagonist treatment of hypertension

Trunk or branch varicose veins

Primary varicosity of greater saphenous vein

Lymphedema of extremities

Lymphedema after mastectomy

Sports injuries, patients w/sprain or contusions of lower limb or ankle

Pregnant women with painful pregnancy-relatedvaricosity of one limb

Pregnancy-relatedsymptoms of venolymphatic insufficiency

Effect of cream on size of femoral veins in healthy volunteers

Focus

Clinical studies on butcher’s broom in edema and varicosities

~

14 days

Increased muscle strength, reduced swelling, decreased temperature, and resolved pain more quickly

Significantly reduced breast tension, pelvic heaviness, and menstrual “psychopathic disorder”

Significant improvement in several microrheologic factors of blood viscosity

90 days

Not found

6-8 weeks 4/9 showed complete improvement; 3/9 showed partial improvement; 2/9 showed no change in edema

* 1 days 2 weeks

7

2 months

Venous capacity and improved at rest; expelled blood volume during exercise improved

Significant changes in some venous parameters

Significant improvement in symptoms, reduction of edema in 81% of participants

90 days

Treatment beginning in second trimester

Statistically significant reduction in size of femoral vein and pain

Reduced edema by second month, positive subjective improvement in symptoms

Women monitored from early pregnancy; infants studied before and after birth

1 day

Length

Improved symptoms based on subjective criteria; “absolute harmlessness” to infant

Change in size of femoral vein

Result

-

been conducted to determine whether butcher's broom in turn interferes with or affects the action of the aforementioned drugs. One author cautions against the use of butcher's broom for patients on alpha-adrenergic

antagonistic therapy for benign prostatic hyperplasia or hypertension, or for patients taking monoamine oxidaseinhibiting drugs.3In vitro, animal, and clinical studies overall do not provide support for this view.

1. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal medicine: expanded Commission E monographs. Newton, MA: Integrative Medicine Communications, 2000:40. 2. Duke JA. Handbook of medicinal herbs, ed 2. Boca Raton, n:CRC PRSS, 2002130-131. 3. Fetrow CW,Avila Jl7.Professional's handbook of complementary and alternative medicines. Springhouse, PA: Springhouse Corp, 1999. 4. Rauwald HW,Grunwidl J. Ruscus uculeutus extract: unambiguous proof of the absorption of spirostanol glycosides in human plasma after oral administration. Planta Med 1991;57A75-A76. 5. Dunouau C, Belle R, W a d - A h A, et al. Triterpenes and sterols from Ruscus uculeutus. Planta Med 1996;62:189-190. 6. Potterton D. Culpeper's color herbal. New York Sterling Publishing, 198335. 7. Hartwell JL. Plants used against cancer. Lawrence, MA: Quarterman Publications, 1982340. 8. Mimaki Y, Kuroda M, Kameyama A, et al. New steroidal constituents of the underground parts of Ruscus muleutits and their cytostatic activity on HL-60 cells. Chem Pharm Bull (Tokyo) 1998;46298-303. 9. Baurain R, Dom G, Trouet A. Protecting effect of Cyclo 3 Fort and its constituents for human endothelial cells under hypoxia. Clin Hemorheol 1994;14:S15. 10. Mimaki Y, Kuroda M, Kameyama A, et al. Steroidal saponins from the underground parts of Ruscus uculeatus and their cytostatic activity on HL-60 cells. Phytochemistry 1998;48:485-493. 11. Bouskela E, Cyrino FZ, Marcelon G . Inhibitory effect of the Ruscus extract and of the flavonoid hesperidine methylchalcone on increased microvascular permeability induced by various agents in the hamster cheek pouch. J Acardiovasc Pharmacol 1993;22:

19. Kiesewetter H, Scheffler P, Jung F, et a1 Effect of Ruscus extract in chronic venous insufficiency stage I, II,and III. In Vanhoutte PM, ed. Return circulation and norepinephrine. Pans: John Libbey Eurotext, 1991:163-169. 20. Beltramino R, l'enenory A, Buceta AM. An open-label, randomized multicenter study comparing the efficacy and safety of Cyclo 3 Fort versus hydroxyethyl rutoside in chronic venous lymphatic insufficiency. Angiology 2OOO;51:535-544. 21. Le Devehat C, Khodabandehlou T, Dougny M. The effects of Cyclo 3 Fort treatment on hemorheological disturbances during a provoked venous stasis in patients with chronic venous insufficiency. Clin Hemorh 1994;14(Suppll):S53-563. 22. Seydewitz V, Berg D, Welbers P, Staubesand J. Biochemical investigations on the action of Ruscus extract and trimethylhesperidinchalcon (TMHC). In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:151-156. 23. Berg D. First mults with Ruscus extract in the treatment of pregnancy related varicose veins. In Vanhoutte PM, ed. Return circulation and norepinephrine. Park John Libbey Eurotext, 1991:5561. 24. Baudet JH, Collet D, Aubard Y, Renaudie P. Therapeutic test of Ruscus extract in pregnant women: evaluation of the fetal tolerance applying the pulse Doppler's method of the cord. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:63-71. 25. Bohmer D. Action of Ruscus extract cream in the treatment of acute sport injuries. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:171-179. 26. Cluzan RV, AUiot F, Ghabboun S, Pascot M. Treatment of secondary lymphedema of the upper limb with Cyclo 3 Fort. Lymphology 1996;29:29-35. 27. Jimenez Cossio JA, Magallon Ortin PJ, Capilla Montes MT, Coya Vina J. Therapeutic effect of Ruscus extract in lymphedemas of the extremities. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:lll-119. 28. Jager K, Eichlisberger R, Jeanneret CH, Lobs KH. Pharmacodynamic effects of Ruscus extract (Cyclo 3 Fort) on superficial and deep veins in patients with primary varicose veins assessment by duplex sonography. Clin Drug Invest 1999;17 265-273. 29. Weindorf N, Schultz-Ehrenburg U.Kontrollierte studie zur oralen venentonisierung der primaeren varikosis mit Ruscus uculeutus und trimethylhesperdinechalckon.Z Huutkr 1987;622&38. 30. Lagrue G, Behar A, Chaabane A, Laurent J. Edema induced by calcium antagonists: effects of Ruscus extract on clinical and biological parameters. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:105-109. 31.Le Devehat C, Khodabandehlou T, Vimeux M, Bondoux G. Hemorheological concepts in venous insufficiency and implications for treatment with Ruscus extract. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991225-236. 32. Monteil-Seurin J, Ladure PH. Efficacy of Ruscus extract in the treatment of the premenstrual syndrome. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:43-53.

225-230.

12. Ali-Shtayeh MS, Yaghmour Rh4, Faidi YR, et al. Antimicrobial activity of 20 plants used in folkloric medicine in the Palestinian area. J Ethnopharmacol1998;60:265-271. 13.Facino RM, Carini M, Stefani R, et al. Anti-elastase and antihyaluronidase activities of saponins and sapogenins from Hederu helix, Aesculus hippocastunum, and Ruscus uculeutus: factors contributing to their efficacy in the treatment of venous insufficiency. Arch Pharm 1995;328:720-724. 14. Pouget G, Ducros L, Marcelon G. Effect of Ruscus extract on peripheral lymphatic vessel pressure and flow. In Vanhoutte PM, ed. Return circulation and norepinephrine. Paris: John Libby Eurotext, 1991~89-95. 15. Bouskela E, Cyrino FZ, Marcelon G. Effects of Ruscus extract on the internal diameter of arterioles and venules of the hamster cheek pouch microcirculation.J Cardiovasc Pharmacol 1993;22:221-224. 16. Cappelli R, Nicora M, Di Perri T. Use of extract of Ruscus nculeufus in venous disease of the lower limbs. Drugs Exp Clin Res 1988;14:277-283. 17. Rudofsky G. Efficacy of Ruscus extract in venolymphatic edema using foot volumetry. In Vanhoutte I'M, ed. Return circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:121-130. 18. Haas S, Lill G, Stiller A, et al: Influence of Ruscus extract and methylhesperidine chalcone on the fibrinolytic activity of the vein wall. In Vanhoutte PM, ed. Retum circulation and norepinephrine. Paris: John Libbey Eurotext, 1991:157-162.

Ruscus aculeatus (Butcher’s Broom) 33. Bennani A, Biadillah MC, Cherkaoui A, Sebti M. [Acute attack of hemorrhoids: Efficacy of Cyclo 3 Fort based on results in 124 cases reported by specialists.] Phlebologie 1999;52:89-93. 34. Archimowicz-CyrylowskaB, Adamek B, Drozdzik M, et al. Clinical effect of buckwheat herb, Ruscus extract and Troxerutin on retinopathy and lipids in diabetic patients. Phytother Res 1996;10659-662. 35. Moore M. Herbal materia medica. Bisbee, Az: Southwest School of Botanical Medicine, 1995:25.

36. Dharancy S, Dapvril V, Dupont-Evrard F, Colombel JF. ICyclo 3 Fortinduced lymphocytic colitis associated with ileal villous atrophy.] Gastroenterol Clin Biol2000;24:134-135. 37. Mennecier D, Thiolet C, Bredin C, et al. [Lymphocyticcolitis after ingestion of Rustacea flavonoid extract.] Presse Med 2001;301063. 38.Rubanyi G, Marcelon G, Vanhoutte PM. Effect of temperature on the responsiveness of cutaneous veins to the extract of Rirscus aculeatus. Gen Pharmacol 1984;15:431-434.

SAMe (S-Adenosylmethionine) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Introduction 1235 Pharmacology 1235 Available Forms 1235 Clinical Indications 1235 Depression 1235 Osteoarthritis 1236 Fibrornyalgia 1237

INTRODUCTION S-Adenosylmethionine (SAMe) is an important physiologic agent formed in the body through combination of the essential amino acid methionine with adenosyl triphosphate (ATP) (Figure 122-1). SAMe was discovered in Italy in 1952. Not surprisingly, most of the research on SAMe has been conducted in the country of its discovery. Because SAMe is manufactured from methionine, one would think that dietary sources of methionine would provide the same benefits as SAMe. However, high doses of methionine have not been shown to raise levels of SAMe, nor do they provide the same pharmacologic activity as SAMe. High doses of methionine are associated with some degree of t0xicity.l Normally the body manufactures all the SAMe it needs from the amino acid methionine. However, a deficiency of methionine, vitamin BI2, or folic acid can result in decreased SAMe synthesis. In addition, tissue levels of SAMe are typically low in the elderly and in patients with osteoarthritis, depression, and various liver disorders.

PHARMACOLOGY SAMe is involved in more than 40 biochemical reactions in the body. It functions closely with folic acid and vitamin BIZin “methylation” reactions. Methylation is the process of adding a single carbon unit (a methyl group) to another molecule. SAMe is many times more effective in transferring methyl groups than other methyl donors.

Liver Disorders 1238 Migraine 1238

Dosage 1238 Toxicology 1238 Interactionsand Contraindications 1239

Methylation reactions are critical in the manufacture of many body components, especially brain chemicals, as well as in detoxification reactions. SAMe is also required in the manufacture of all sulfurcontaining compounds in the human body, including glutathione (discussed later) and various sulfur-containing cartilage components. The beneficial effects of SAMe supplementation are far-reaching owing to this agent’s central role in so many metabolic processes.

Available Forms SAMe has been available commercially in Europe since 1975 and in the United States since 1999. The commercial form of SAMe is a stabilized salt produced under U.S. patents no. 3,954,726 (1976) and no. 4,057,686 (1977).

CLINICAL INDICATIONS The five principal uses of SAMe are in depression, osteoarthritis, fibromyalgia, liver disorders, and migraine headaches.

Depression SAMe is necessary in the manufacture of important brain compounds, such as neurotransmitters and phospholipids like phosphatidylcholine and phosphatidylserine. Supplementing the diet with SAMe in depressed patients raises levels of serotonin, dopamine, and phosphatidylserine and improves binding of neurotransmitters to receptor sites, resulting in increased 1235

Pharmacology of Natural Medicines

I

CHZ

H,C--Sf

CH20

I/

HO

\

I

OH

Figure 122-1 S-Adenosylmethionine (SAMe)

SAMe has also been shown to produce sigruficant effects on other conditions associated with depression, such as during the postpartum (after pregnancy) period and in drug rehabilitation. SAMe's benefits in these conditions are probably a combination of its effect on brain chemistry and liver function (discussed later). In the study in postpartum depression (after-pregnancy "blues"), the administration of SAMe (1600 mg/day) was associated with significantly better mood scores In another study, SAMe compared with a placeb~.'~ (1200 mg/day) was shown to sigrhcantly reduce psychologic distress (chiefly anxiety and depression) in the detoxification and rehabilitation of opiate abusers.16 Detailed clinical evaluations utilizing electroencephalograms (EEGs), event-related potentials (EMS), and low-resolution brain electromagnetic tomography (LORETA) have clearly indicated a central nervous system antidepressant action of SAMe.14

serotonin and dopamine activity and better brain cell membrane fluidity, leading to significant clinical improvement.22 The antidepressiveeffects of folic acid (seeChapter 144) are mild compared with the effects noted in clinical trials Osteoarthritis using SAMe. On the basis of results from a number of clinical studies it appears that SAMe is perhaps the most SAMe has also demonstrated impressive results in the effective natural antidepressant (although a strong argutreatment of o~teoarthritis."-'~A deficiency of SAMe in ment could be made for the extract of St. John's wort the joint tissue, just like a deficiency of glucosamine, standardized to contain 0.3% hypericin)."s leads to loss of the gel-like nature and shock-absorbing Although most of the early studies utilized injectable qualities of cartilage. As a result, osteoarthritis can SAMe, the later studies have used an oral dose of 400 mg develop. four times daily (1600 mg total) and have demonstrated In vitro studies have shown that SAMe exerts a that SAMe is just as effective given orally as when given number of effects that appear to be highly relevant in intraven~usly.~-'~ the treatment of osteoarthritis. First, the agent has been Several studies have compared SAMe with tricyclic shown to be very important in the manufacture of cartiantidepressants. These studies have shown that SAMe lage components.20This effect has been demonstrated is better tolerated and has a quicker onset of anti very well in humans. In one double-blind study condepressant action. In one study comparing SAMe with ducted in Germany, the 14 patients with osteoarthritis of the hands who were given SAMe showed greater desipramine in addition to determining the clinical response, the blood level of SAMe was determined in cartilage formation on magnetic resonance imaging (MRI).*' These results indicate that SAMe is capable both groups. At the end of the 4-week trial, 62% of the of improving the structure and function of cartilage patients treated with SAMe and 50% of the patients treated with desipramine had significantly improved. in joints affected by osteoarthritis. Second, SAMe has Regardless of the type of treatment, patients with a 50% shown some mild pain-relieving and anti-inflammatory decrease in Hamilton Depression Scale score showed effects in animal studies.' All of these effects combine a sigruficant rise in plasma SAMe concentration. These to produce exceptional clinical benefits. results suggest that one of the ways that tricyclic antideA total of 21,524 patients with osteoarthritis have pressant agents exert their antidepressive effects utilized SAMe in detailed clinical trials. In double-blind is by raising SAMe 1e~els.I~ trials, SAMe has demonstrated similar reductions in In two separate double-blind studies, SAMe was pain scores and clinical symptoms to those produced by nonsteroidal antiinflammatory drugs (NSAIDs) like given orally (1600 mg daily) or intramuscularly (400 mg ibuprofen, indomethacin, naproxen, and piroxicam. daily) and compared with 150 mg imipramine given orally daily. In both studies, the results of SAMe and In one double-blind study, SAMe was compared imipramine treatment did not differ significantly for any with ibuprofen.22The 36 subjects with osteoarthritis of efficacy measure. However, significantly fewer adverse the knee, the hip, and/or the spine received a daily oral events were observed in the patients treated with SAMe. dose of 1200 mg of SAMe or 1200 mg of ibuprofen for The researchers concluded that the antidepressive 4 weeks. Morning stiffness, pain at rest, pain on motion, efficacy of 1600 mg SAMe orally and 400 mg SAMe crepitation (crackling noise upon movement of a joint), intramuscularly is comparable with that of 150 mg swelling, and limitation of motion of the affected joints imipramine, but SAMe is sigruficantly better t01erated.I~ were assessed before and after treatment. The total

SAMe (S-Adenosylmethionine)

score obtained by the evaluation of all the individual clinical parameters improved to the same extent in patients treated with SAMe and in those treated with ibuprofen. In two other studies, SAMe was actually shown to produce slightly better results.2324 SAMe has also been compared with naproxen (Naprosyn). In one double-blind study, 20 patients with osteoarthritis of the knee were given either SAMe or naproxen for 6 weeksE During the first week, SAMe was administered at a dose of 400 mg three times daily and afterwards at a dose of 400 mg twice daily, whereas the dose of naproxen during the first week was 250 mg three times daily and subsequently 250 mg twice daily. During the first 2 weeks, the patients were allowed to take the drug paracetamol as an additional analgesic if the pain was severe. The patients were examined at the beginning of the study and after 2,4, and 6 weeks. The parameters tested were pain, crepitation, joint swelling, circumference of joint, extent of motility, and walking time over 10 meters. At the end of the sixth week no statistically sigruficant difference between the two patient groups treated was found; both groups exhibited a marked improvement on all parameters. Another double-blind study compared SAMe with both naproxen and a placebo in the treatment of osteoarthritis of the hip, knee, spine, and hand. The study involved 33 rheumatologic and orthopedic medical centers and a total of 734 subjects. SAMe administered orally at a dose of 1200 mg daily was shown to exert the same analgesic (pain-relieving) activity as naproxen at a dose of 750 mg daily. However, SAMe was significantly better than naproxen, both in terms of physicians’ and patients’ judgments and in terms of the number of patients with side effects. In fact, SAMe was better tolerated than the placebo. Ten patients in the SAMe group and 13 in the placebo group withdrew from the study because of intolerance to the Other double-blind studies have shown SAMe to offer the pain-relieving and antiinflammatory benefits of drugs like indomethacin and piroxicam but is generally much better tolerated than these potent N S A I D S . ~ ~ , ~ ~ Perhaps the most meaningful study of SAMe in the treatment of osteoarthritis was a long-term, multicenter, open 2-year trial involving 97 patients with osteoarthritis of the knee, hip, and spine.29The patients received 600 mg of SAMe daily (equivalent to three tablets of 200 mg each) for the first 2 weeks and thereafter 400 mg daily (equivalent to two tablets of 200 mg each) until the end of the 24th month of treatment. Separate evaluations were made for osteoarthritis of the knee, hip, cervical spine, and dorsal/lumbar spine. The severity of the clinical symptom (morning stiffness, pain at rest, and pain on movement) was assessed with scoring before the start of the treatment,

at the end of the first and second weeks of treatment, and then monthly until the end of the 24-month period. SAMe showed good clinical effectiveness and was well tolerated. The improvement of the clinical symptoms during therapy with SAMe was already evident after the first weeks and continued to the end of treatment. Nonspecific side effects occurred in 20 patients, but in no case did therapy have to be discontinued. Most side effects disappeared during the course of therapy. Moreover, during the last 6 months of treatment, no adverse effect was recorded. Detailed laboratory tests carried out at the start and after 6,12,18, and 24 months of treatment showed no pathologic changes. SAMe administration also improved the depressive feelings often associated with osteoarthritis. And finally, in the largest study, 20,641 patients with osteoarthritis of the knee, the hip, and the spine and also with osteoarthritic polyarthritis of the fingers, were studied over 8 weeksN The patients were given 400 mg three times daily for the first week, 400 mg twice daily for the second week, and 200 mg twice daily from the third week on. No additional analgesic/ anti-inflammatory treatment was allowed. The efficacy of SAMe was comparable to results achieved with NSAIDs. Efficacy was described as very good or good in 71% of cases, as moderate in 21%, and as poor in 9%; tolerance to the agent was assessed as very good or good in 87Y0, as moderate in 8%, and as poor in 5%. What all of these studies indicate is that SAMe appears to offer significant advantages over NSAIDs. The drugs are associated with sigruhcant risk of toxicity, side effects, and actual promotion of the disease process in osteoarthritis, but SAMe offers similar benefits without risk or side effect.

Fibromyalgia SAMe has been shown in four double-blind clinical studies to produce excellent benefits in patients suffering from f i b r ~ m y a l g i a .In ~ ~two - ~ of the studies, injectable SAMe (200 mg daily) was used. During treatment, subjects demonstrated sigruficant in reduction in the number of trigger points and painful areas as well as improvements in m ~ ~ d . ~ ~ , ~ ~ In one of the studies oral SAMe (800 mg daily) was compared with a placebo for 6 weeks in 44 patients with fibromyalgia.33Tender point score, muscle strength, disease activity, subjective symptom, mood parameters, and side effects were evaluated. Patients given SAMe demonstrated improvements in clinical disease activity, pain experienced during the last week, fatigue, morning stiffness, and mood; however, the tender point score and muscle strength did not differ in the two treatment groups. SAMe was without side effect. In one of the studies, SAMe was compared with transcutaneous electrical nerve stimulation (TENS)-a

Pharmacology of Natural Medicines popular treatment for fibromyalgia-in 30 patients with this disorder.34Patients receiving SAMe (200 mg by injection and 400 mg orally daily) experienced significantly greater clinical benefit as shown by a decreased number of tender points, diminished subjective feelings of pain and fatigue, and improved mood. TENS offered little benefit for most symptoms, whereas SAMe was deemed “effective in relieving the signs and symptoms of primary fibromyalgia.”w

Liver Disorders SAMe has been shown to be quite beneficial in several liver disorders, including cirrhosis, Gilbert syndrome, and oral contraceptiveinduced liver damage. Its benefits are related to its function as the major methyl donor in the liver as well as its lipotropic activity. One of the leading contributors to impaired liver function is diminished bile flow, or cholestasis. SAMe is beneficial for a variety of liver disorders because of its ability to promote bile flow and relieve chole~tasis.~~3 One of the key functions of SAMe in the liver is the inactivation of estrogens. Clinical studies have shown that SAMe is quite useful in protecting the liver from damage and improving liver function in conditions associated with estrogen excess-namely, oral contraceptive use, pregnancy, and premenstrual ~yndrome.~’-~~ Another key indication for the use of SAMe is in the treatment of Gilbert syndrome, a common disorder characterized by a chronically elevated serum bilirubin level (1.2 to 3.0 mg/dl). Previously considered rare, this disorder is now known to affect as much as 5% of the general population. The condition is usually without symptoms, although some patients complain about loss of appetite, malaise, and fatigue (typical symptoms of impaired liver function). SAMe at a dosage of 400 mg three times daily has resulted in a significant decrease in serum bilirubin in patients with Gilbert syndrome.& In addition to these relative minor disturbances in liver function, SAMe offers benefits in the treatment of more severe liver disorders including cirrhosis. Its effect in cirrhosis appears to be due to an abihty to overcome the SAMe depletion characterized by the disorder. Because SAMe is involved in so many liver processes, depleted levels of SAMe within the liver has serious consequences. Supplementation with SAMe in patients with liver cirrhosis not only improves bile flow and clinical signs and symptoms, but also promotes membrane function and increases levels of glutathione>14 Glutathione assumes a critical role in detoxification as well as in the defense against a variety of injurious agents by combining directly with these toxic substances to eventually form water-soluble compounds.

Because many of the toxic compounds are lipid (fat) soluble, conversion to water-soluble compounds results in more efficient excretion via the kidneys. When higher levels of toxic compounds are present or when the liver function is impaired, higher glutathione levels are required. One of the greatest risks of chronic liver diseases such as chronic hepatitis is liver cancer. Supplementation with SAMe appears to be very much indicated in patients with such diseases in the attempt to reduce the risk for liver cancer. Animal studies have shown a significant protective effect of supplemental SAMe against liver cancer in animals exposed to liver ~arcinogens.4~

Migraine SAMe has also been shown to be of benefit in the treatment of migraine headaches. The benefit arises gradually, and long-term treatment is required for therapeutic eff ectiveness.46

DOSAGE In general, the longer SAMe is used, the more beneficial the results. This agent is perfectly suited for longterm use because of its excellent safety profile. The dosage ranges for the various clinical indications are as follows:

Depression. 400 mg three to four times daily. Because SAMe can cause nausea and gastrointestinal disturbances in some people, it is recommended that SAMe be started at a dosage of 200 mg twice daily for the first day, increased to 400 mg twice daily on day 3, then 400 mg three times daily on day 10, and finally to the full dosage of 400 mg four times daily after 20 days if needed. Osteoarthrifis. Start out as above for depression. After 21 days at a dosage of 1200 mg daily, reduce to the maintenance dosage of 200 mg twice daily. Fibromyalgia. 200 mg to 400 mg two times daily. Liver Disorders. 200 mg to 400 mg two to three times daily. Migraine Headaches. 200 mg to 400 mg two times daily.

TOXICOLOGY No significant side effects have been reported with oral SAMe other than the occasional nausea and gastrointestinal disturbances. However, individuals with bipolar (manic) depression should not take SAMe unless

SAMe (S-Adenosylmethionine)

under strict medical supervision because SAMe‘s antidepressant activity may lead to the manic phase in these individuals; this effect is exclusive to some people with bipolar depression.

INTERACTIONS AND CONTRAINDICATIONS SAMe functions very closely with vitamin BI2, folic acid, vitamin B6, and choline in methylation reactions. Because of SAMe‘s effects on the liver, it may enhance the elimination of various drugs from the body!’ The clinical significance of this effect has not been fully determined.

1.Stramentinoli G. Pharmacologic aspects of Sadenosylmethionine. Pharmacokinetics and pharmacodynamics. Am J Med 1987;83 35-42. 2. Bottiglieri T, Hyland K, Reynolds EH. The clinical potential of

ademetionine (Sadenosylmethionine) in neurological disorders. Drugs 1994;48:137-152. 3. Fava M, Rosenbaum JF, MacLaughlin R, et al. Neuroendocrine effects of Sadenosyl-L-methionine, a novel putative antidepressant. J Psychiatr Res 1990;24:177-184. 4. Bressa GM. Sadenosyl-L-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl 1994; 154:7-14. 5. Janicak PG, Lipinski J, Davis JM, et al. Parenteral Sadenosylmethionine (SAMe) in depression: literature review and preliminary data. Psychopharmacol Bull 1989;25:238-242. 6. Friedel HA, Goa KL, Benfield P. Sadenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. Drugs 1989;38:389-416. 7. Carney MW, Toone BK, Reynolds EH. Sadenosylmethionine and affective disorder. Am J Med 1987;83:104-106. 8. Vahora SA, Malek-Ahmadi P. Sadenosylmethionine in the treatment of depression. Neurosci Biobehav Rev 1988;12:139-141. 9. Kagan BL, Sultzer DL, Rosenlicht N, et al. Oral Sadenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry 1990;147591-595. 10. Rosenbaum JF, Fava M, Falk WE, et al. An open-label pilot study of oral Sadenosylmethionine in major depression: interim results. Psychopharmacol Bull 1988;24189-194. 11. De Vanna M, Rigamonti R. Oral S-adenosyl-L-methionine in depression. Curr Ther Res 1992;52:478-485. 12. Salmaggi E Bressa GM, Nicchia G, et al. Double-blind, placebocontrolled study of Sadenosyl-L-methionine in depressed postmenopausal women. Psychother Psychosom 1993;59:34-40. 13. Bell KM, Potkin SG, Carreon D, et al. Sadenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl1994;15415-18. 14. Delle Chiaie R, Pancheri P,Scapicchio P. Efficacy and tolerability of oral and intramuscular Sadenosyl-L-methionine 1,4butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. Am J Clin Nutr 2OO2;76:117251176s.

It has been cautioned that SAMe be avoided in patients Parkinson’s disease. Animal studies indicate that excessive methylation is associated with Parkinson’s disease and SAMe excess has caused Parkinson’s disease-like effects in animal In addition, both animal and human studies indicate that increased methylation can cause the depletion of dopamine and block the effects of do dopa.^,*^,^ This line of research is contradicted, however, by preliminary evidence that SAMe may improve the emotional depression and the impaired mental function that are often associated with the disorder.50 Nonetheless, it is recommended that patients with Parkinson’s disease avoid supplementing with SAMe until more is known.

15. Cerutti R, Sichel MP, Perin M, et al. Psychological distress during puerperium: A novel therapeutic approach using Sadenosylmethionine. Curr Ther Res 1993;53:707-717. 16. Lo Russo A, Monaco M, Pani A, et al. Efficacy of SadenosylL-methionine in relieving psychological distress associated with detoxification in opiate abusers. Curr Ther Res 1994;55:905-913. 17.Soeken KL, Lee WL, Bausell RB, et al. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract 2002;51:425-430. 18. Schumacher HR Jr. Osteoarthritis: the clinical picture, pathogenesis, and management with studies on a new therapeutic agent, Sadenosylmethionine. Am J Med 1987;83:1-4. 19. Montrone F, Fumagalli M, Sarzi Puttini P, et al. Double-blind study of Sadenosyl-methionine versus placebo in hip and knee arthrosis. Clin Rheumatol1985;4:484-485. 20.Harmand MF, Vilamitjana J, Maloche E, et al. Effects of Sadenosymethionine on human articular chondrocyte differentiation. An in vitro study. Am J Med 1987;83:48-54. 21. Konig H, Stahl H, Sieper J, et al. Magnetic resonance tomography of finger polyarthritis: morphology and cartilage signals after ademetionine therapy. Aktuelle Radio1 1995;5:36-40. 22. MulIer-Fassbender H. Double-blind clinical trial of Sadenosylmethionine versus ibuprofen in the treatment of osteoarthritis. Am J Med 1987;8381-83. 23. Glorioso S, Todesco S, Mazzi A, et al. Double-blind multicentre study of the activity of Sadenosylmethionine in hip and knee osteoarthritis. Int J Clin Pharmacol Res 1985;5:39-49. 24. Marcolongo R, Giordano N, Colombo B, et al. Double-blind multicentre study of the activity of Sadenosyl-methionine in hip and knee osteoarthritis. Curr Ther Res 1985;3782-94. 25. Domljan Z, Vrhovac B, Durrigl T, et al. A double-blind trial of ademetionine vs naproxen in activated gonarthrosis. Int J Clin Pharmacol Ther Toxic01 1989;27329-333. 26. Caruso I, Pietrogrande V. Italian double-blind multicenter study comparing Sadenosylmethionine, naproxen, and placebo in the treatment of degenerative joint disease. Am J Med 1987;83:66-71. 27. Vetter G. Double-blind comparative clinical trial with Sadenosylmethionine and indomethacin in the treatment of osteoarthritis. Am J Med 1987;83:78-80. 28. Maccagno A, Di Giorgio EE, Caston OL, et al. Double-blind controlled clinical trial of oral Sadenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med 1987;83:72-77.

29. Konig B. A long-term (two years) clinical trial with Sadenosylmethionine for the treatment of osteoarthritis. Am J Med 1987; 83:89-94. 30.Berger R, Nowak H. A new medical approach to the treatment of osteoarthritis. Report of an open phase IV study with ademetionine (Gumbaral)..AmJ Med 1987;8384-88. 31. Tavoni A, Vitali C, Bombardieri S, et al. Evaluation of Sadenosylmethionine in primary fibromyalgia. A double-blind crossover study. Am J Med 1987;83:107-110. 32. Volkmann H, Norregaard J, Jacobsen S, et a]. Double-blind, placebo-controlled cross-over study of intravenous Sadenosyl-Lmethionine in patients with fibromyalgia. Scand J Rheumatol 1997;26206-211. 33. Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral Sadenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. S a n d J Rheumatol1991;20294-302. 34. Di Benedetto P, Iona LG, Zidarich V. Clinical evaluation of Sadenosyl-L-methionine versus transcutaneous nerve stimulation in primary fibromyalgia. Curr Ther Res 1993;53:222-229. 35. Frezza M, Surrenti C, Manzillo G, et al. Oral Sadenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A doubleblind, placebo-controlled study. Gastroenterology 1990;99:211-215. 36. Avila MA, Garcia-Trevijano ER, Martinez-Chantar ML, et al. SAdenosylmethionine revisited: its essential role in the regulation of liver function. Alcohol 2002;27163-167. 37.Di Padova C, Tritapepe R, Di Padova F, et al. Sadenosyl-Lmethionine antagonizes oral contraceptive-induced bile cholesterol supersaturation in healthy women: preliminary report of a controlled randomized trial. Am J Gastroenterol1984;79:941-944. 38. Nicastri PL, Diaferia A, Tartagni M, et al. A randomised placebccontrolled trial of ursodeoxycholic acid and Sadenosylmethionine in the treatment of intrahepatic cholestasis of pregnancy. Br J Obstet Gynaecol 1998;105:1205-1207. 39. Frezza M, Pozzato G, Pison G, et al. Sadenosylmethionine counteracts oral contraceptive hepatotoxicity in women. Am J Med Sci 1987;293:234-238.

40.Bombardieri G, Milani A, Bemardi L, et al. Effects of Sadenosylmethionine (SAMe) in the treatment of Gilbert’s syndrome. Curr Ther Res 1985;37580-585. 41.Angelico M, Gandin C, Nistri A, et al. Oral S-adenosyl-Lmethionine (SAMe) administration enhances bile salt conjugation with taurine in patients with liver cirrhosis. Scand J Clin Lab Invest 1994;54:459-464. 42. Kakimoto H, Kawata S, Imai Y, et al. Changes in lipid composition of erythrocyte membranes with administration of Sadenosyl-Lmethionine in chronic liver disease.GastroentemlJpn 1992;2750&513. 43.Loguercio C, Nardi G, Argenzio F, et al. Effect of SadenosylL-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease. Alcohol Alcohol 1994;29597-604. 44. Mato JM, Camara J, Femandez de Paz J, et al. Sadenosylmethionine in alcoholic liver cirrhosis: a randomized, placebocontrolled, double-blind, multicenter clinical trial. J Hepatol1999;30:1081-1089. 45. Pascale RM, Marras V, Simile MM, et al. Chemoprevention of rat liver carcinogenesis by S-adenosyl-L-methionine: a long-term study. Cancer Res 1992;52:4979-4986. 46.Gatto G, Caleri D, Michelacci S, et al. Analgesizing effect of a methyl donor (Sadenosylmethionine) in migraine: an open clinical trial. Int J Clin Pharmacol Res 1986;6:15-17. 47. Reicks M, Hathcock JN. Effects of methionine and other sulfur compounds on drug conjugations. Pharmacol Ther 1988;3767-79. 48. Cheng H, Gomes-Trolin C, Aquilonius SM, et al. Levels of L-methionine Sadenosyltransferase activity in erythrocytes and concentrations of Sadenosylmethionine and Sadenosylhomocysteine in whole blood of patients with Parkinson’s disease. Exp Neurol 1997;145580-585. 49.Charlton CG, Crowell B Jr. Parkinson’s disease-like effects of Sadenosyl-L-methionine: effects of L-dopa. Pharmacol Biochem Behav 1992;43:423-431. 50. Di Rocco A, Rogers JD,Brown R, et al. SAdenosyl-methionine improves depression in patients with Parkinson’s disease in an open-label clinical trial. Mov Disord 2000;15:1225-1229.

Sarsaparilla Species Michael T. Murray, ND JosephE. Pizzorno Jr, ND CHAPTER C O N T E N T S General Description 1241

Clinical Application 1242 Psoriasis 1242

Chemical Composition 1241 Dosage History and Folk Use 1241 Historical Use in the Treatment of Syphilis 1241

1242

Toxicology

1242

Drug Interactions 1242 Pharmacology 1242 Endotoxin Binding 1242

Smilax aristolochiifoliu (family: Liliaceae) Synonym: Smilax medica Common name: Mexican sarsaparilla Smilax ofzcinalis (family: Liliaceae) Synonym: Smilax regelii Common name: Honduras sarsaparilla

GENERAL DESCRIPTION Sarsaparilla is a tropical American perennial plant. Its long slender root and short thick rhizomes produce a vine that trails on the ground and climbs by means of tendrils growing in pairs from the petioles of the alternate, obicular to ovate, evergreen leaves. The root is the part of the plant utilized for medicinal purposes.

CHEMICAL COMPOSITION Sarsaparilla contains 1.8% to 2.4% steroid saponins, including the following: Sarsaponin Smilasaponin Sarsaparilloside and its aglycones, sarsapogenin (Figure 123-l), smilagenin, and pollinastanol Other constituents are starch, resins, and a trace of volatile oi1.l

HISTORY AND FOLK USE Sarsaparilla’s medicinal use has been as a tonic and blood purifier. Tonics are defined as agents that ”permanently exalt the energies of the body at large, without vitally affecting any one organ in particular. . . . In short, tonics tone the whole system. A blood purifier or depurative refers to an agent which cleanses and purifies the system.”2Sarsaparilla’s reputation in this regard probably stems from its importation from the Caribbean and South America to Europe in the sixteenth century for the treatment of ~yphilis.~

Historical Use in the Treatment of Syphilis A French physician, Nicholas Monardes, published a comprehensive account of sarsaparilla and several other “new” drugs for the treatment of syphilis in 1574. Many Europeans at the time believed that syphilis had come to Europe from the West Indies with Columbus’s sailors, and because there was a general belief that whatever disease was native to a country might be cured by the medicinal herbs growing in that region, it was only natural for sarsaparilla to become a popular remedy. Furthermore, the standard treatment for syphilis, mercury, often resulted in greater morbidity and mortality than the disease itself. Sarsaparilla was a welcome alternative, but despite initial excitement, Monardes’ sarsaparilla cure sank in favor. This was probably due to other aspects of the cure,

1241

Pharmacology of Natural Medicines

R

HO Figure 123-1

Sarsasapogenin.

which involved confinement to a warm room for 30 days followed by 40 days of abstinence from both wine and sexual inter~ourse.~ However, sarsaparilla continued to be used in the treatment of syphilis. During military operations in Portugal in 1812, a British Inspector General of Hospitals noted that the Portuguese soldiers suffering from syphilis who used sarsaparilla recovered much faster and more completely than their British counterparts, who were treated with m e r c ~ r y . ~ Sarsaparilla was also used by the Chinese in the treatment of syphilis. Clinical observations in China show that sarsaparilla is effective, according to blood tests, in about 90% of acute cases and 50% of chronic Although sarsaparilla was clearly more beneficial in the treatment of syphilis, it was mercury that established itself as the standard treatment for more than four-anda-half centuries. It has been stated that “the use of mercury in the treatment of syphilis may have been the most colossal hoax ever perpetrated” in the history of medi~ine.~ Mercury represented a new kind of medicine, one formulated and prepared in a laboratory using the new techniques of chemistry. It helped prepare the way for the future use of drugs rather than herbal medicines. An interesting note is that sarsaparilla species have been used all over the world in many different cultures for the same conditions, namely gout, arthritis, fevers, digestive disorders, skin disease, and cancer.’

PHARMACOLOGY

compounds before they reach the general circulation. If the amount of endotoxin absorbed is excessive or if the liver is not functioning adequately, the liver can become overwhelmed, and endotoxins spill into the blood. If endotoxins are allowed to circulate, activation of the alternate complement system occurs. This system plays a critical role in aggravating inflammatory processes, and activation of complement is responsible for much of the inflammation and cell damage that occur in many diseases, including gout, arthritis, and psoriasis. Historically, these conditions have been treated with sarsaparilla. In further support of sarsaparilla’s effect as a binder of endotoxin is its historical use in the treatment of fever, because absorbed endotoxins produce fever. Sarsaparilla also exhibits some antibiotic activity, but it is probably secondary to the endotoxin-binding action.’

CLINICAL APPLICATION Sarsaparilla’s medicinal action appears to be a result of its binding of bacterial endotoxins in the gut, which makes them unabsorbable. This action greatly reduces the stress on the liver and other organs and is probably responsible for sarsaparilla’s historical use as a tonic and blood purifier. The ability to bind endotoxins is also probably the reason that sarsaparilla is effective in many cases of psoriasis, gout, and arthritis.

Psoriasis Individuals with psoriasis have been shown to have high levels of circulating endotoxins. Binding of endotoxin in the gut is associated with clinical improvement in these individuals. In a controlled study of 92 patients, an endotoxin-binding saponin (sarsaponin) from sarsaparilla greatly improved the psoriasis in 62% of the patients and resulted in complete clearance in 18Yk6

DOSAGE Dried root: 1 to 4 g or by decoction three times/day Liquid extract (1:l):8 to 15 ml three times/day Solid extract (4:l):250 mg three times/day

Sarsaparilla’s mechanism of action is largely unknown, although the plant does contain several saponins and has been shown to be clinically effective in the treatment of ps~riasis.’,~,~ This evidence points to a possible effect on binding of cholesterol and bacterial toxins in the intestines. Sarsaparilla has also demonstrated hepatoprotective effects.’

TOXICOLOGY

Endotoxin Binding

No drug interactions have been reported for sarsaparilla. However, it has been theorized that sarsaparilla may increase the absorption of certain drugs, notably digitalis and bismuth, thereby potentially increasing the chance of drug toxicity.

Evidence seems to support sarsaparilla as an endotoxin binder. Endotoxins are cell wall constituents of bacteria that are absorbed from the gut. Normally, the liver plays a vital role by filtering these and other gut-derived

Although no adverse effects have been reported for sarsaparilla, it is possible that problems could arise if large doses are used over a long time.

DRUG INTERACTIONS

1. Leung AY, Foster S. Encyclopedia of common natural ingredients used in food, drugs and cosmetics, ed 2. New York JohnWdey, 1996. 2. Felter HW. The eclectic materia rnedica, pharmacology and therapeutics. Portland, OR Eclectic Medical Publications, 1983. 3. Van der Zee B, Griggs B. Green pharmacy: A history of herbal medicine. London: Jill Norman & Hobhouse, 1981. 4. Bensky D, Gamble A. Chinese herbal medicine: materia medica. Seattle, WA: Eastland Press, 1986.

5. Duke JA. CRC handbook of medicinal herbs. Boca Raton, FL: CRC Press, 1985. 6. Thurmon FM. The treatment of psoriasis with sarsaparilla compound. N Engl J Med 1942;337128-133. 7. Rafatullah S, Mossa JS,Ageel AM, et al. Hepatoprotective and safety evaluation studies on sarsaparilla. Int J Pharmacognosy 1991;29: 296-301.

Serenoa repens (Saw Palmetto) Eric L. Yarnell, ND, RH(AHG) Kathy Abascal, BS, JD, RH(AHG) CHAPTER CONTENTS General Description 1245 Chemical Composition 1245

Clinical Applications 1246 Benign Prostatic Hyperplasia 1246 Male-Pattern Baldness 1248

History and Folk Use

Dosage 1248

1245

Pharmacology 1246

Serenoa repens (family: Arecaceae) Common names: saw palmetto, palmetto scrub, Saba2 serrulafa

GENERAL DESCRIPTION Serenoa repens is a small palm tree native to the West Indies and the Atlantic coast of North America from South Carolina to Florida. The plant grows from 6 to 10 feet high, with a crown of large spiny-toothed leaves, 2 to 4 feet high, that form a circular, fan-shaped outline. The fruit of the plant, commonly called a berry, is the component used for medicinal purposes. The deep red-brown to black berries are wrinkled and oblong, measuring 0.5 to 1 inch in length with a diameter of 0.5 inch.l

CHEMICAL COMPOSITION Saw palmetto berries contain about 1.5% of a fruitysmelling oil containing saturated and unsaturated fatty acids and sterols.' About 63% of this oil is composed of free fatty acids, including capric, caprylic, caproic, lauric, palmitic, and oleic acids. The remaining portion is composed of ethyl esters of these fatty acids and sterols, including beta-sitosterol and its glucoside. The lipidsoluble compounds are thought to be the major phannacologic components. Other components of the berries are proanthocyanidins, carotenes, lipase, tannins, and sugars. The purified fat-soluble extract, the most-researched medicinal product, contains 85% to 95% fatty acids and sterols. It is made up predominantly of a complex

Toxicology

1249

mixture of saturated and unsaturated free fatty acids, their methyl- and ethyl-esters (approximately 7%), longchain alcohols in free and esterified forms, and various free and esterified sterol derivatives. The free fatty acids in this extract are identified by gas chromatography and mass spectrometry as follows: Caproic acid (C6) Capric acid (C8) Caprylic acid (C10) Lauric acid (C12) Myristic acid (C14) Isomyristic acid (C14) Palmitic acid (C16) Oleic acid (C18:l) Stearic acid (C18) Lauric and myristic acid are the major fatty acids, accounting for approximately 30% of the fatty acid content. The identified alcohols include those with n-C22, n-C23, n-C24, n-C26, n-C28, and n-C30 chains, phytol, famesol, and geranylgeraniol, in addition to high-molecularweight unsaturated polyphenols. The sterolic fraction is composed of beta-sitosterol, stigmasterol, cycloartenol, lupeol, lupenone, and 24-methylcycloarteno1. Many of these sterols are esterified with the fatty acids of the extract.

HISTORY AND FOLK USE The American Indians, and later Eclectic and Naturopathic physicians, used saw palmetto berries in the treatment of genitourinary tract disturbances and as 1245

a tonic to support the body nutritionally.2,3This substance was strongly recommended as a remedy for symptoms of benign prostatic hyperplasia as early as 1919.4It was used in men to increase the function of the testicles and relieve irritation in mucous membranes, particularly those of the genitourinary tract and prostate. Saw palmetto has been used in women with disorders of the mammary glands; long-term use was reputed to cause the breasts to enlarge slowly? Many herbalists have regarded saw palmetto as an aphrodisiac.’

PHARMACOLOGY A standardized liposterolic (fat-soluble) saw palmetto berry extract has demonstrated numerous pharmacologic effects relating to its primary clinical application in the treatment of the common disorder of the prostate gland, benign prostatic hyperplasia (BPH). BPH is a complex disease process in which testosterone in the prostate (primarily when converted to the more potent dihydrotestosterone [DHT]) plays a permissive role, but other factors are critical in its pathogenesis.’ The primary therapeutic action of saw palmetto extract in the treatment of BPH has been thought to be inhibition both of the intraprostatic conversion of testosterone to DHT and of its intracellular binding and tran~port.~,’However, later research suggested additional mechanisms of action, including antiestrogenic and receptor site-binding effects.s Estrogen may contribute to BPH because it inhibits the hydroxylation and subsequent elimination of DHT. Serenoa appears to inhibit the activity of estrogen in the prostate. For example, in a double-blind study of 35 men with BPH, 18 were given the saw palmetto extract at 160 mg twice daily, and 17 were given placebo.6 At the end of the 90-day study, androgen, estrogen, and progesterone receptors from prostate tissue samples were evaluated with two different techniques. The men receiving the saw palmetto extract had significantly lower cytosol and receptor values for estrogen and progesterone than the placebo group. Because the progesterone receptor content is linked to estrogenic activity, the results of the evaluation imply that at least part of the efficacy of the saw palmetto extract is through its antiestrogenic effect. The results of the androgen receptor analysis were quite interesting: There was no change in the number of cytosol androgen receptors, but the number of nuclear androgen receptors was significantly lower in the saw palmetto group (60% of the placebo group tested positive for the nuclear receptor, compared with 10% of the saw palmetto group). These results indicate that the saw palmetto extract probably competitively blocks the translocation of the cytosol androgen receptor to the nucleus.

The overall results of the study show that the standardized extract of saw palmetto exerts both antiandrogenic and antiestrogenic activities. Preliminary analysis of the extract demonstrates that separate fractions are responsible for these effects. Researchers in this study concluded, ”It cannot be excluded, however, that the primary effect is antiestrogenic and that the inactivation of androgen receptors and progesterone receptors and of the 5-alpha-reductase activity is secondary to the estrogen receptor blockade.”8 Serenoa standardized extracts do not affect systemic levels of androgens, follicle-stimulating hormone, or luteinizing hormone in men with BPH.9 This may help explain the relatively low incidence of adverse effects of this substance in clinical trials. These findings do not, however, rule out localized effects of saw palmetto on androgen or estrogen effects in other tissues of the body. Endocrinologic factors in addition androgens and estrogen play a role in the pathogenesis of BPH. Various locally produced growth factors are important, and liposterolic extracts of Serenoa block the ability of one of them, basic fibroblast growth factor, to induce prostatic hyperplasia in vitro.’” High prolactin levels may also stimulate prostate hyperplasia; Serenoa extracts interfere with this process in rats but the drug finasteride does not.” Saw palmetto extracts exert antispasmodic effects on smooth muscle. Rat smooth muscle was originally shown to be inhibited by two Serenoa extracts owing to inhibition of calcium ion influx.12A later study found that Serenoa extract, but not pumpkin seed extract, stinging nettle root extract, or beta-sitosterol, consistently inhibited human alphal-adrenergic receptors in ~ i t r 0 . I ~ Whether this effect is relevant clinically is still unknown. The standardized extract has demonstrated antiedematous effects, and the polysaccharide components have been shown to have immunostimulatory effect^.'^,'^ Serenoa extract and myristoleic acid induced apoptosis and necrosis in an androgen-sensitive human prostate cancer cell line in vitro.”j

CLINICAL APPLICATIONS Currently, the primary clinical application of saw palmetto berries (specifically the fat-soluble extract) is in the treatment of BPH. There is initial evidence that saw palmetto may also help counter androgenetic andropecia (male-pattern baldness). On the basis of its pharmacology, this extract may also be of benefit in conditions of androgen excess in women, such as hirsutism and polycystic ovarian disease.

Benign Prostatic Hyperplasia In the United States, between 50% and 60% of men between the ages of 40 and 59 years have BPH. This disorder is characterized by increased urinary frequency,

Serenoa repens (Saw Palmetto) linical studies demonstrating the efficacy of Serenoa repens extract* No. of patients

Study

Type of study

Length of study

Results

Boccafoschi and Annoscia”

Double-blind, placebo-controlled

22

60 days

Significant difference for volume voided, maximum flow, mean flow, dysuria, nocturia

Cirillo-Maruccoet all8

Open

47

4 months

Significant difference for dysuria, nocturia, urine flow

Tripodi et all9

Open

40

30-90 days

Significant difference for dysuria, nocturia, volume of prostate, voiding rate, residual urine

Emili et aIz0

Double-blind, placebo-controlled

30

30 days

Significant difference for number of voided, strangury, maximum and mean urine flow, residual urine

Greca and VolpiZ1

Open

14

1-2months

Significant difference for dysuria, perineal heaviness, nocturia, volume of urine per voiding, interval between two diurnal voidings, sensation of incomplete voiding

Duvia et alzz

Controlled

30

30 days

Significant difference for voiding rate vs. Pygeum africanum

Tasca et a P

Double-blind, placebo-controlled

30

31-90 days

Significant difference for frequency, urine flow measurement

Cukier et aIz4

Double-blind, placebocontrolled

168

60-90 days

Significant difference for dysuria, frequency, residual urine

Champault et alz5

Double-blind, placebo-controlled

168

60-90 days

Significant difference for objective and subjective parameters

Crimi and RussoZ6

Open

32

4 weeks

Significant difference for dysuria, nocturia, volume of prostate, voiding rate

Champault et aIz7

Double-blind, placebo-controlled

110

28 days

Significant difference for dysuria, nocturia, flow measurement, residual urine

Mattei et aIz8

Double-blind

40

3 months

Significant difference for dysuria, nocturia, residual urine

BraeckmanZ9

Open

305

3 months

Significant difference for maximum urine flow, prostate volume, international prostate score

‘85% to 95% fatty acids and sterols at a dosage of 320 mgday.

nighttime awakening to empty the bladder, and reduced force and caliber of urination (see Chapter 154). These major symptoms have been shown to be significantly improved in more than a dozen double-blind, placebocontrolled clinical trials (summarized in Table 124-1).17-29 At least two metaanalyses have combined data from these and other trials and concluded that, despite some limitations in trial design, Serenoa extracts have been shown to reduce symptoms of BPH and increase urine flow in comparison with p l a c e b ~ .One ~ , ~of ~ these also concluded that Serenoa extracts are as effective as the 5-alpha-reductase-inhibiting drug finasteride (Proscar) with sipficantly fewer adverse effects.31 In one of the larger studies, involving 110 patients with BPH, impressive clinical results were reported: Nocturia decreased by more than 4570, flow rate (ml/sec) rose by

more than 50%, and postmicturition residue (ml) diminished by 42% in the group receiving the Serenoa extract.26 In contrast, those being given placebo showed no significant improvement in nocturia or flow rate, and postmicturition residue actually worsened. Sigruficant improvements were also noted in selfrating by the patients and global rating by the physicians. Of the 50 treated subjects completing the 30-day study, physicians rated 14 greatly improved, 31 improved, and only 5 unchanged or worse. In contrast, no subjects in the placebo group had greatly improved, 16 showed some improvement, and 28 remained unchanged or worse. Although the saw palmetto extract has shown excellent results in numerous double-blind, placebo-controlled clinical trials, results from a recent open, multicenter study are perhaps the most revealing.29 The results

Pharmacology of Natural Medicines

corroborate those from numerous double-blind, controlled studies showing that the liposterolic extract of saw palmetto (S. repens) standardized to contain 85% to 95% fatty acids and sterols is an effective treatment for BPH. Whereas drugs like finasteride typically take up to a year to show sigrulicant benefit, the saw palmetto extract produces better results in a much shorter time. Most patients experience some relief of symptoms within the first 30 days of treatment with the saw palmetto extract. In this study, 305 men were given a dosage of 160 mg twice daily. The subjective evaluations of treatment made by patients after 45 and 90 days of treatment were quite favorable. After 45 days, 83% of patients estimated that the drug was effective. After 90 days, 88% did so. Similarly, global evaluations made by physicians after 45 and 90 days demonstrated 81% and 88% effectiveness, respectively. The objective evaluations demonstrated remarkable improvements in all measurements. Maximum urinary flow increased from 9.8 to 12.2 ml/sec, mean urinary flow rate increased from 5.8 to 7.4 ml/sec, prostatic volume decreased from 40,348 to 36,246 mm3, and the International Prostate Symptom Score decreased from 19.0 to 12.4. No serious adverse reactions were reported. Although these results are impressive, perhaps the most profound changes occurred in the quality of life scores, as shown in Table 124-2. These improvements in quality of life scores demonstrate just how powerful an effect improving bothersome symptoms such as nocturia can have on an individual’s mental outlook. Another important finding was that the saw palmetto extract had no demonstrable effect on serum prostatic specific antigen levels. A further study evaluated the long-term efficacy of saw palmetto.32This 3 year, multicenter, open-label study evaluated 160 mg of a standardized extract (Strogen)in 435 men (age 41 to 89 years) with stage I or stage I1 BPH. By the end of the study, 120 patients had withdrawn-12 for lack of efficacy, 41 because of the need for surgery, 41 lost to follow-up, and 8 owing to

Evaluation Delighted Happy Satisfied Mitigated Unsatisfied Unhappy Hopeless

Responses on Day 0 (%)

Responses on Day 90 (%)

0.6 2.3 9.7 22.7 43.8 18.5 2.3

5.4 24.0 36.8 20.9 9.5 2.4 1 .o

adverse reactions. In the remaining 315 subjects, the following results were reported: Nocturia normalized or improved in 73% Daytime frequency improved in 54% Feeling of incomplete emptying improved in 75% Rectal examination revealed improvement in prostate congestion in 55% *Average residual volume decreased from 64 to 38 ml Peak urine flow increased by an average of 6.1 ml/sec A total of 14.7% of the men experienced a continued deterioration of prostate function. The primary adverse events were mild gastrointestinal disturbance. In a comparison double-blind trial, 542 men with BPH symptoms were randomly assigned to receive either the alpha blocker tamsulosin or Serenoa extract for 1 year.33 The two groups showed identical levels of improvement in symptoms. Tamsulosin was more frequently associated with ejaculatory disorders than Serenoa extract. In a separate double-blind trial involving 329 men with BPH symptoms, tamsulosin combined with placebo was just as effective as tamsulosin combined with Sereiiou extract at relieving symptoms.M Adding Serenoa extract to tamsulosin caused no alteration in adverse effects.

Male-Pattern BaIdness A combination of 400 mg Serenou extract and 100 mg beta-sitosterol daily was found effective for male-pattern baldness in a pilot double-blind, placebo-controlled trial.35The trial lasted 5 months and involved 19 men with mild to moderate baldness. Sixty percent (6/10) of men in the treatment group were rated as having improved by blinded observers, whereas only 11%(1/9) of men in the placebo group were rated as improved. Thirty-three percent (3/9) of men in the placebo group showed deterioration compared with none in the treatment group. There were no major adverse effects, although two men originally entered into the study dropped out because of adverse effects (it is not clear from the study report which group these men had been assigned to).

DOSAGE The dosage for the liposterolic extract of saw palmetto berries (containing 85% to 95% fatty acids and sterols) is 160 mg twice daily or 320 mg daily; the two regimens have been shown to be equally e f f e ~ t i v eA. ~similar ~ dose using fluid extracts and tinctures would require extremely large quantities of alcohol if the liposterolic components are the primary active constituents. The Eclectics used comparatively small dosages of saw palmetto in crude extracts effectively for BPH with

Serenoa repens (Saw Palmetto) apparent clinical success. Ellingwood4lists as his dose as 10 drops to 1dram of specific Serenou (meaning basically a fresh berry tincture). We are unaware of any published clinical study of a crude extract. Dosages are as follows:

The dose of fluid extracts or tinctures is unknown owing to a lack of research.

TOXICOLOGY

Crude berries: 10 g twice daily Liposterolic extract (standardized at 85-95% fatty acids and sterols): 160 mg twice daily or 320 mg once daily

No significant adverse effects have been reported in the clinical trials of the saw palmetto berry extract or for saw palmetto berry ingestion. Mild gastrointestinal upset and erectile dysfunction (in approximately 1%of users in clinical trial^)^ occasionally occur.

1.Duke JA. CRC Handbook of medicinal herbs. Boca Raton, F L CRC Press, 1985:118. 2. Felter HW, Lloyd JU. King’s American dispensatory (1898). Portland, OR: Eclectic Medical Publications (reprint), 1983: 1750-1752. 3. Kuts-Cheraux AW. Naturae medicina and naturopathic dispensatory. Yellow Springs, OH: Antioch Press, 1953:249. 4. Ellingwood F. American materia medica, therapeutics and pharmacognosy. Sandy, OR Eclectic Medical Publications, 1919, reprinted 1998457459. 5. Sant GR, Long JP. Benign prostatic hyperplasia. In Sant GR, ed. Pathophysiologic principles of urology. Boston: Blackwell Scientific Publications, 1994123-154. 6. Carilla E, Briley M, Fauran F, et al. Binding of Permixon, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate. J Steroid Biochem 1984;20:521-523. 7. Sultan C, Terraza A, Devillier C, et al. Inhibition of androgen metabolism and binding by a liposterolic extract of “Serenou repens B” in human foreskin fibroblasts. J Steroid Biochem 1984;20515-519. 8. Di Silverio F, DEramo G, Lubrano C, et al. Evidence that Serenou repens extract displays antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy. Eur Urol1992;21:309-314. 9. Casarosa C, Cosci di Coscio M, Fratta M. Lack of effects of a liposterolic extract of Serenou repens on plasma levels of testosterone, follicle-stimulating hormone, and luteinizing hormone. Clin Ther 1988;10585-588. 10. Paubert-Braquet M, Cousse H, Raynaud JP, et al. Effect of the lipidosterolic extract of Serenou repens (Permixon) and its major components on basic fibroblast growth factor-induced proliferation of cultures of human prostate biopsies. Eur Urol1998;33340-347. 11.Van Coppenolle F, Le Bourhis X, Carpentier F, et al. Pharmacological effect of the lipidosterolicextract of S m o n repens (Permixon) on rat prostate hyperplasia induced by hyperprolactinemia. comparison with finasteride. Prostate 2000;43:49-58. 12.Gutierrez M, Garcia de Boto J, Cantabrana B, Hidalgo A. Mechanisms involved in the spasmolyhc effect of extracts from Subal serrulutu fruit on smooth muscle. Gen Pharmacol1996;27171-176. 13. Goepel M, Hecker U, Krege S, et al. Saw palmetto extracts potently and noncompetitively inhibit human alpha-1-adrenoceptors in vitro. Prostate 1999;38208-215. 14.Tarayre JF‘, Delhon A, Lauressergues H, et al. [Anti-edematous action of a hexane extract of the stone fruit of Serenou repens Barb]. Ann Pharm Fr 1983;41:559-570. 15. Wagner H, Proksch A. Immunostimulatory drugs of fungi and higher plants. Econ Med Plant Res 1985;1:113-153. 16. Iguchi K, Okumura N, UsUi S, et al. Myristoleic acid, a cytotoxic component in the extract from Serenou repens, induces apoptosis

and necrosis in human prostatic LNCaP cells. Prostate 2001; 4759-65. 17. Boccafoschi C, Annoscia S. Comparison of Serenou repens extract with placebo by controlled clinical trial in patients with prostatic adenomatosis. Urologia 1983;50:1257-1268. 18. Cirillo-Marucco E, Pagliarulo A, Tritto G, et al. Extract of Serenou repens (PermixonR)in the early treatment of prostatic hypertrophy. Urologia 1983;5:1269-1277. 19. Tripodi V, Giancaspro M, Pascarella M, et al. Treatment of prostatic hypertrophy with Serenoa repens extract. Med Praxis 1983;4:41-46. 20. Emili E, Lo Cigno M, Petrone U. Clinical trial of a new drug for treating hypertrophy of the prostate (Permixon). Urologia 1983;501042-1048. 21. Greca P, Volpi R. Experience with a new drug in the medical treatment of prostatic adenoma. Urologia 1985;52532-535. 22. Duvia R, Radice GP, Galdini R. Advances in the phytotherapy of prostatic hypertrophy. Med Praxis 1983;4143-148. 23. Tasca A, B a d M, Cavazzana A, et al. [Treatment of obstructive symptomatology caused by prostatic adenoma with an extract of Serenou repens: double-blind clinical study vs. placebo]. Minerva Urol Nefrol 1985;3787-91. 24. Cukier J, Ducassou J, Le Guillou M, et al. Permixon versus placebo. C R Ther Pharmacol Clin 1985;415421. 25. Champault G, Patel JC, Bonnard AM. A double-blind trial of an extract of the plant Serenoa repens in benign prostatic hyperplasia. Br J Clin Pharmacol1984;18:461-462. 26. Crimi A, Russo A. Extract of Serenou repens for the treatment of the functional disturbances of prostate hypertrophy. Med Praxis 1983;4:47-51. 27. Champault G, Bonnard AM, Cauquil J, Patel JC. Medical treatment of prostatic adenoma. Controlled trial. PA 109 vs placebo in 110 patients. Ann Urol (Pans) 1984;18:407-410. 28. Mattei FM, Capone M, Acconcia A. Serenoa repens extract in the medical treatment of benign prostatic hypertrophy. Urologia 1988;55547-552. 29. Braeckman J. The extract of Serenoa repens in the treatment of benign prostatic hyperplasia. A multicenter open study. Curr Ther 1994;55:776-785. 30. Boyle P,Robertson C, Lowe F, Roehrbom C. Meta-analysis of clinical trials of Permixon in the treatment of symptomatic benign prostatic hyperplasia. Urology 2000;55533-539. 31. Wilt TJ, Ishani A, Stark G, et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998;2801605-1609. 32. Bach D, Ebeling L. Long-term drug treatment of benign prostatic hyperplasia-results of a prospective 3-year multicenter study using Sabal extract IDS89. Phytomedicine 1996;3105-111.

33. Debruyne F, Koch G, Boyle P, et al. [Comparison of a phytotherapeutic agent (Permixon)with an alpha-blocker (Tamsulosin)in the treatment of benign prostatic hyperplasia: a 1-year randomized international study.] Eur Urol2002;41:497-506. 34.Glemain P, Coulange C, Billebaud T, et al. [Tamsulosin with or without Serenoa repens in benign prostatic hyperplasia: the OCOS trial.] Pmg Urol2002;12:395-403. 35. Prager N, Bickett K, French N, Marcovici G. A randomized, doubleblind, placebocontrolled trial to determine in the effectiveness

of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J Altem Complement Med 2002;8:143-152. 36. Braeckman J, Bruhwyler J, Vandekerckhove K, GPczy J. Efficacy and safety of the extract of Serenoa repens in the treatment of benign prostatic hyperplasia: therapeutic equivalence between twice and once daily dosage forms. Phytother Res 1997;11:55&563.

Silybum maximum (Milk Thistle) Michael T. Murray, ND Joseph E. Pizzorno Jr, ND CHAPTER CONTENTS Viral Hepatitis 1254 Gallstones 1254 Psoriasis 1254 Protection against Chemical-Induced Renal Damage 1254 Silybin Bound to Phosphatidylcholine 1254

General Description 1251 Chemical Composition 1251 History and Folk Use 1251 Pharmacology 1251 Hepatoprotection Effects 1251 Other Pharmacologic Actions 1252

Dosage 1255 Toxicity

Clinical Applications 1253 Chemical-Induced Liver Damage Cirrhosis 1253

1253

Silybum marianum (family: Compositae) Synonym: Carduus marianus Common names: milk thistle, marian thistle, St. Mary's thistle

GENERAL DESCRIPTION Silybum rnarianum is a stout, annual or biennial plant found in dry rocky soils in southern and Western Europe and some parts of the United States. The branched stem grows 1 to 3 feet high and bears alternate, dark green, shiny leaves with spiny, scalloped edges that are markedly streaked with white along the veins. The solitary flower heads are reddish purple with bracts ending in sharp spines. Flowering season is from June to August. The seeds, fruit, and leaves are used for medicinal purposes.

CHEMICAL COMPOSITION SiZybum mariunum contains silymarin, a mixture of flavanolignm, consisting chiefly of silybin, silydianin, and ~ilychristine.'-~ The concentration of silymarin is highest in the fruit, but it is also found in the seeds and leaves. Other flavanolignans contained in Silybum include silandrin, silyhermin, silymonin, and neosilyhermin.' Silybin is the silymarin component with the greatest degree of biologic activity (Figure 125-1).

1255

Drug Interactions 1255

HISTORY AND FOLK USE Perhaps the most widespread folk use of this plant has been in assisting the nursing mother in the production of milk. It was also used in Germany for curing jaundice and biliary derangements. It is interesting to note that the discovery of the liver-protecting flavanolignans in S. marianum was the result not of systemic pharmacologic screening but rather of investigation of SiZybum's empirical effects in liver disorders.'

PHARMACOLOGY Currently S. marianum extracts (usually standardized to contain 70% silymarin) are widely used in European pharmaceutical preparations for hepatic disorders. Silymarin is one of the most potent liver-protecting substances k110wn.l~

Hepatoprotection Effects Free Radical Scavenging Silybum's ability to prevent liver destruction and enhance liver function is due largely to silymarin's inhibition of the factors that are responsible for hepatic damage-free radicals and leukotrienes-coupled with its ability to stimulate liver protein synthesis. Silybum components prevent free radical damage by acting 1251

Pharmacology of Natural Medicines

as antioxidants.I4 Silymarin is many times more potent in antioxidant activity than vitamin E.

the patients. Treatment with intravenous silybinin at a dose of 20 mg per kg body weight, penicillin, and glucose for 3 days resulted in reversal of both the organ failures and encephalopathy. Silymarin may also be of great value as an adjunct in patients receiving long-term drug therapy. A very interesting study found that silymarin, in an unusually high dose of 800 mg/day, given to psychiatric patients receiving phenothiazines or butyrophenones resulted in significant protection of the liver as measured by malondialdehyde serum liver enzyme levels? The silymarin did not interfere with the efficacy of the antidepressants.

Effects on Hepatic Glutathione

Stimulation of Hepatic Protein Synthesis

Silymarin prevents the depletion of glutathione (GSH) induced by alcohol and other liver toxins. Even in normal people, silymarin has been shown to raise the basal GSH level in the liver by 35%.

Perhaps the most interesting effect of Silybum components on the liver is their ability to stimulate protein synthe~is.~,'~," This results in an increase in the production of new liver cells to replace the damaged old ones. Sonnenbichler and Zetl" have suggested that "silybinin imitates in some way a physiological regulator in animal cells, so that the structure fits into a specific binding site on the polymerase and in such a way causes the observed effects on rRNA synthesis making the drug from Silybum marianum indeed interesting for liver therapy." Interestingly, silybinin does not have a stimulatory effect on malignant hepatic tissue.'O

CH2OH

FvOY

OH

0 Figure 125-1

Silybin.

Protection from Liver-Damaging Chemicals and Drugs

The protective effect of Silybum against liver damage has been demonstrated in a number of experimental and clinical studies. Experimental liver damage in animals can be produced by such diverse toxic chemicals as carbon tetrachloride, galactosamine, ethanol, and praseodymium nitrate. Silymarin has been shown to protect the liver Antiinflammatory Effects from all of these Perhaps the most impressive of silymarin's protective Leukotrienes, key chemical mediators of inflammaeffects is against the severe poisoning by Arnanifa phalloides tion that are produced by the transfer of oxygen to (the death cap or toadstool mushroom), an effect that polyunsaturated fatty acids (a reaction catalyzed by the has long been recognized in folk medi~ine."~ Ingestion enzyme lipoxygenase), can also damage the liver. of A. phalloides or its toxins causes severe poisoning and, Silymarin has been shown to be a potent inhibitor of this in approximately 30%of victims, death. enzyme, thereby inhibiting the formation of damaging leukotrienes. Among the experimental models for measuring protection against liver damage, those based on amanitin or Silymarin has also been demonstrated to inhibit phalloidin toxicity are the most important, because these prostaglandin synthesis during inflammati~n.'~ Free radical damage to membrane structures due to organic two peptides from A. phalloides are the most powerful liver-damaging substances known. Silymarin has demondisease or intoxication results in increased release, strated impressive results in these experimental models. through lipolysis, of fatty acids. This leads, among other When silymarin was administered before amanita toxin things, to greater prostaglandin and leukotriene synthepoisoning, it was 100% effective in preventing toxi~ity.~,~sis. Silymarin counteracts this deleterious process by suppressing the pathologic decomposition of memEven if given 10 minutes after the amanita toxin, it combrane lipids and inhibiting prostaglandin f0rmati0n.l~ pletely counteracted the toxic effects. In two cases reported in the literature, silymarin Leukotrienes and inflammatory prostaglandins are also involved in the damage of the liver by toxins, so their prevented death and greatly reduced the amount of neutralization by silybin is another mechanism for its liver damage as long as 24 hours after ingestion.6 This protection of the liver. study reported on a husband and wife who ate toxic mushrooms and experienced gastrointestinal symptoms Other Pharmacologic Actions 18 hours later. Despite initial conventional treatment with gastric emptying, intravenous fluids, activated Silymarin has demonstrated several other physiologic charcoal, and a duodenal tube, both patients' laboratory effects. In animal studies it has been shown to increase parameters showed deteriorating liver and renal funclymphocyte proliferation as well as increase in interferontion. Mild hepatic encephalopathy developed in one of gamma, interleukin-4 (IL-4), and IL-10 cytokines in a

Silyburn rnarianurn (Milk Thistle)

dose-dependent manner.14It has also shown a broad range of anticancer effects in various animal models and in vitro studies.’”” Silymarin is a strong inhibitor of cyclic adenosine monophosphate (CAMP)phosphodiesterase, being 13 to 50 times more active than theophylline and 1to 3 times more active than papaverine.18 Silymarin has also been shown to prevent the toxic effects of a variety of compounds, such as hemolysis induced by phenylhydrazine, damage from x-irradiation, and brain edema induced by Presumably, these effects are triethyltinsulfate (TZS).19-21 related to silymarin’s sigruhcant membrane-stabilizing and antioxidant actions. Its action in increasing the osmotic resistance of red blood cells is also quite Silymarin has also been shown to lower cholesterol levels in animal studies and may block cholesterol synthesis.23

CLINICAL APPLICATIONS Silymarin’s primary use is as an aid to the liver, although additional clinical applications are regularly being discovered. This substance can be used to support detoxification reactions or in the treatment of more severe liver disease. In numerous clinical studies, silymarin has been shown to have positive effects in treating several types of liver disease, including the following2‘%

9

Cirrhosis Chronic hepatitis Fatty infiltration of the liver (chemical- and alcoholinduced fatty liver) Subclinical cholestasis of pregnancy Cholangitis and pericholangitis

The therapeutic effect of silymarin in these disorders has been confirmed by histologic, clinical, and laboratory data. Silymarin may also be useful in improving the solubility of the bile in the treatment of gallstones as well as in psoriasis.

Chemical-Induced Liver Damage In one of the first extensive double-blind clinical trials investigating silymarin’s therapeutic effect in liver disorders, the substance demonstrated impressive results in 129 patients with toxic metabolic liver damage, fatty degeneration of the liver of various origin, or chronic hepatitis, who were compared with a control group of 56 patients. The results might have been even more impressive if the study had lasted longer than 35 days.24 A follow-up study of patients with liver damage due to alcohol, diabetes viruses, or toxic exposure yielded even more striking results. Patients were monitored for a long time (7 weeks). Not only were clinical findings markedly improved in the silymarin-treated groups,

but laboratory and liver biopsy data improved as well. Highly sigruficant results were obtained in bromsulphalein retention as well as in measurements of alanine transaminase (ALT), iron, and cholesterol levels. Biopsy showed remarkable tissue restorative effects. Upon completion of silymarin therapy, restitution of normal cell structure was found even in severely damaged livers. These effects on the tissue level correlated well with improvements in blood chemistry values.25 Another study highlighted the benefit of silymarin in individuals exposed to toxic chemicals. In this study, abnormal results of liver function tests (elevations levels of AST, ALT activity), and/or abnormal hematologic values (low platelet counts, increased white blood cell [WBC] counts, and a relative increase of lymphocytes compared with other WBCs) were observed in 49 of 200 workers exposed to toxic toluene and/or xylene vapors for 5 to 20 years.%Thirty of the affected workers were treated with silymarin, and the remaining 19 were left without treatment. Under the influence of silymarin, the liver function parameters and platelet counts significantly improved. The WBC counts also showed a tendency toward improvement. Pooled data from case record studies involving 452 patients with A. phalloides poisoning show a highly sigruficant difference in mortality in favor of silymarin therapy. The mortality rate for silymarin therapy is 9.8%,compared with 18.3%for standard treatment.“

Cirrhosis As previously described, silymarin is quite effective in treating alcohol-related liver disease. There is a tremendous range in severity of alcohol-related liver disease, from relatively mild to serious damage such as cirrhosis. Even in this severe state, silymarin has shown benefit. Perhaps the most significant benefit is extending the life span of patients with these disorders. In one study, 87 patients with cirrhosis (46 with alcoholic-related cirrhosis) received silymarin, whereas 83 patients (45 with alcoholic cirrhosis) received a pla~ebo.~’ The mean observation period was 41 months. In the treatment group, there were 24 deaths, 18 related to liver disease; in the control group, there were 37 deaths, 31 related to liver disease. The Cyear survival rate was 58% in the treatment group compared with 39% in the controls. Analysis performed on results of five trials involving a total of 602 patients with liver cirrhosis demonstrated that, although it produced a statistically insignificant reduction of total mortality by 4.2%in comparison with placebo, silymarin did lead to a statistically sigruficant reduction in liver-related mortality of 7%.“ Silymarin can also improve immune function in patients with cirrhosis.38

Viral Hepatitis Silymarin is useful in helping reverse virally induced liver damage. It is effective in both acute and chronic viral hepatitis. In one study of acute viral hepatitis, 29 patients treated with silymarin showed a definite therapeutic influence on the characteristic increased serum levels of bilirubin and liver enzymes compared with a placebo The laboratory parameters had regressed more in the silymarin group than in the placebo group by the fifth day of treatment. The number of patients attaining normal liver values after 3 weeks of treatment was significantly higher in the silymarin group than in the placebo group. In a study of chronic viral hepatitis, silymarin was shown to result in dramatic improvement. Used at a high dose (420 mg) for periods of 3 to 12 months, silymarin resulted in a reversal of liver cell damage (as noted on biopsy), a rise in protein level in the blood, and a lowering of liver enzyme values. Common symptoms of hepatitis (e.g., abdominal discomfort, decreased appetite, and fatigue) were all improved.J0

Gallstones Silymarin may help prevent or treat gallstones through its ability to increase the solubility of the bile. In one study, the composition of the bile was assayed in 19 patients with a history of gallstones (4patients) or removal of the gallbladder due to gallstones (15) before and after silymarin (420 mg/day for 30 days) or placebo. Silymarin treatment led to significant reduction in the biliary cholesterol concentration and bile saturation index.41

Psoriasis Correction of abnormal liver function is indicated in the treatment of psoriasis. Silymarin has been reported to be of value in the treatment of psoriasis, and this effect may be due to its ability to inhibit the synthesis of leukotrienes and improve liver function.43 The connection between the liver and psoriasis relates to one of the liver’s basic tasks, filtering the blood. Psoriasis has been shown to be linked to high levels of circulating endotoxins, such as those found in the cell walls of gut bacteria. If the liver is overwhelmed by an increased number of endotoxins or chemical toxins, or if the liver’s functional ability to filter and detoxify is decreased, the psoriasis is aggravated. Another factor in psoriasis is excessive production of leukotrienes. Silymarin has been shown to reduce leukotriene formation by inhibiting lipooxygenase.12Therefore, silymarin would inhibit one of the causes of the excessive cellular replication. Silymarin has other effects of value in patients with psoriasis. Most of them revolve around correcting the abnormal ratio of cAMP to cyclic guanosine monophosphate (cGMP) observed in the skin of patients with

psoriasis. The ratio of these two cellular control agents controls cellular replication. In psoriasis, cGMP levels are high relative to cAMP levels. Silymarin works to lower cGMP levels and raise cAMP levels.18

Protection against Chemical-Induced Renal Damage Some research has indicated that the antitoxin, free radical-scavenging effects of silymarin may be of value in protecting the kidneys.44In a very provocative study, female rats were given the anticancer drug cisplatin either with or without silybinin (300 mg/kg). Compared with the drug-only group, the silybinin-treated group lost significantly less weight and experienced no loss in creatinine clearance, no changes in urea level or magnesium excretion, and only slight degenerative changes in the glomerulus and tubules. Considering the significant problem of serious nephrotoxicity from cisplatin and other chemotherapeutic agents, silybinin may be of great value as an adjunct in the treatment of cancer.

Silybin Bound to Phosphatidylcholine One form of silymarin has emerged that may provide the greatest benefit. This form binds silybin to phosphatidylcholine. Preliminary research indicates that phosphatidylcholine-bound silybin is better absorbed and produces better clinical results.

Absorption Studies Several human and animal studies have shown that phosphatidylcholine-bound silybin is better absorbed. In one study, the excretion of silybin, the major component of silymarin, in the bile was evaluated in patients undergoing gallbladder removal (cholecystectomy). A drainage tube, the T-tube, was used to sample the bile. Patients were given either a single oral dose of the silybin-phosphatidylcholine complex or silymarin. The amount of silybin recovered in the bile in free and conjugated form within 48 hours was 11%for the silybin-phosphatidylcholine group and 3% for unmodified ~ilybin.4~ One of the significant features of this study is the fact that silymarin has been shown to improve the solubility of the bile. Because more silybin is being delivered to the liver and gallbladder when the phosphatidylcholine-bound silybin is used, this form is ideal for individuals with gallstones or fatty infiltration of the liver, two conditions characterized by decreased bile solubility. In another study, plasma silybin levels were determined after administration of single oral doses of silybinphosphatidylcholine complex and a similar amount of silymarin to nine healthy volunteers. Although absorption was rapid with both preparations, the bioavailability of the silybin-phosphatidylcholine complex was

Si/ybum marianum (Milk Thistle)

much greater than that of silymarin, as indicated by higher plasma silybin levels at all sampling times after intake of the complex. The researchers in this study concluded that complexation with phosphatidylcholine greatly increases the oral bioavailability of silybin, probably by facilitating its passage across the gastrointestinal m~cosa.~~

Clinical Studies Several clinical studies have shown phosphatidylcholinebound silybin to be more effective. In one study, eight patients with chronic viral hepatitis (three with hepatitis 8, three with both hepatitis B and hepatitis C, and two with hepatitis C) were given one capsule of phosphatidyl-choline-boundsilybin (equivalentto 140 mg silymarin)between meals for 2 months.47After treatment, serum malondialdehyde levels (an indicator of lipid peroxidation) decreased by 36% and the quantitative liver function evaluation, as measured by galactose elimination capacity, increased by 15%. A statistically significant reduction of liver enzymes was also seen: AST diminished by 17%and ALT rose by 16%. In another study designed primarily to evaluate the dose-response relationship of phosphatidylcholinebound silybin, positive effects were again displayed.48 In this study, patients with chronic hepatitis due to either a virus or alcohol were given different doses for 2 weeks: 20 patients received 80 mg twice daily, 20 patients received 120 mg twice daily, and 20 patients received 120 mg three times daily. At all tested doses, phosphatidylcholine-boundsilybin produced a remarkable and statistically significant decrease in mean serum and total bilirubin levels. When used at the dose of 240 or 360 mg/day, it also resulted in a remarkable and statistically significant decrease in the liver enzymes ALT and gamma-glutamyl-transpeptidase (GGTP). These results indicate that even short-term treatment of viral- or alcohol-induced hepatitis with relative low doses of phosphatidylcholine-bound silybin can be effective, but that for the best results, higher doses are needed.

DOSAGE The standard dose of milk thistle is based on its silymarin content (70 to 210 mg three times daily). For this reason, standardized extracts are preferred. The best results are achieved at higher dosages-140 to 210 mg of silymarin three times daily. The dosage for silybin bound to phosphatidylcholine is 120 to 240 mg twice daily. Alcohol-based extracts are virtually always contraindicated in liver disease, because a relatively large amount of alcohol is administered to obtain an adequate dose of silymarin in this form.

TOXICITY Silymarin preparations are widely used medications in Europe, where a considerable body of evidence points to very low toxicity.' When used at high doses for short periods, silymarin given by various routes to mice, rats, rabbits, and dogs has shown no toxic effects. Studies in rats receiving silymarin for protracted periods have also demonstrated a complete lack of toxicity.' Because silymarin possesses choleretic activity, it may produce a looser stool as a result of greater bile flow and secretion. If higher doses are used, it may be appropriate to use bile-sequesteringfiber compounds (e.g., guar gum, pectin, psyllium, oat bran) to prevent mucosal irritation and loose stools. Because of silymarin's lack of toxicity, its long-term use is feasible when necessary.

DRUG INTERACTIONS Although silymarin components have been shown to interact with drug-metabolizing cytochrome PjSO enzymes in in vitro studies, the concentrations showing an inhibitory effects are not achieved with normal dosage recommendations." Clinical studies have shown that coadministration of silymarin with drugs metabolized by enzymes (e.g., indinavir) cause no adverse interaction^.^^,^^

Pharmacology of Natural Medicines

1.Wagner H. Antihepatotoxic flavonoids. In Cody V, Middleton E Jr, Harboume JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and structure-activity relationships. New York Liss, 1986545-558. 2. Adzet T. Polyphenolic compounds with biological and pharmacclogical activity. Herbs Spices Medicinal Plants 1986;1:167-184. 3. Hikino H, Kiso Y, Wagner H, Fiebig M. Antihepatotoxic actions of flavonolignans from Silybum marianum fruits. Planta Med 19843: 248-250. 4. Wagner H. Plant constituents with antihepatotoxic activity. In Bed JL, Reinhard E, eds. Natural products as medicinal agents. Stuttgart: Hippokrates-Verlag, 1981. 5.Vogel G, Tuchweber B, Trost W, Mengs U. Protection against Amanita phalloides intoxication in beagles. Toxic01Appl Pharm 1984; 73355-362. 6. Seme EH, Toorians AWF, Gietema JA, et al. Amanifa phlloides, a potentially lethal mushroom: its clinical presentation and therapeutic options. Neth J Med 1996;49:19-23. 7.Vogel G, Trost W, Braatz R, et al. [Pharmacodynamics, site and mechanism of action of silymarin, the antihepatoxic principle from Silybum mar. (L.) Gaertn]. Arzneimittelforschung 1975;25:82-89. 8. Poser G. [Experiencein the treatment of chronic hepatopathies with silymarin]. Arzneimittelforschung 1971;21:1209-1212. 9. Palasciano G, Portincasa P, Palmieri V, et al. The effect of silymarin on plasma levels of malondialdehyde in patients receiving longterm treatment with psychotropic drugs. Curr Ther Res 199455: 537-545. 10. Sonnenbichler J, Goldberg M, Hane L, et al. Stimulatory effect of silybinin on the DNA synthesis in partially hepatectomized rat livers: non-response in hepatoma and other malignant cell lines. Biochem Pharmacol1986;3553&541. 11. Sonnenbichler J, Zetl I. Biochemical effects of the flavanolignane silybinin on RNA, protein and DNA synthesis in rat livers. In Cody V, Middleton E, Harboume JB, eds. Plant flavonoids in biology and medicine: biochemical, pharmacological, and s t r u c t u r e activity relationships. New York Liss, 1986:319-331. 12.Fiebrich F, Koch H. Silymarin, an inhibitor of lipoxygenase. Experientia 1979;351548-1550. 13.Fiebrich F, Koch H. Silymarin, an inhibitor of prostaglandin synthetase. Experientia 1979;35:1150-1152. 14. Wilasrusmee C, Kittur S, Shah G, et al. Immunostimulatory effect of Silybum marianum (milk thistle) extract. Med Sci Monit 2002;8: BR439-BR443. 15. Tyagi A, Bhatia N, Condon MS, et al. Antiproliferative and apoptotic effects of silybinin in rat prostate cancer cells. Prostate 200233: 211-217. 16.Kohno H, Tanaka T, Kawabata K, et al. Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethaneinduced colon carcinogenesis in male F344 rats. Int J Cancer 2002;lOl: 461-468. 17. Yanaida Y, Kohno H, Yoshida K, et al. Dietary silymarin suppresses 4nitroquinohe l-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis 2002;23:787-794. 18. Kock HP,Bachner J, Loffler E. Silymarin: potent inhibitor of cyclic AMP phosphodiesterase. Methods Find Exptl Clin Pharmacol 1985;7:409413. 19. Valenzuela A, Barria T, Guerra R, Garrido A. Inhibitory effect of the flavonoid silymarin on the erythrocyte hemolysis induced by phenylhydrazine. Biochem Biophys Res Comm 1985;126712-718. 20. Flemming K. [Therapeutic effect of silymarin on X-irradiated mice]. Arzneimittelforschung 1971;21:1373-1375. 21. Zoltan OT, Gyori I. [Studies on the brain edema of the rat induced by triethyltinsulfate. Part 7 The therapeutic effect of silymarin,

theophylline, and mannitol in the conditioned reflex test]. Arzneimittelforschung 1970;201248-1249. 22. Seeger R. [Effect of silymarin on osmotic resistance of erythrocytes]. Arzneimittelforschung 1971;21:1599-1605. 23. Skottova N, Krecman V. Silymarin as a potential hypocholesterolaemic drug. Physiol Res 1998;471-7. 24. Schopen RD, Lange OK, Panne C, Kimberger EJ. Searching for a new therapeutic principle: experience with hepatic therapeutic agent Legalon. Med Welt 1969;20888-893. 25. Schopen RD, Lange OK. [Therapy of hepatoses: therapeutic use of silymarin]. Med Welt 1970;21:691-698. 26.Canini F, Bartolucci, Cristallini E, et al. [Use of silymarin in the treatment of alcoholic hepatic steatosis]. Clin Ter 1985; 114307-314. 27. Salmi HA, Sama S. Effect of silymarin on chemical, functional, and morphological alteration of the liver: a double-blind controlled study. Scand J Gastroenterol1982;17517-521. 28. Scheiber V, Wohlzogen FX. Analysis of a certain type of 2 x 3 tables, exemplified by biopsy findings in a controlled clinical trial. Int J Clin Pharmacol Biopharm 1978;16:533-535. 29. Boari C, Montanari M, Galleti GP, et al. [Occupational toxic liver diseases: therapeutic effects of silymarin]. Minerva Med 1981; n.2679-2688. 30. Grossi F, Viola F. [Membrane protectors and silymarin in herpatology therapy]. Clin Ter 19819611-23. 31. Maneschi M, Tiberio C, Cittadini E. [Metabolic impairment of the hepatocyte in pregnancy: prevention and therapy with a membranestabilizing drug]. Clin Ter 198197625-630. 32. Bulfoni A, Gobbato F. Evaluation of the therapeutic activity of silymarin in alcoholic hepatology. Gazz Med Ital 1979;138: 597-608. 33. Cavalieri S. A controlled clinical trial of Legalon in 40 patients. Gazz Med Ital 1974;133:62&635. 34. Saba P, Galeone GF, Salvadorini F, et al. Therapeutic effects of silymarin in chronic liver diseases due to psychodrugs. Gazz Med Ital 1976;135236-251. 35. De Martiis M, Fontana M, Sebastiani F, Parenzi A. [Silymarin, a membranotropic drug: clinical and experimental observations]. Clin Ter 1977;81:333-362. 36. Szilard S, Szentgyorgyi D, Demeter I. Protective effect of Legalon in workers exposed to organic solvents. Acta Med Hung 1988;45: 249-256. 37. Ferenci P, Dragosic SB, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol1989;9:105-113. 38. Deak G, Muzes G, Lang I, et al. [Immunomodulator effect of silymarin therapy in chronic alcoholic liver diseases]. Orv Hetil 1990;131:1291-1296. 39. Magliulo E, Gagliardi B, Fiori GP. [Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres]. Med Klin 1978;73:1060-1065. 40.Berenguer J, Carrasco D. Double-blind trial of silymarin versus placebo in the treatment of chronic hepatitis. Munch Med Wochenschr 1977;119:240-260. 41. Nassauto G, Iemmolo RM, Strazzabosco M, et al. Effect of silybinin on biliary lipid composition: experimental and clinical study. J Hepatol 1991;12:290-295. 42. Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs 2001;61:2035-2063. 43. Weber G, Galle K. The liver-a therapeutic target in dermatoses. Med Welt 1983;34:108-111. 44. Gaedeke J, Fels LM, Bokemeyer C, et al. Cisplatin nephrotoxicity and protection by silybinin. Nephrol Dial Transplant 1996;11:56-62.

Silybum marianum (Milk Thistle) 45. Schandalik R, Gatti G, Perucca E. Pharmacokinetics of silybin in bile following administration of silipide and silymarin in cholecystectomy patients. Arzneimittelforschung 1992;42.964-968. 46. Barzaghi N, Crema F, Gatti G, et al. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidykhohe complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 1990;15:333-338. 47. Moscarella S, Giusti A, Marra F, et al. Therapeutic and antilipoperoxidant effects of silybin-phosphatidylcholinecomplex in chronic liver disease: preliminary results. Curr Ther Res 1993;53:98-102. 48.Vailati A, Aristia L, Sozze E, et al. Randomized open study of the dose-effect relationship of a short course of IdB 1016

in patients with viral or alcoholic hepatitis. Fitoterapia 1993;64: 219-228. 49. Zuber R, Modriansky M, Dvorak Z, et al. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 2002;16632-638. 50. DiCenzo R, Shelton M, Jordan K, et al. Coadministration of milk thistle and indinavir in healthy subjects. Pharmacotherapy 2003;23866-870. 51. Piscitelli SC,Formentini E, Burstein AH, et al. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002;22:551-556.

Soy Isoflavones and Other Constituents Kathleen A. Head, ND

JulieS. 3urenka, BS, MT(ASCP) CHAPTER C O N T E N T S Introduction 1259 Chemical Composition 1259 lsoflavones 1259 Other Soy Constituents 1261 Pharmacology 1262 Hormonal Effects in Infants 1262 Hormonal Effects in Adults 1263 Mechanisms of Action of Soy lsoflavones 1265

INTRODUCTION In the past several years, soy and its constituents have received considerable attention, from both researchers and health practitioners. Epidemiologic data indicating that people from Asian cultures have lower rates of certain cancers, including cancer of the breast, prostate, and colon, sparked an interest in soy as a contributing factor. Although soy constituents-saponins, lignans, phytosterols, protease inhibitors, and phytates-have come under investigation, the constituents that seem to hold the most promise from a therapeutic standpoint are the two isoflavones, genistein and daidzein. Numerous epidemiologic, human, animal, and in vitro studies have demonstrated that soy isoflavones are effective chemopreventive agents for certain types of cancer. Mechanisms involved include the following: Antiangiogenesis Estrogen receptor binding Enhanced immune response due to increased interleukin-6 (IL-6) levels Modulation of sex hormone-binding globulin (SHBG) Antiinflammatory and antioxidant effects Inhibition of the enzymes protein tyrosine b a s e (pnlP5), researchers concluded that the effect of genistein at the lower concentrations appeared to be estrogen receptormediated but that the effects at higher concentrations were independent of estrogen receptors. Genistein, when administered to neonatalg0or prepubescent rats?l suppressed the development of chemically induced mammary tumors without causing toxicity to the development of the endocrine or reproductive systems. Barnes et a192found that soy in the form of raw soybeans as well as soy protein isolate inhibited mammary tumors in experimental models.

Prostate Cancer Epidemiologicevidence points to the benefits of soy constituents in the prevention of prostate cancer. Japanese men who consume a low-fat, high-soy diet have low mortality rates from prostate cancer. Isoflavones in the plasma of Japanese men were between 7 and 110 times higher than in Finnish men, with genistein present in the highest ~oncentrations.9~ Suggested mechanisms of protection include genistein-induced prostate cancer cell adhesion, direct growth inhibition, and induction of apoptosis. Growth inhibition appears to be independent of genistein's estrogenic effe~ts.9~ An in vitro study indicated that the isoflavones genistein, biochanin A, and equol were potent inhibitors of 5-alpha-reductase,@the enzyme necessary for conversion of testosterone to dihydrotestosterone (implicated in prostate cancer). Studies have found that animals fed soy isolates high in the isoflavones genistein and daidzein demonstrated a lower incidence of prostate cancer and a 27% longer disease-free period after exposure to chemical carcinogens than animals fed a soy isolate low in is0flavones.9~ This finding not only points to the potential chemoprotectiveeffects of soy but seems to highlight the importance of the isoflavones over other soy constituents.

Pharmacology of Natural Medicines Peterson and Barnes96found that the isoflavones genistein and biochanin A, but not daidzein, inhibited several human prostate cancer cell lines.

National Institutes of Health Recommendations The committee of the National Institutes of Health (NIH) studying chemoprevention from soy products made the following recommendations: Future dietary studies involving soybeans should use soy products rather than isolated compounds, because soybeans appear to contain several potential anticarcinogens. Standardized and improved analytical methods are needed so that the contents of all soy-based materials employed in soybean research, whether soybean fractions or soy products, can be accurately described. Basic research in the absorption, metabolism, and physiology of potential anticarcinogens in humans should be conducted.

Cardiovascular Disease Studies of monkeys have confirmed the cardioprotective effects of soy. Soy protein diets, compared with casein diets, resulted in significant improvements in lipid profiles and insulin sensitivity and a decrease in arterial lipid per~xidation.~~ Furthermore, animal studies indicate that the isoflavone content of the soy is an important factor. In addition to reducing elevations of blood cholesterol, isolated soy protein may decrease oxidation of LDL cholesterol, impede the formation of arteryblocking blood clots, improve dilator response in arteries already exhibiting plaque formation, reduce restenosis after balloon angioplasty, and generally decrease atheroscler~sis.~~~~

Lipid-Lowering Effects A large meta-analysis of 38 controlled studies comparing soy- and animal-protein diets found a statistically significant decrease in serum lipids in the soy group. The changes were most significant in subjects with

hypercholesterolemia (Table 126-4).99The intakes of energy, total fat, saturated fat, and cholesterol were similar in the two groups. Gooderham et allm reported no effect on platelet aggregation or serum lipid levels in healthy, normocholesterolemic men fed soy protein in comparison with casein. One of the proposed mechanisms for the hypoEpidemic effect involves an increase in LDL receptor activity in both humans and animal^.^' Other metabolic changes that have been noted in animals and humans on soy diets are increases in bile acid synthesis and apolipoprotein B and E receptor activity, and a decrease in hepatic secretion of lipoproteins (associated with greater clearance of cholesterol from the blood stream).lo1 Proposals for the specific constituents involved include the amino acid profile, saponins, phytic acid, and fiber as well as the effects of isoflavones discussed later.lo1 In one study, monkeys were fed soy isolates high in isoflavones and results were compared in a crossover trial with those of a soy isolate in which the isoflavones had been removed via alcohol extraction. Serum LDL and VLDL levels and ratio of total to HDL cholesterol were significantly lowered, but HDL levels were significantly elevated in the group consuming the isoflavonerich diet.12 No lipid-lowering effect occurred in a third group on a casein diet. Two separate clinical trials completed in 2002 demonstrated the beneficial effects of soy isoflavones on lipid profiles in humans. Uesugi et all0*demonstrated that in healthy perimenopausal women, 61.8 mg soy isoflavones daily resulted in sigruficant decreases in total and LDL cholesterol.102Another study involved 41 hyperlipidemic men and postmenopausal women who were given one of three diets for 4 weeks: a low-soy isoflavone diet (10 mg isoflavones daily), a high-soy isoflavone diet (73 mg isoflavones daily), or a control diet of low-fat dairy food. Examination of the results found no significant differences between the lowand high-isoflavone diets. Both soy diets, however, resulted in significantly lower calculated coronary artery disease risk, total cholesterol level, and ratios of total to HDL cholesterol, LDL to HDL cholesterol, and

Results of a metaanalysis of the effects on serum lipids of soy-protein diet in comparison with meat-protein diet LiDid

Sov diet

Meat Drotein diet

Total cholesterol

23.2 mg/dl decrease

9.3% decrease

Low-density lipoprotein cholesterol

21.7 mg/dl decrease

12.9% decrease

Trig1ycerides

13.3 mg/dl decrease

10.5% decrease

High-density lipoprotein cholesterol

1.2 mg/dl increase (not significant)

2.4% increase

Modifiedfrom Anderson JW, Johnstone BM, Cook-NewellME. N Engl J Med 1995;333:276-282.

Soy lsoflavones and Other Constituents

of soy milk consumption (isoflavonecontent unknown) on hypertension. Three months of soy milk consumption resulted in decreases in diastolic, systolic, and mean blood pressure values compared with those in subjects in a cow's milk (placebo) group. Urinary genistein measurements showed significant association with the decrease in blood pressure, particularly for the diastolic values, suggesting a hypotensive effect of isoflav~nes.'~~ In a previously cited study measuring the effects of soy isoflavones on lipid values and blood pressure, a significant hypotensive effect was seen in men consuming soy isoflavone diets.lo3

apolipoprotein B to apolipoprotein A-1 compared with placebo. No significant sex differences were observed, with the exception of systolic blood pressure, which was significantly lower in men, but not women, eating the soy diets.lo3 In Finland 60 patients in a primary care clinic were enrolled in a double-blind, placebo-controlled, 6-week trial. Patients in the treatment group received Abacor, a product based on isolated soy protein, in addition to their regular diet. Although the soy isoflavone content was not noted, the Abacor diet sigruficantly reduced both total and LDL cholesterol levels.'04

Effects on the Atherosclerotic Process

Menopause

Arterial thrombus formation is generally initiated by an injury to the endothelial cells lining the blood vessels. One of the first events after an injury is thrombin formation. This leads to a cascade of events including platelet activation and resulting in thrombus formation. Genistein has been found to inhibit thrombin formation and platelet activation.&The pathogenesis of atherosclerotic plaque formation involves, in addition to lipid accumulation, the infiltration of monocytes and T lymphocytes into the artery wall, which contributes to the thickening of the wall and eventual occlusion of the vessel. Monocytes and lymphocytes are able to adhere to the endothelial cell surfaces via the expression of certain "adhesion molecules." The infiltration and proliferation appear to be controlled by peptide growth factors. Increased levels of isoflavones, genistein in particular, appear to alter the platelet growth factor activity and to inhibit cell adhesion and proliferation, all activities necessary for lesion formation in the intima of the blood vessels (Figure 126-4).98

A review of clinical trials studying the effects of soy isoflavones on menopausal symptoms yielded mixed results. Observational data indicate that Japanese women, who consume 50 to 100 times greater amounts of soy isoflavones than women consuming Western diets, have a nearly tenfold lower incidence of vasomotor symptoms, such as hot flashes.lo6In a 2-month study 20 menopausal women were given a daily soy drink containing 80 mg soy isoflavones. A significant decline in hot flashes, compared with the placebo group given a casein drink, was observed. The soy group also exhibited lower total cholesterol and LH levels and higher prolactin and growth hormone levels.107 A double-blind Brazilian study of 80 menopausal women showed that 100 mg soy isoflavone daily for 4 months resulted in a decrease in menopausal symptoms as measured by endogenous hormone levels. An additional benefit was a sigruficant decrease in LDL and total cholesterol.lo8 Conversely, other studies have not shown soy isoflavone consumption to be of benefit in reducing menopausal symptoms. In a double-blind, placebocontrolled study of 94 healthy menopausal women, Kotsopoulos et a P found that soy isoflavone supplementation consisting of 118 mg daily did not provide

Hypotensive Effects Dietary soy may help modulate blood pressure. One double-blind randomized trial of 40 men and women with mild to moderate hypertension examined the effect

Thrombus formation

Infiltrationand proliferation of monocytes and T-lymphocytes

xxx

+

.1 XXX

T

Inhibits thrombus formation Flgure 126-4

Atheroscleroticplaque

Lipid accumulation

Inhibits proliferation and adhesion to vessel walls

+xxx

T

Improves lipid profile Impact of soy on atherosclerotic plaque formation.

Pharmacology of Natural Medicines

signhcant symptomatic relief compared with placebo. The one parameter that yielded positive results was a decrease in vaginal dryness.54Furthermore, a study conducted in 123 postmenopausal women with moderate hot flushes did not show benefit of soy consumption. Fifty-nine of the women consuming a soy beverage containing 90 mg isoflavones for 12 weeks, and the remaining 64 received a rice beverage. There was no difference in hot flashes between the soy and rice beverage groups.’Og

Osteoporosis An animal study indicated that soy isolates may enhance bone density. Ovariectomized rats fed a high-soy diet demonstrated enhanced bone density of the vertebral bodies and femoral bone compared with the group fed a casein diet. Although there was considerable bone turnover in the soy-fed group, bone densities suggest that formation exceeded resorption.”” A review of research over the past 35 years showed that genistein, which appears to bind estrogen receptors, stimulates protein synthesis in osteoblast cell lines in vitro.”’ Clinical studies of the effect of soy isoflavone’s on bone density have confirmed a protective effect in older women but not in healthy younger women. One study involving 208 postmenopausal women examined the effect of dietary soy on markers of bone turnover over 1 year. Examination of both markers of bone resorption and bone formation showed that women with the highest level of isoflavone consumption possessed greater spinal bone density.112A community-based cohort study found that premenopausal, but not perimenopausal, Japanese-American women with genistein intake in the highest tertile had higher spinal and femoral bone mineral density than women in the lowest tertile.lI3 However, a clinical trial in which 28 young, healthy, menstruating women were given 90 mg soy isoflavones daily for 12 months found no differences in bone mineral content or bone mineral density compared with the control group (receiving soy protein with isoflavones rem~ved).”~

Thyroid Effects Emerging epidemiologic and pathologic data suggest that thyroid cancer may be an estrogen-dependent disease. A popula tion-based, case-controlled study conducted in the San Francisco Bay area examined 817 cases of thyroid cancer diagnosed between 1992 and 1998. The study concluded that intake of the isoflavones daidzein and genistein in soy-based food and alfalfa sprouts was associated with a lower risk of thyroid cancer. Findings were similar for both white and Asian women and for premenopausal and postmenopausal women.115 The effect of soy isoflavones on thyroid hormone levels was studied in 73 hypercholesterolemic, postmenopausal women in a 6-month, double-blind trial.

Patients were assigned to one of three diets: control (casein from nonfat dry milk), isolated soy protein containing 56 mg isoflavones, and isolated soy protein containing 90 mg isoflavones. Slight rises were observed in thyroid hormone levels in both groups consuming soy diets compared with placebo. Results did not, however, provide evidence of changes in a variety of other endogenous hormones, including estrogens, DHEAS,and i n ~ u l i n . ” ~ On the other hand, there is some evidence that soy isoflavone supplementation may inhibit thyroid funct i ~ and n ~cause ~ ~ diet-induced goiter. In vitro analysis found that both daidzein and genistein blocked iodination of tyrosine and that genistein inhibited thyroxine synthesis.118A study of 37 healthy Japanese adults demonstrated that 30 g per day of soybeans for 3 months led to a slight elevation in thyroid-stimulating hormone (TSH)values.119Another study from Cornell University’s Department of Pediatrics also found that the frequency of feedings with soy-based formulas early in life was significantly higher in children with autoimmune thyroid disease (31%) than in siblings (12%) and unrelated controls (130/,).120

Other Potential Therapeutic Effects Although research on the health benefits of soy constituents has focused primarily on the chemopreventive effects for cancer, cardiovascular disease, and women’s health issues, a few other conditions might benefit from the addition of soy isoflavones to the diet.

Eye Disorders Neovascularization complicates many eye disorders, such as proliferative diabetic retinopathy, and is responsible for corneal transplant rejection. Substances that exhibit the capacity to inhibit angiogenesis could play an important role in preventing this vascularization. An animal study demonstrated that genistein, when injected subconjunctivally, inhibited corneal neovascularization.Iz1Although this was not a human study with the use of oral doses, the findings open the door for future investigation.

Cognitive Function Studies examining the effect of soy intake on cognitive function are limited, and results have varied. However, preliminary animal studies indicate that soy isoflavones may attenuate hyperphosphorylation of the tau protein, a hallmark of Alzheimer’s disease and several other human dementias.l’ On the other hand, an analysis from a large longitudinal study of 764 elderly men, originally conducted to assess diet, heart disease, stroke, and cancer, demonstrated that poor cognitive performance, enlargement of ventricles, and low brain weight were sigrulicantly and independently associated with high

Soy lsoflavones and Other Constituents levels of midlife tofu consumption. Although it is unclear which soy constituents in the tofu were responsible for these results, these findings suggest a need for further study.123

inhibition of dysplastic and malignant epithelial breast cancer cells. The addition of tamoxifen to the cell cultures had a synergistic and additive effect that was independent of estrogen receptor status.12'

DRUG-NUTRIENT INTERACTIONS

CONCLUSION

Dietary supplementation of soy protein concurrent with oral levothyroxine therapy appears to decrease absorption of levothyroxine and lead to the need for higher oral dosing to achieve therapeutic levels of free thyroxine (T4) and TSH. Temporal separation of levothyroxine intake and soy protein supplements results in suppressive serum levels of T4 and TSH with lower doses of levothyro~ine.~~~ Genistein has been shown to inhibit breast cancer cell growth in vitro at doses of 10 pM or above. In a model of estrogen receptor-positive postmenopausal breast cancer, lower doses of genistein have been shown to inhibit the therapeutic effects of tamoxifen therapy.'= An animal study demonstrated that tamoxifen suppression of breast tumor growth in ovariectomized athymic mice was negated by the administration of 1000 ppm dietary genistein.'26 Therefore, postmenopausal women undergoing tamoxifen therapy for estrogen-responsive breast cancer should use caution when consuming dietary genistein. However, in contrast, another in vitro study of genistein (doses of 1 to 10 pg/ml) showed growth

Research indicates that soy and its individual constituents have several potential health benefits. The primary isoflavones, genistein and daidzein, as well as their metabolites exert a wide array of effects that may offer protection against cancer, cardiovascular disease, and osteoporosis. Soy and its constituents also appear to have therapeutic applications in menopause and ocular neovascularization. Whether soy has a negative or positive effect on thyroid and cognitive functions remains to be elucidated. Many of the studies to date have been epidemiologic, animal, or in vitro. Controlled human trials are emerging, and some confirm the preliminary findings reported in earlier studies. Soy constituents, particularly the isoflavones, have come under scrutiny owing to their phytoestrogen effects. Because in some cases they act as estrogen agonists, and in others as antagonists, the use of these isoflavones in patients with cancer and in infant formulas remains controversial. Further study to determine whether their use in these situations is harmful or beneficial is indicated.

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Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements Alexander G . Schauss, PhD, FACN CHAPTER C O N T E N T S Introduction 1275 The Recommended Daily Allowances 1275 The Need for a Guideline to Optimal Intake Levels of Nutrients 1277 The Development of Suggested Optimum Nutrient Intakes 1277 Revelations from the Birmingham Study 1278 Survey Questionnaire for Suggested Optimum Nutrient Intake 1278

INTRODUCTION In 1998, the Food and Nutrition Board of the U.S. Institute of Medicine recommended that to reduce the likelihood of neural tube defects offspring, women should eat a varied diet and take an extra 400 vg of folic acid to be absolutely sure that they get enough of the nutrient.* Further, the Board found that “the evidence for a protective effect from folate supplements is much stronger than for food folate.”’ That the public should use a dietary supplement, not just food, to ensure that they are consuming the necessary level of a nutrient to prevent a disease or condition is nothing less than a paradigm shift in official public health policy concerning the issue of nutrient supplementation. In recent years a convincing link between the intake of folic acid and neural tube defects has been established. As a result the National Institutes of Health and U.S. Department of Health and Human Services gave special attention to the need for folic acid in the diet in the prevention of such neural tube defects as spina bifida Folic acid is but one of the B vitamins that has been the subject of research on the role nutrients play in the prevention, mitigation, or treatment of cancers, cardiovascular diseases, mental disorders, and other diseases and condition^."'^ For example, researchers are continuing to unravel the association between levels of folate, pyridoxine (vitamin B6), and inositol and the reduction ?p3

Dietary Supplementation: An Idea Whose Time Has Come? 1279 The Suggested Optimum Nutrient Intakes 1279 Fat-Soluble Vitamins 1280 Water-Soluble Vitamins 1284 Minerals 1290

of excessive levels of blood homocysteine, a marker associated with the risk for cardiovascular disease. This chapter discusses the daily suggested optimal nutrient intake (SONI) of nutrients necessary to maintain health and reduce the risk of disease. The conclusion I have reached for each nutrient is based on a review of thousands of epidemiologic, clinical, and experimental papers, offering evidence for optimal versus minimal intake levels to maintain health and reduce the risk of disease in humans of 27 vitamins, minerals, and trace elements.

The Recommended Daily Allowances Since the mid-l940s, the U.S. Recommended Daily Allowances (RDAs) have served as a nutritional guideline.I3These guidelines were developed from minimalist criteria aimed solely at the prevention of nutritionally related clinical deficiencies. In the late 1990s the RDAs were gradually replaced with new nutritional guidelines, the Recommended Daily Intakes (RDIs).’~Curiously, the RDIs show no more promise than the RDAs did in providing the public with useful information on the intake of nutrients in the prevention, mitigation, and treatment of a wide range of conditions and diseases for which diet does or may play a role. Hence, it is worthwhile to understand the limits of the RDAs and RDIs to fully appreciate the need for SONIs. Because our understanding of the optimal level of each nutrient in the prevention, mitigation, and treatment of disease

1275

Pharmacology of Natural Medicines

remains a somewhat primitive science, the discussion is framed around the concept of SONIs. As our understanding of the role of each nutrient in disease processes becomes more sophisticated, the values for the SONIs are certain to change, yet they certainly provide us better guidelines to maintain health than the minimalist basis from which the RDAs were constructed.

The History In May 1941, a committee of the National Academy of Sciences (NAS) suggested for the first time that a ”Recommended Daily Dietary Allowance” of essential nutrients be established. These guidelines were developed with the goal of reducing the incidence of nutritional deficiency diseases in the general population such as scurvy (deficiency of vitamin C), pellagra (deficiency of niacin), and beriberi (deficiency of vitamin BJ. Over time, nutritionists, dietitians, and physicians have relied on the RDAs, through nine revisions, as a guideline for advising public health officials and the public about recommended nutrient intake levels. According to the committee that established them, RDAs were intended (1) as guidelines for the prevention of nutritional deficiencies and (2) to be related to the nutrient status of population groups, not individuals. In essence, the RDAs provide no information on the role of nutrients in the prevention, amelioration, or treatment of conditions or diseases.

The Weaknesses A common mistake made by many public health practitioners is to use the RDAs to evaluate the adequacy of an individual‘s diet. Even worse is the assumption that maintaining a diet that provides an RDA level of nutrients will somehow ensure wellness over an individual’s lifetime. Only recently has it become apparent that “healthy normal people” are an ideal population group to study. Among Americans 60 years and older, more than 80% suffer from at least one or more chronic diseases, such as cancer, atherosclerosis, osteoporosis, macular degeneration, osteoarthritis, rheumatoid arthritis, diabetes, and hypertension, and age-related degenerative diseases, such as presbycusis (hearing loss). Since at least 1951, critics of the RDA have asserted that the RDA’s lack the abillty to recommend levels of nutrients sufficient to maintain health for a person seeking a healthy lifespan that is associated with a morbidity-free existence. Studies that have been used to determine the level of a nutrient sufficient to prevent a nutritional deficiency is typically conducted for only 6 to 9 months, about 1% of the average person‘s lifespan. This fact suggests that these minimalist dietary standards are based on data incapable of determining levels of nutrients essential to prevent many conditions and diseases associated with morbidity over a lifetime.

Even more germane to this issue is the attention focused in recent years on the role of substances not generally recognized as nutrients that appear to be directly involved in the prevention or mitigation of a diverse host of diseases from colon cancer to coronary heart disease, cataracts, birth defects, and stroke. Early editions of the RDAs, published in the 1940s, clearly stated that the RDAs “vary greatly in disease.” In spite of this realization, the RDAs continued to focus only on the prevention of nutritional deficiencies in population groups. This focus began to change in 1989 with the release of the tenth edition of the RDA by the National Academy of Sciences. The tenth edition acknowledged for the first time that levels of a nutrient, specifically the nutrient vitamin C, may need to be higher than the RDA for groups at risk for development of chronic diseases, particularly smokers. This recommendation opened the door to an entirely new paradigm, namely, the determination of optimal nutrient intake levels to minimize the risk of development of conditions and diseases affecting various population groups (i.e., women at risk for birth defects). Unfortunately, the NAS’s noble attempt to keep up with the science of nutrition continues to be inadequate because of its minimalist foundation. A higher level of vitamin C intake for smokers is in indeed suggested in the tenth edition, but studies of smokers‘ blood levels of vitamins and minerals have shown that levels of other nutrients, such as beta-carotene, zinc, vitamin Bb and vitamin E, also may have to be significantly higher than that recommended for vitamin C or prescribed by the RDAs. Mounting evidence suggests that all of these nutrients, not just vitamin C, and probably many other nutrients and nonnutritive substances found in food, may have to be taken by smokers to compensate for the nutrient loss their habit produces. Chromium intake is another area in which the RDAs fall short. The RDA for chromium is 35 pg/day for adult men. Clinical trials have confirmed the safety of up to loo0 pg/day of supplemental chromium. Hence, individuals consuming diets containing less then 50 pg/day of chromium might benefit from a supplement containing an additional 200 to 500 pg/day to reduce the risk of type 2 diabetes while helping maintain normal blood glucose levels, because of chromium’s role in insulin regulation. The RDAs also fail to address the excessive use of alcohol, yet another example of a common addiction that raises nutrient requirements. Individuals who habitually consume excessive amounts of alcohol have been found to have lower levels of folate, vitamin BI, vitamin B6, vitamin A, beta-carotene, zinc, and vitamin C. The lifestyles of individuals are also neglected in the RDA. Dieters, for example, commonly consume inadequate levels of nutrients. Studies have shown that it is extremely difficult, if not impossible, for someone

Suggested Optimum Nutrient intake of Vitamins, Minerals, and Trace Elements

consuming less than 1200 calories/day to meet the RDAs. An analysis of 11major reducing diets shows that none can provide 100% of the RDAs for vitamins. What about individuals with eating disorders (i.e., bulimia nervosa)? Individuals who work under conditions of chronic stress? Individuals who smoke cigarettes? People who get insufficient vitamin D from sunlight or have darker skin pigmentation and need more vitamin D to reduce cancer risk? We have come to realize that people with habits or lifestyles require nutrient levels well above those recommended by the RDAs. It is important to understand the limits of the RDAs and to appreciate the potential benefits of higher nutrient intake levels, when prudent. Box 127-1 outlines seven limitations of the RDAs as dietary intake guidelines in the prevention of conditions and diseases that affect the quality of life, morbidity, and mortality. Item number 7 on the list found in Box 127-1 is an important point. It identifies the folly of relying on RDAs or the most recent guideline, the RDI, as a yardstick to determine safe or adequate intake of a nutrient. There is no known toxicity associated with vitamin B12. The adult RDA for vitamin BIZ is 2 to 2.5 pg/day. Conventional foods such as liver provide nearly 100 pg of this vitamin per 100-g serving, more than 40 times the RDA! Would we recommend that individuals should avoid eating liver because it contains so much vitamin B12 (cobalamin)? Yet for decades the RDAs have been used by critics of dietary supplementation as a tool to warn people that nutrient intakes higher than RDA levels are not safe and may actually have serious adverse effects. If the level of various nutrients in foods can be significantly higher than the RDAs, why support this

1. They are meant to serve as a guideline for the prevention

of nutritional diseases, not the promotion of health. 2. The recommendations are based on the nutrient status of large

population groups numbering in the millions, not as a guideline to determine individual dietary-nutrient requirements. 3. The estimates of the RDAs are based only on short-term research that represents less than 1% of the average person’s life span, so they cannot provide nutrient recommendations that may be of benefit over a lifetime in the prevention or amelioration of diseases associated with aging or certain life styles. 4. They do not make adjustmentsfor variations in nutrient needs associatedwith conditions or diseases that affect nutrient requirements. 5. They provide no data on compensatory levels of nutrient intake needed to compensate for nutrient-demanding lifestyle factors such as: chronic stress, chronic intense exercise, cigarette smoking, alcoholism, restrictive dieting routines, polluted environments, exposure to chemical carcinogens, etc. 6. They neither define nor identify a safety limit for total or supplemental nutrient intake. 7. They do not relate to levels of nutrients found in food.

minimalistic approach to nutrient intake levels? And why do so for more than 50 years? Especially in the face of mounting evidence, for almost all of the nutrients for which an RDA has been set, that higher levels may prevent, mitigate, or treat a wide range of diseases? Each discussion of vitamin, mineral or trace element, has a separate titled section in the reference list. Although it is a standard practice to report the latest studies on a subject in the scientific literature, I have intentionally included references to papers several decades old to illustrate how long ago our knowledge about the benefits of these nutrients above the RDA was gained. These historical references place the concept of suggested optimal nutrient intakes in perspective.

The Need for a Guideline to Optimal Intake Levels of Nutrients A growing body of evidence indicates that intakes of certain vitamins and minerals at levels well above the RDAs may be necessary to protect against the development of certain conditions and diseases that affect the quality of life and/or lifespan. For example, antioxidants such as vitamin C, beta-carotene, vitamin E, and selenium may prevent free radical damage to vascular endothelial cells associated with the most common form of cardiovascular disease, atherosclerosis. These vitamins and minerals may be required in much higher amounts to prevent atherosclerosis than the RDAs, which were determined to prevent deficiency symptomsunless, of course, the development of atherosclerosis is a symptom of vitamin/mineral deficiencies, a concept well worth exploring. The same might be said of many cancers, heart disease, birth defects, eye diseases (e.g., macular degeneration and cataracts), hearing loss, diabetes, and other maladies and diseases.

The Development of Suggested Optimum Nutrient Intakes As a result of numerous epidemiologic, clinical, and experimental studies, it is now possible to create SON1 levels for the vitamins, minerals, and trace elements essential to health. Nearly 20 years ago, an effort was made by Drs. Cheraskin and Ringsdorf at the University of Alabama School of Medicine in Birmingham to establish optimum nutrient intake levels. Their prospective study of the intake levels of vitamins and minerals in humans spanned 15 years. They examined the dietary intake and physiologic levels of nutrients in more than 13,500 subjects, male and female, living in six diverse regions of the United States. The results of their multimillion dollar study was compiled into 153 volumes containing more than 49,000 pages of data. Only a small but sigruficant portion of their findings were ever released. A series of some 100 research papers

Pharmacology of Natural Medicines were published during a 20-year span ending in the early 1990s, but it seems that their work has been neglected because it is rarely cited in the literature. Cheraskin and Ringsdorf 's research, with the assistance of specialists in various disciplines, investigated the health status of study participants through a timeconsuming evaluation of each person's health status over a 15-year period. Each subject completed the following tests and procedures: 1. The 195-item Cornell Medical Index Health Questionnaire (CMI) 2. Physical and anthropometric measurements 3. Dental examination 4. Eye examination 5. Cardiac function tests, including an electroencephalogram (EEG) 6. Glucose tolerance test (GTT) 7. Panel of 50 blood chemistry analyses 8. A comprehensive study of the diet, including a study of food intake over 7 days This study attempted to find evidence whether there existed an "ideal" combination of macronutrients, micronutrients, carbohydrates, protein, and fat that would suggest which nutrients contributed to health and longevity, and at what level. The hypothesis of the study was that relatively symptomless and disease-free individuals are healthier than those with clinical symptoms and signs and that this difference was due to the intake of nutrients from the diet and/or dietary supplementation. Of course, any study, even one involving some 13,500 subjects studied prospectively in six diverse geographical regions over 15 years has inherent weaknesses and shortcomings. But it remains the only study of its nature that made its findings available to researchers to analyze and mine for data on what optimal nutrient levels in humans living in a Western culture might be.

Revelations from the Birmingham Study Cheraskin and Ringsdorf's 15-year study of 13,500 subjects found that the healthiest individuals, meaning those with the fewest clinical symptoms and signs over the life of the study, were those who had consumed dietary supplements and eaten a diet nutritionally dense in nutrients relative to their caloric intake. Nutritional density of the diet proved to be a key variable among the healthiest subjects. For example, Cheraskin and Ringsdorf discovered that the "healthiest" subjects had a mean vitamin C intake of 410 mg/day, a good portion of which was consumed in food and the balance from supplementation. The finding of a vitamin C intake just above 400 mg/day is particularly interesting in light of anthropologic evidence of vitamin C intake in preagricultural ancestral diets studied by coprologists. One study found that humans living before the dawn of agriculture (before 10,000 BC)

consumed approximately 392 mg of vitamin C a day on the basis of the composition of their diet, well above the 60 mg level suggested by the RDAs. (These and many other studies are cited in the relevant vitamin and mineral discussion sections that follow.) The Birmingham Study results for vitamin C represents only a 4% difference in daily vitamin C intake between humans living today and those who lived more than 12,000 years ago. Equally intriguing is emerging evidence that cancer and other chronic diseases of modern civilization are relatively rare in ancestral humans, who lived before the advent of agriculture.Could the higher intake of vitamin C and other nutrients in primitive diets be related to the lower incidence of such chronic degenerative diseases? This is a question that may take years to resolve, but it does warrant research interest, especially given what we now know about vitamin C. Epidemiologic evidence of a protective effect of vitamin C for non-hormone-dependent cancers is strong, according to a 1991 National Cancer Institute report. Of the 46 studies in which dietary vitamin C was calculated, 33 found statistically significant protection against cancer, with the highest vitamin C intake conferring the most protection. Of 29 additional studies that assessed fruit intake, 21 found significant protection. For cancers of the esophagus, larynx, oral cavity, and pancreas, evidence for a protective effect of vitamin C or some component in fruit ( e g , polyphenols, flavonoids, and carotenoids) remained strong and consistent. For cancers of the stomach, rectum, breast, and cervix there has also emerged strong evidence of a protective effect against these cancers. Several recent lung cancer studies, for example, have found evidence suggesting a protective effect of vitamin C. Therefore the concept of an "ideal" level or SON1 of 410 mg of vitamin C or more per day may not be out of line, even though it is more than four times higher than the RDA or the more recently created RDI." The evidence in support of vitamin C at higher intake levels, along with similar findings for other nutrients such as selenium and chromium, suggests that the RDAs and RDIs may represent the nutritional equivalent of the minimum wage. Clearly, if the emerging research suggesting a preventive role and even mitigative role for higher nutrient intake levels is correct, there is a profound need for a new paradigm to replace the minimalistic and outmoded RDAs and RDIs. SONI represents an estimate of the vitamin and mineral intake levels that may reduce the risk of maladies and diseases that impair our ability to function or remain healthy or that increase the risk of various diseases.

Survey Questionnaire for Suggested Optimum Nutrient Intake The following questions can serve as a guideline to determine whether higher nutrient requirements than the RDAs/RDIs for an individual are warranted.

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements If the patient answers "yes" to any of the 16 items listed, the SONI that follows in the next section of this chapter may be of benefit in determining a reasonable and safe daily intake of the respective nutrient. It should be noted that for each question in the questionnaire there exists a reasonable body of scientific evidence to support that a nutrient intake of some vitamins and/or minerals above the RDAs is worth considering.

1. Are you under chronic emotional stress? 2. Do you have frequent colds and flus (more than 3 per year)? 3. Do you wish to reduce your risk for development of cardiovascular disease? 4. Do you wish to reduce your risk for development of cancer? 5. Do you wish to reduce your risk for development of 0steoporosis? 6. Do you wish to reduce your risk for development of macular degeneration of the eye? 7. Do you have skin problems? 8. Do you smoke cigarettes? 9. Are you regularly exposed to sidestream smoke at home or work? 10. Do you frequently drink alcohol? 11. Do you take birth control pills? 12. Are you pregnant? 13. Are you older than 50 years? 14. Are you postmenopausal? 15. Do you exercise more than three times a week for 1 hour at a time? 16. Is the air you breath polluted?

Dietary Supplementation: An Idea WhoseTime Has Come? In June 2002, the Journal of the American Medical Association (JAMA) published a two-part paper by two researchers associated with Harvard Medical School that sparked widespread media attenti~n.'~,'~ The abstract of that paper reads as follows: Vitamin deficiency syndromes such as SCUNY and beriberi are uncommon in Western societies. However, suboptimal intake of some vitamins, above levels causing classic vitamin deficiency, is a risk factor for chronic diseases and common in the general population, especially the elderly. Suboptimal folic acid levels, along with suboptimal levels of vitamins B, and B1= are a risk factor for cardiovascular disease, neural tube defects, and colon and breast cancer; low levels of vitamin D contribute to osteopenia and fractures; and low levels of the antioxidant vitamins (vitamins A, E, and C) may increase risk for several chronic diseases. Most people do not consume an optimal amount of all vitamins by diet alone. Pending strong evidence of effectiveness from randomized trials, it appears prudent for all adults to take vitamin supplements. The evidence base for tailoring the contents of multivitamins to specific characteristics of patients such as age, sex, and physical

activity and for testing vitamin levels to guide specific supplementation practices is limited. Physicians should make specific efforts to learn about their patients' use of vitamins to ensure that they are taking vitamins they should, such as folate supplementation for women in the childbearing years, and avoiding dangerous practices such as high doses of vitamin A during pregnancy or massive doses of fat-soluble vitamins at any age.12

This paper is the first report to appear in a leading peer-reviewed medical journals to state that "most people do not consume an optimal amount of all vitamins by diet alone" and that it would be "prudent for all adults to take vitamin supplements."12The IAMA report is the beginning of a paradigm shift in public health thinking on this subject that is long overdue. The health care system can no longer disregard or argue against the mounting evidence that something more than guidelines for preventing nutrient deficiencies are needed. If one looks into the future, it is likely that this shift will take the form of new recommendations that will identify upper limits through risk assessment, rather than by the minimalistic orientation that has been employed to create the RDA and RDI in the past. Even the National Academy of Sciences' Committee on Use of Dietary Reference Intakes at the Institute of Medicine, Food and Nutrition Board, has admitted that since the publication of the tenth and final edition of the RDA in 1989, "there has been a significant expansion and evolution of the research based toward defining functional endpoints that are relevant to the understanding of nutrient requirements and food constituents and their relationship to a number of aspects of human health.""

THE SUGGESTED OPTIMAL NUTRIENT INTAKES The section that follows is divided into various nutrients according to categories. A SONI is provided on the basis of my review of the literature for each nutrient. The evaluation of the literature began with submission of the first edition of this work, nearly 10 years ago, and is an ongoing project. The format for each nutrient is identical, allowing the reader to contrast the RDA and RDI with the SONI for the nutrient. SONIs are divided by gender and age along the same parameters as the RDAs for easy comparison. Some liberty has been taken with the RDIs to fit them into the same age range as the RDAs for convenience. The recommendations made are based on the median weight and height for each designated age group, as listed in Table 127-1. If the patient's height and weight are significantly higher or lower than the figures found for the age group, the SONI should be adjusted accordingly. Given that the prevalence of overweight and obesity in the United States and many other Western countries has reached critical

Ipopulation of designated age Gender Male

Female

Age (Yr)

Weight (Ib)

Height (in)

15-18

145

69

19-24

160

70

25-50

174

70

51+

170

68

11-14

101

62

15-18

120

64

19-24

128

65

25-50

138

64

51+

143

63

Fat-Soluble Vitamins

Minerals

Carotenedbetacarotene Vitamin A Vitamin D Vitamin E Vitamin K

Boron Calcium Chromium Copper Iodine Iron Magnesium Manganese Phosphorus Potassium Selenium Sodium Vanadium

Water-Soluble Vitamins Ascorbic acid (vitamin C) Cyanocobalamin (vitamin B12) Folic Acid Niacidniacinamide (vitamin B3) Pyridoxine (vitamin B), Riboflavin (vitamin B2) Thiamin (vitamin B,)

7i-e Ic.

LII

levels, it is very likely that the SONI underestimates requirements. The nutrients discussed in the following section are divided into three nutrient classifications with nutrients presented in alphabetical order in each classification (Box 127-2). The reference list is divided in the same way and order. Each nutrient section contains a table listing the following values for each gender and age group: RDA: as defined earlier. EAR: Estimated Average Requirement, the daily intake value that is estimated to meet the requirement, as defined by the specified indicator or criterion of adequacy, in half of the apparently healthy individuals in a life stage or gender group. 0 DRI/RII: DRI is Dietary Reference Intakes; RII is Recommended Intakes for Individuals; a set of reference values for specific nutrients, each category of which has

special uses. The development of the DRIs replaces the reports on RDAs issued periodically from 1941 to 1989; hence those that have not been issued are included in the table but designated as not available (n/a). UL (some tables): Tolerable Upper Intake Level, the maximum level of daily nutrient intake that is likely to pose no risk of adverse effects. The UL represents total intake from food, water, and supplements. SONI: defined earlier; also represents the total intake from food, water, and supplements.

Fat-Soluble Vitamins Vitamin A Vitamin A is a fat-soluble vitamin that is measured as retinol activity equivalents (RAEs). 1RAE = 1 pg retinol, 12 pg beta-carotene, 24 pg alpha-carotene, or 24 pg beta-cryptoxanthin. The RAE for dietary provitamin A caroteinoids is twofold greater than retinol equivalents (RE), whereas the RAE for preformed vitamin A is the same as RE.] To determine the bioavailability of fat-soluble vitamins, one must know the plasma response and plasma clearance curves. The importance of this information has been eloquently demonstrated in a study in which both curves were determined in young and old adults? It was shown that although older individuals had a greater small intestinal absorption of vitamin A, their clearance of the vitamin in circulation was significantly delayed compared with that in young adults. Such factors explain why care must be taken in the consideration of supplementation with vitamin A; once the vitamin in the form of retinyl esters enters the circulation, it can be carried around in the blood for of days, not just hours, eventually building up toxic precursors. Reports of vitamin A toxicity, nevertheless, remain rare, owing to either increasing knowledge about the risks associated with prolonged intake of foods rich in the vitamin or vitamin A-containing supplements or to a lower order of risk than might be suggested by experimental evidence. Estimates of the number of adverse events associated with excessive vitamin A intake are unreliable, especially the adverse events reporting system managed by the U.S. Food and Drug Administration. This system has been criticized by toxicologists and public health officials as an unreliable passive reporting system that lacks validation. Large intake of vitamin A, but not of the provitamin A carotenoids, can cause toxicity, the most serious of which are birth defect^.^ Hence, women of childbearing age should show prudence in taking large amounts of vitamin A without the advice of a health practitioner. Pregnant women should preferentially ingest foods rich in carotenoids or should consume beta-carotene or a mixed carotene supplement to ensure adequate

Suggested Optimum

vitamin A supplies, given the role of vitamin A in cell differentiation. Vitamin A toxicity in adults is uncommon at doses below 100,000 IU/day. If any symptoms of toxicity develop, such as nausea, abdominal cramps, and severe headaches, they will quickly dissipate after vitamin A intake is discontinued. Vitamin A is required for reproduction, embryonic development, maintenance of epithelial tissue (i.e., skin, lung, vagina, uterus, gastrointestinal tract), cell differentiation, and Vitamin A may also play an important role in cancer prevention and the treatment of precancerous conditions. Illness, in particular febrile conditions, and lipid malabsorption can markedly raise vitamin A requirement^.^-'^ Low intakes of vitamins A, C, and E, have been found in premenopausal women diagnosed with breast cancer and in women treated for m e l ~ n o m a . ' ~The J ~ value of vitamin A and associated retinoids in health maintenance has been recognized since the early 198Os.l5 The mean intakes of vitamin A in the United States, based on the NHANES for 1999-2000, were 961 RE and 916 RE, for males and females of all ages, respectively.16 Given the evidence for a protective role for this vitamin, especially against diseases associated with aging,I7 a higher optimal intake level for vitamin A is suggested for all age groups than that recommended by the RDA, EAR or DRI. This suggestion is supported by the 15-year prospective Birmingham Study, which found levels of vitamin A intake higher than the RDA required to support health maintenance (Table 127-2).18

Carotenes and Beta-carotene Carotene is an unsaturated hydrocarbon pigment found in many plants. It is a class of carotenoids that include

Gender

Aae Ivr)

Male

11-14 15-18 19-24 25-50 51+ 11-14 15-18 1 9-24 25-50 51+

Female

RDA

_____

1000 1000 1000 1000 1000 800 800 800 800 800

EAR

DRI/RII

445 630 625 625 625 420 485 500 500 500

600 900 900 900 900 600 700 700 700 700

~ _ _ _ _ _

~~

Ootimal

UL

~

1000 1000 2000 2000 1750 800 800 2000 2000 1800

1700 2800 2000 3000 3000 1700 2800 2000 3000 3000

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRVRII, Dietary Reference IntakedRecommended Intakes for Individuals;RE, retinol equivalent(s): 1 RE = 1 pg retinol or 6 l g betacarotene; UL, Tolerable Upper Intake Level.

alpha-, beta-, gamma-, and zeta-carotene, which have provitamin A activity. Some carotenes, however, such as lycopene, do not have provitamin A activity. Most carotenes are found in fruits and leafy vegetables. Carotene is thought to assist in trapping light energy for photosynthesis or to aid in reduction-oxidation (redox) reactions; hence its interest to researchers studying antioxidants.'" The main dietary source of vitamin A it is produced by splitting one molecule of carotene into two molecules of vitamin A in either the intestinal wall or the liver, explaining why it is called provitamin A. The absorption of carotene is less efficient than that of vitamin A. The absorption of dietary carotene depends on the action of bile acid. Beta-carotene is a known source of vitamin A, because it is the most nutritionally active vitamin A precursor among the carotenes. Of the nearly 600 carotenoids, a family of natural pigments found in plants and animals, less than 50 are vitamin A precursors like beta-carotene.4 Animal studies have shown that beta-carotene is not mutagenic, teratogenic, embryotoxic, or carcinogenic,nor does it cause hypervitaminosis A (vitamin A t~xicity).~ N o signs of organ toxicity have been found in subacute, subchronic,or chronic oral toxicity studies in experimental animals receiving doses of up to 1000 mg/day betacarotene per kilogram of body weight via the diet. Even synthetic beta-carotene has not been shown to exert any carcinogenic effect in rodents or in CD1 mice in particular. Two studies have reported a n enhanced risk of lung cancer in human intervention studies? "Although dose and timing of exposure, smoking status, and imbalance of antioxidant defense have been recognized as potential factors accounting for the outcome of these studies,"6 no conclusive explanation has not yet been promulgated to explain these findings. However, examination of the design of these studies, particularly the use of a single carotenoid (beta-carotene) at a low supplemental dose, may explain the anomaly, especially given the lack of any evidence from animal toxicology studies that synthetic beta-carotene is carcinogenicat even exceptionally high intake levels7 More likely the administration of beta-carotene may have been administered too late in the carcinogenicprocess to be of any benefit for smokers. That human studies found a slightly increased risk of lung cancer in long-term smokers may discourage smokers from maintaining optimal levels of carotene, including beta-carotene. This possibility is worrisome, in that epidemiology studies have found an inverse correlation between high dietary beta-carotene intake and cardiovascular disease, particularly angina pectoris and myocardial infarction, conditions associated with smoking.&" Beta-carotene and its related carotenoids have been shown to protect against various cancers and to enhance cancer resistance directly as an antimutagen and anticarcinogen or indirectly as an antioxidant by reducing

cell damage.12-22 In particular, increased beta-carotene levels seem to reduce the risk of development of lung cancer, important information for cigarette smokers and people regularly exposed to sidestream smoke. Individuals with low intakes of beta-carotene have a 30%to 220% higher risk of lung cancer than those with a high intake of this nutrient. A 12-year study of almost 3000 men living in Switzerland found an association between low blood levels of vitamin A and beta-carotene and higher risk of lung cancer and death from all cancers.= Men with low carotene levels had nearly twice the risk of lung cancer compared with men who had normal levels, and nearly 3.5 times the risk of stomach cancer. Lycopene is not a provitamin but is a carotene, but it should be mentioned that epidemiologic studies suggest a link between lycopene intake and lower risk of both pancreatic, prostate, and stomach cancers and myocardial infarction.2427 Beta-carotene also has non-vitamin A functions, on the basis of its ability to act as an antioxidant by scavenging free r a d i ~ a l s . For ~ , ~example, ~ carotenoids protect against the damage from excessive exposure ultraviolet light that can lead to ultraviolet light-related tissue damage and skin cancer.M31 No RDA or RDI intake level for carotenes or betacarotene has been determined, although the mean intakes of carotenes in the United States, based on the NHANES for 1999-2000, were 426 RE and 480 RE, for males and females of all ages, respectively (Table 127-3).32

Vitamin D Vitamin D is a prohormone classified as a vitamin. Vitamin D3 (the natural form) is more effective at raising serum 25(OH)D concentrations than vitamin D2. Important for bone maintenance and the metabolism

Recommended intake of beta-carotene (mg) Gender

Age (Yr)

RDA

Optimal

Males

11-14

n/a

50

15-18

n/a

70

Females

19-24

n/a

100

25-50

n/a

100

51+

nla

100

11-14

n/a

50

15-18

n/a

60

19-24

n/a

25-50

n/a

80 80

51+

n/a

80

n/a, Not available; Optimal, Suggested RDA, Recommended Daily Allowance.

Optimal

Nutrient

Intake;

and absorption of phosphorus and calcium, vitamin D also contributes to the functioning of the reproductive system, the digestive system, and the immune system.'" Vegetarians, the elderly, and individuals who have limited exposure to sunlight or ultraviolet light or dark skin pigmentation may be at risk of inadequate vitamin D The elderly may be at particular risk of poor vitamin D status due to decreases in exposure to sunlight, intake of vitamin D-fortified foods, absorption of the nutrient in the gastrointestinal tract, and caloric intake. The skin of elderly individuals also produces approximately half the vitamin D after exposure to the sun as that of a young pers0n.5,~ Good bone mineral density is known to reduce the risk of fractures and osteoporosis. There is considerable experimental and epidemiologic evidence to support the need for calcium and vitamin D supplementation to reduce the risk of fracture and o s t e o p ~ r o s i s . ~ ~ ~ ~ ~ These studies have found that a daily dose of 800 IU of vitamin D, or 100,000 IU given three times a year, reduces the frequency of both falls and factures. Ensuring adequate levels of vitamin D throughout adulthood and as one ages is important, especially give the prevalence of vitamin D deficiency in virtually all institutionalized elderly persons.I6 Even in infants and adolescents, vitamin D supplementation can ensure higher bone mineral density, especially in prepubertal g i r l ~ . ' ~ ItJremains ~ unclear whether vitamin D alone reduces fracture rates or whether supplemental calcium is required. Optimal vitamin D status may be associated with a reduced risk of hypertension and also plays a role in regulating blood p r e s s ~ r e . ' ~ , ~ ~ There is also growing evidence that vitamin D combined with calcium might reduce the number of colorectal t ~ m o r s . ~Some l - ~ ~ evidence suggests that adequate vitamin D intake and/or production (via the skin) may decrease the risk of breast ~ancer.2~ At physiologic concentrations, vitamin D has been found to protect cell proteins and membranes from oxidative stress. When levels are optimal, vitamin D probably induces apoptosis of certain cancer cells. It is hoped that future research into vitamin D regulation of genes involved in neoplastic processes will elucidate its role in reducing malignancies. Patients with multiple sclerosis who are given vitamin D, calcium, and magnesium supplements have experienced a lower rate of relapse.25Women who were found to have the highest vitamin D intake via supplements (400 Tu or higher per day) were found to be 40% less likely to have multiple sclerosis than women not taking vitamin D supplements.26Interestingly, this finding did not hold if the vitamin was derived from food. Sunlight ultraviolet exposure on the skin promotes vitamin D production. It is important to note that this process is self-limiting and will not cause vitamin D

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements

toxicity (hypervitaminosis D) in healthy people or the elderly.27~28 One hour of total-body sun exposure can provide the equivalent of 10,000 IU of vitamin without

Gender

Ape (vr)

RDA

DRI/RII

Optimal

UL

Male

11-14

10

5

10

50

Vitamin D can be toxic at prolonged (several months) 5 15-18 10 10 50 high intakes. However, the data to support this finding 19-24 10 12 50 5 come wholly from literature reporting on the use of 20 50 5 25-50 10 vitamin DZ.No adverse effects have been reported in 24 50 51+ 5 10 healthy adults who have consumed up to 62 times the RDA of this nutrient. Because vitamin D has been shown Female 11-14 10 10 50 5 to be teratogenic in animals, a pregnant or potentially 5 15-18 10 12 50 pregnant woman should take vitamin D supplements 19-24 10 12 50 5 with caution, although doses as high as 600,000 IU have 5 25-50 5 18 50 been given to women during their seventh and eighth 51+ 5 22 50 10 months of pregnancy without evidence of harm.29 There is controversy about the risk of sunlight expoOptimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRVRU, Dietary Reference IntakedRecommended Intakes for sure and melanoma.30 Evidence from several studies Individuals; UL, Tolerable Upper Intake Level. has found that non-sun-exposed areas of the skin have 'As cholecalciferol in pg. 10 pg cholecalciferol = 400 IU of vitamin D. a higher incidence of melanoma, including malignant melanoma, than sun-exposed area^.^'-^^ A very large with a free radical, the tocopherol molecule is converted epidemiologic study of U.S. Navy personnel found that adequate vitamin D levels may decrease the chance of into the tocopheroxyl radical, which can then be development of certain lethal skin melanomas (skin reduced back to harmless tocopherol by either vitamin C cancers) in adults with occupations and lifestyles that or glutathione. Any deficiency of this vitamin can affect prevent regular exposure to sunlight for up to 15 minutes the life span of red blood cells. a day? All of the cases of vitamin D toxicity with hyperVitamin E contributes to human health in numerous For example, it plays a role in preventing calcemia involve intakes higher than 40,000 IU a day. A careful examination of the vitamin D toxicity literamutagenesis, in the repair of membranes and DNA, and ture found that the consumption of more than 4000 IU a in maintenance of immunocompetence, especially as it day of vitamin D3caused no harm but raised 25(OH)Dto relates to normal T-lymphocyte function. high-normal concentrations in practically all a d ~ l t s . 3 ~ Many studies have found that the incidence of variFor individuals living in northern latitudes, daily ous cancers is higher in individuals with low levels of vitamin D3 supplementation is indicated to overcome vitamin E. Evidence to date is strong that a low intake the decline in 25(OH)D and to control parathyroid of vitamin E is a risk factor for cancer in many, but hormone levels in postmenopausal women.% not all, organs. The expression of its protective effect A dose of vitamin A at levels corresponding to may depend on the primary cause, which vanes. This is particularly important for smokers and persons exposed approximately one serving of liver has been found to to cigarette smoke, because vitamin E is a respiratory interfere with the action of vitamin D. It has been demonstrated that a dose of vitamin A antagonizes the tract antioxidant.%" There is evidence that vitamin E serum calcium response to vitamin D (Table 127-4).37 inhibits platelet aggregation, thereby reducing the risk of blood clots that can potentially lead to myocardial Vitamin E (Tocopherols and Tocotrienols) infarcts or s t r ~ k e . l ~ - ' ~ Vitamin E a fat-soluble vitamin essential to all mammals. Adequate vitamin E levels may protect against The term vitamin E applies to a family of eight related cataract de~elopment.'~J~ In one study, vitamin E supplecompounds, the tocopherols and the tocotrienols. The mentation reduced the risk of cataracts by more than four major forms of vitamin E are designated alpha, half. The benefit of vitamin E supplementation is unclear for both recreational exercisers and high-intensity beta, delta, and gamma. The tocotrienols are less widely athletes. However, vitamin E may play an important distributed in nature, and less biologically active, than the tocopherols. Although vitamin E is required role in preventing exercise-inducedmuscle and throughout an individual's life span, its levels decline coronary heart disease.20,21 There is mounting evidence that immune function with aging, probably owing to lowered caloric intake or can be enhanced by vitamin E supplementation.22 poor food choices. Vitamin E may prevent and reduce the risk of cancer, on One of the most important functions of vitamin E is to protect cell membranes from damage by reactive oxygen the basis of numerous cohort studies and randomized species (ROS),known as oxidative damage. By reacting trials.=%

Vitamin E supplementation raises plasma tocopherol concentration?' In general, high intake of vitamin E seems very safe.% Very few side effects have been reported in any scientifically controlled studies, with intakes as high as 3200 mg (3200 IU)?9,40Vitamin E supplementation is not, however, recommended for individuals undergoing anticoagulant therapy, who may also be vitamin K deficient. The suggested optimal levels are for natural vitamin E (d-alpha-tocopherol, d-alpha-tocopheryl acetate, or d-alpha-tocopheryl succinate). AU forms of natural vitamin E become active antioxidants (free radical scavengers) inside the body. The synthetic forms of vitamin E have the dl- designations in front of the form provided. The mean intakes of Vitamin E (total alpha-tocopherol equivalents in mg) in the United States based on the N H A N E S for 1999-2000 were 9.6 mg and 8 mg, for males and females of all ages, respectively (Table 127-5).4l

There is no known toxicity association with the administration of high doses of phylloquinone. However, patients undergoing warfarin therapy who are taking vitamin K should know that the vitamin can inhibit the vitamin K-dependent gamma-carboxylation of coagulation factors n, W, IX,and X. Even dietary variation in vitamin K intake can lead to difficulty in warfarin dosing.18 There is insufficient evidence to support supplemental intake of vitamin K beyond that found in most diets, except possibly in postmenopausal women and in women suffering from menorrhagia. Phylloquinone is the natural form of the vitamin and the primary dietary source of vitamin K. A normal mixed diet contains 300 to 500 pg of vitamin K per day, well in excess of the RDA. The RDA is 1 pg of phylloquinone per kilogram of body weight for adults and children. No tolerable upper intake level has been determined for vitamin K (Table 127-6).

Vitamin K (Phylloquinone)

Water-Soluble Vitamins Ascorbic Acid (Vitamin C)

Vitamin K is a fat-soluble vitamin found in food and created by bacteria in normal intestines.14 It is essential for normal clotting, particularly for the production of prothrombin and proteins C and S, as well as normal bone metabolism and development, especially loss of bone mass in postmenopausal osteoporosis.51o Studies show that women with low intakes of vitamin K may be at higher risk of hip fracture." It has also been reported that the vitamin helps maintain good bone mineral density and lower the risk of One study suggests that vitamin K may play a role during the acute insulin response associated with glucose t01erance.l~

Vitamin C (ascorbic acid) is a water-soluble antioxidant that acts as a cofactor in hydroxylation reactions required for collagen synthesis. Adequate vitamin C (ascorbic acid) intake is necessary for immunity, maintenance of bones, formation of collagen, and a broad range of other biologic functions.'-* In a study that measured the vitamin C intake of 1038 doctors and their wives, subjects with the fewest signs and symptoms of illness or degenerative diseases consumed an average of 410 mg of vitamin C a day, about seven times the RDA, which is 60 mg?-16To achieve this level of intake, supplementation would be required.

Recommended intake of vitamin E (mg tocopherol)* Gender

Aae (vr)

RDA

EAR

DRVRII

Optimal

UL

Male

11-14 15-18 19-24 25-50 51+ 11-14 15-18

10 10 10 10 10 8 8 8 8 8

9 12 12 12 12 9 12 12 12 12

11 15 15 15 15 11 15 15 15 15

70 100 400 400 800 70 90 400 400 800

600 800 1000 1000 1000 600 800 1000 1000 loo0

Female

19-24

25-50 51+

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance: DR//R//, Dietary Reference IntakedRecommendedIntakes for Individuals; UL. Tolerable Upper Intake Level. 'Alpha-tocopherol equivalents: 1 mg d-alpha tocopherol = 1 IU alpha-tocopherol.

Gender

Age (Yr)

RDA

DRllRll

Optimal

Male

11-14 15-18 19-24 25-50 51+ 11-14 15-18 19-24 25-50 51+

45 65 70 80 80 45 55 60 65 65

60 75 120 120 120 60 75 90 90 90

45 64 70 80 80 45 55 60 65 65

Female

Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DR//Rl/, Dietary Reference Intakes/Recommended Intakes for Individuals.

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elem Cigarette smoking is associated with a sigruficant drop in vitamin C levels. For a typical smoker to attain the same vitamin C level as a nonsmoker requires consumption of three to four times as much vitamin C.17-25 The third NHANES (NHANES 111) showed that 11%of nonsmoking women and 21% of nonsmoking men in the United States do not get enough vitamin C. Alcoholics, many of whom smoke, have low vitamin C status and require considerably more vitamin C. The elderly may especially benefit from vitamin C s u p p l e m e n t a t i ~ n .Increased ~ ~ , ~ ~ lipid (fat) peroxidation has been associated with accelerated aging and degeneration. One study demonstrated that supplementation 1 year for with vitamin C at levels much higher than RDA significantly decreased lipid peroxide levels in elderly subjects.28 Research suggests that vitamin C may reduce the risk of cataracts, cancers of the gastrointestinal tract, and cardiovascular disease.2945In a 12-year study of 3000 men living in Switzerland, the subjects with low blood levels of vitamin C had a higher risk of stomach and intestinal cancers. For people older than 60 years, low vitamin C levels are associated with nearly a threefold increased risk of stomach cancer and twice the risk for intestinal cancer. The interest in vitamin C in the treatment of cancer is partially based on studies showing significantly reduced levels in patients with malignancies. Most evidence suggests that doses of vitamin C larger than RDA may be beneficial in reducing the risk of various cancers, rather than in treating them. The reason may be that higher levels of vitamin C improve certain indices of immune competence and response that boost disease resistance. High dietary intake of vitamin C has been reported to be associated with lower rates of death from cerebrovascular and cardiovascular diseases. A cohort study of 11,348 noninstitutionalized U.S. adults found that women and men with the highest vitamin C intake derived from food and/or vitamin C supplements had, respectively, a 25% and 42% decrease in cardiovascular mortality. Vitamin C supplementation may reduce the risk of cardiovascular mortality by influencing cholesterol levels, platelet values, and even blood pressure.4649 Because the levels of vitamin C decline with age after midlife, there is evidence that suboptimal levels of vitamin C may raise the risk of cataract^.^^,^ People who consume the lowest levels of vitamin C seem to have the highest incidence of cataractous lenses. Whether this is due to other components in food (i.e., antioxidants such as polyphenols) or vitamin C alone is not known. One study has shown that subjects who supplemented with vitamin C significantly lowered their risk of cataracts. Vitamin C markedly increases nonheme iron absorption.m51In some diets, only 3% of nonheme iron is absorbed, compared with as much as 23% of the heme

iron form. The addition of 50 to 100 mg of vitamin C to meals can double or triple nonheme iron absorption. Two grams (2000 mg) of vitamin C taken throughout the day with meals increases the absorption of nonheme iron fivefold. Bone density and vitamin C status decline after age 35. Vitamin C is an important nutrient in bone metabolism, especially in the synthesis of collagen, which forms the structural framework of bones. A number of studies show that vitamin C supplementation results in improved maintenance of bone mineral density in postmenopausal Studies have also shown reductions in healing time of wounds with high-dose vitamin C ~ u p p l e m e n t a t i o nand ~ ~ , enhancement ~ of the bactericidal activity of le~kocytes.5~ The vitamin’s ability to prevent the common cold or shorten its duration continues to be controversial.56 Vitamin C supplementation has been shown to improve glucose metabolism and lower blood sugar levels associated with h y p e r g l ~ c e m i a . ~ ~ ; ~ ~ Vitamin C taken at optimal ranges or at less than 1000 mg/day is virtually free of any known or observed side effects. Doses in excess of 1000 mg at a time have been known to cause diarrhea (bowel tolerance), hyperuricosuria, and hyperoxaluria in healthy individuals. There is also evidence that doses as high as 10,000 mg/day have no adverse side effects, but long-term studies to support this position are lacking. The mean intakes of vitamin C in the United States, based on the NHANES for 1999-2000, were 103 mg and 91 mg, for males and females of all ages, respectively? Higher recommended levels of vitamin C for adults, 200 mg/day, have been suggested by the U.S. Department of Agriculture and the National Cancer Institute, because fruit and vegetable consumption results in vitamin C intakes exceeding 210 mg/day. However, these higher levels have not become part of the RDIs. Instead the RDIs have raised the vitamin C intakes to 90 mg and 75 mg for adult men and women, respectively, well below the level that is optimal (Table 127-7).61

Cyanocobalamin (Vitamin BIZ) Vitamin B12 (cyanocobalamin)is water soluble, is synthesized by bacteria, and is found in virtually all animals but rarely in any plant foodstuffs. Vitamin BI2is essential for the functioning of the central nervous system and a number of enzymes involved in amino acid, nucleic acid, and fatty acid metabolism. It is also necessary in the metabolism of folic acid (folate), which is essential for thymidine and, thus, DNA synthesis. The vitamin acts as a coenzyme for fat and carbohydrate metabolism, hematopoiesis, and protein synthesis.’-3 Vitamin BI2 deficiency is common among the elderly, in whom it can cause macrocytic anemia and neurologic abnormalities (loss of proprioception and vibration sense),

Pharmacology of Natural Medicines Recommended intake of vitamin BI2 (cyanocobalamin) (pg) Gender Male

Female

Age(yr)

RDA

EAR

DRllRll

Optimal

UL

11-14

50

39

45

150

1200

15-18

60

63

75

200

1800

19-24

60

75

90

200

2000

25-50

60

75

90

400

2000

51+

60

75

90

800

2000

11-14

50

39

45

150

1200

11-14

2.0

15-18

60

56

65

200

1800

15-18

2.0

19-24

60

75

200

2000

19-24

2.0

25-50

60 60

60

75

400

2000

25-50

51+

60

60

75

1000

2000

51+

EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance; DRMRII. Dietary Reference IntakedRecommended Intakes for Individuals; UL, Tolerable Upper Intake Level. 'A new RDA for adults for vitamin C of 200 mg/day has been suggested, following US. Department of Agriculture and National Cancer Institute recornmendations for fruit and vegetable consumption that results in vitamin C intakes of greater than 210 maday.

owing to an absence of intrinsic factor.& In the elderly, it often results in neurologic, cerebral, and psychiatric abnormalities? Any assessment of elderly patients with depression or impaired memory should include a determination of vitamin B12status.a1oIndividuals who suffer depression with a history of gastric or ileal disease may also experience a deficiency of this vitamin." Many elderly patients who had a "normal" serum vitamin B12 concentration were found to be metabolically deficient in cobalamin.12This finding would suggest that deficiency of vitamin BI2 is often ~nderdiagnosed.'~ In some cases fatigue may suggest the presence of pernicious anemia, along with neurologic indication^.'^ In such cases, treatment with vitamin B12 and folic acid should begin im~nediately.'~,'~ Some evidence shows that after the development of pernicious anemia, risk of cancer is increased.17 There is now convincing evidence that vitamin BI2 may reduce one risk factor for arteriosclerosis, the accumulation of homocysteine (homocysteinemia). High levels of homocysteine has been associated with an increased risk of cardiovascular disease. Vitamin B12 levels have been found to be inversely related to homocysteine concentration^.'^^^ When a vitamin deficiency is diagnosed, administration of vitamin B12injections has proven superior to oral vitamin BI2 supplement. Yet there is growing evidence that oral vitamin B12 (cyanocobalamin) is a completely safe alternative to vitamin B12 injections. One study has found that some individuals with gastric disease who absorb vitamin BI2from food poorly can absorb the

Gender

Age (yr)

RDA

EAR

DRI/RII

Optimal

Male

11-14

2.0

1.5

1.8

2.0

15-18

2.0

2.0

2.4

2.0

19-24

2.0

2.0

2.4

25-50

2.0

2.0

2.4

51+

2.0

2.0

2.4

3.0

1.5

1.8

2.0

2.0

2.4

2.0

2.0

2.4

2.0

2.0

2.0

2.4

2.0

2.0

2.0

2.4

3.0

Female

2.0 .

2.0

EAR. Estimated Average Requirement; Opfimal, Suggested Optimal Nutrient Intake; RDA. Recommended Daily Allowance; DRVRII, Dietary Reference IntakedRecommendedIntakes for Individuals.

crystalline supplement form. Some experts have argued that the only legitimate need for vitamin B12supplementation is in patients with a congenital defect of vitamin B12 metabolism, such as vitamin BI2-responsive methylmalonic acidemia. Vitamin B12 deficiency is more likely in very strict vegetarians, because the best sources of vitamin BI2 are meat and meat products and, to a lesser extent, milk and milk products, some seafoods, and egg yolk. There is growing evidence that vitamin BI2 may play a role in the prevention of some types of cancers. Smokers, for example, have been found to have significantly lower levels of precancerous bronchial squamous metaplasia when given vitamin B12 (500 yg/day) and folic acid supplements than those receiving placebo.3O Other benefits of vitamin B12supplementation reported in the literature are the treatment of osteoarthritic anorexia nerv0sa,3~and chronic exposure to gaseous nitric oxide.34 There is insufficient evidence to advocate an intake of vitamin B12 above the RDA in any population group except the elderly or the patient with evidence of pernicious anemia. For the patient with pernicious anemia, vitamin BI2 injections (parenteral cobalamin) or weekly oral doses of 1000 yg is suggested. During such treatment, however, the patient should take care to not to consume large amounts of folic acid, which might mask the nerve damage associated with vitamin B12deficiency. Nevertheless, persons with atrophic gastritis should consume oral vitamin B12supplements to ensure normal vitamin B12n ~ t r i t u r e . ~ ~ Vitamin B12 is not carcinogenic, teratogenic, or mutagenic.%It is considered safe in doses up to 1000 times the RDA. The UL has not been determined (Table 127-8).

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements

Folk Acid (Pteroylglutamic Acid) Recognition of the critical importance of folate for maintaining health is growing. Folic acid is required in the metabolism of some amino acids, for the synthesis of nucleic acids, and in a number of enzyme cofactors.I4 Certain population groups are at particular risk for development of folate deficiency, especially pregnant Like newborn infants, women and adolescent who are also at risk, these groups experience considerable growth, confirming the importance of folic acid in protein synthesis and DNA and RNA replication required in cell growth. Inadequate folic acid is also seen in the elderly, in whom it is less well Because folic acid deficiency is a well-documented cause of birth defects in animals, numerous studies have looked at its role in such human congenital malformations as neural tube defects, cleft palate, and cleft lip.12J3 Folic acid and multivitamin supplementation have been demonstrated in numerous studies to decrease or eliminate the recurrence of neural tube defects or cleft palate/ cleft lip in human Folic acid deficiency rises in prevalence with age.22,23 The vitamin may also reduce a risk factor associated with atherosclerosis, in that folic acid is required for the conversion of homocysteine to methionine." A deficiency of folic acid is associated with elevated homocysteine (homocystinemia),which is a risk factor for atheroscleroS ~ SNormal . ~ ~ subjects given 5 mg/day of folic acid for 2 weeks had significant decreases in homocysteine levels, especially those whose initial homocysteine levels were high.26 There is also mounting evidence that smokers and heavy coffee drinkers require a higher intake of folic acid.27 Given the growing popularity of coffee as a beverage consumed in most homes and offices and neighborhood coffee houses and chains, its influence on folic acid status, especially among heavy consumers, needs to be considered. Folate is required for critical brain metabolic functions. A wide range of neuropsychiatric disorders has been linked to folic acid deficiency including, insomnia, depression, myelopathy, peripheral neuropathy, restless leg syndrome, dementia, irritability, and organic psychosis.28 Low folate levels have been implicated to poorer antidepressant response to selective serotonin reuptake inhibitors.29Borderline to deficient serum or red blood cell folate levels have been detected in from 15% to 38% of adults diagnosed with depressive disorders. The risk associated with the development of cataracts may be reduced by maintaining folic acid (and vitamin BIZ) levels.30Folic acid taken with cobalamin has been found to be helpful in the treatment of osteoarthritis of the hands.3I There are two reports of its benefits in the treatment of bronchial squamous metaplasia in heavy smokers using folic acid along with vitamin B12t h e r a ~ y . ~ ~ J ~

Folic acid supplementation in healthy adults is safe even at high levels of intake, although such supplementation can mask clinical signs of pernicious anemia, which if left untreated can lead to permanent nerve damageM There is also continuing controversy about whether folic acid supplementation of 400 pg or more reduces zinc absorption. Folate catabolism progressively rises during pregnancy, reaching a peak in the third trimester when maximal fetal growth is 0ccurring.3~This is due to increased demand for folate in cellular bio~ynthesis.~~ For lactating and pregnant women, the RDAs are inadequate; at least 600 pg folic acid should be taken as a dietary supplement daily to ensure adequate supplies for the mother, her fetus, and then her infant during brea~tfeeding.~' For individuals with elevated plasma total homocysteine concentration who are at risk for cardiovascular disease, a minimum of 250 pg of folic acid as a supplement should be taken in addition to a diet providing at least an additional 400 pg of f01ate.~~ Folic acid is particularly important for people with defects in the absorption and metabolism of folate, an essential nutrient that is a contributing factor in agi11g.3~Studies have shown that folate from dietary sources alone results in a modest reduction in the risk of colon cancer. However, the benefit of long-term folic acid intake has been demonstrated in the Nurses' Health Study involving 88,756 women. Women who consumed a multivitamin for more than 15 years had substantially reduced their risk for colon cancer.40The researchers concluded that this effect may be related to the folic acid contained in multivitamins. The mean intakes of folate in the United States, based on the NHANES for 1999-2000, are 405 pg and 319 pg, for males and females of all ages, respectively (Table 127-9).4]

Gender

Age (yr)

RDA

EAR

DRI/RII

Optimal

UL

Male

11-14 15-18 19-24 25-50 51+ 11-14

150 200 200

250 330

200 150

320 320 320 250

300 400 400 400 400 300

15-18 19-24 25-50 51+

180 180 180 180

330 320 320 320

400 400 400 400

500 750 1000 2000 2000 500 750 1000 1000 2000

600 800 1000 1000 1000 600 800 1000 1000 1000

Female

200

EAR, Estimated Average Requirement: Optimal, Suggested Optimal Nutrient Intake: RDA, Recommended Daily Allowance; DRlVRll, Dietary Reference IntakeslRecommended Intakes for Individuals; UL, Tolerable Upper Intake Level.

Pharmacology of Natural Medicines

Niacin (Nicotinic Acid) and (Niacinamide) Nicotinamide

in humans supplementing with the esterified form of vitamin B3 (inositol hexaniacinate). The mean intakes of niacin in the United States, based on the NHANES for 1999-2000, were 25.9 mg and 18.9 mg for males and females of all ages, respectively (Table 127-10).20

Niacin is a water-soluble vitamin. The term is the generic descriptor for nicotinic acid (pyridine-3-carboxylicacid) and derivatives exhibiting biologic activity of nicotinamide (nicotinic acid amide). Niacin is critical in many biochemical processes, Vitamin B6 particularly those involving energy metabolism and lipid rnetabolism.'s2 The requirement for niacin in Vitamin B6 is a water-soluble vitamin comprising the humans is met in part by conversion of the essential group of nitrogen-containing compounds (pyridoxine, amino acid tryptophan to niacin? Several studies have pyridoxal, pyridoxal-5'-phosphate, pyridoxamine, and corresponding phosphorylated forms) that occur natucalculated that from 39 to 86 mg of tryptophan produces rally in the following three primary forms: pyridoxine, the same levels of niacin metabolites as 1 mg of niacin. pyridoxal, and pyridoxamine. Vitamin B6 is required for For this reason the convention is to consider 1 mg of growth and maintenance of almost every bodily funcniacin as equivalent to 60 mg of tryptophan. Because tion, amino acid metabolism, and production of neuromost proteins contain at least 1%to 2% tryptophan, it is transmitters derived from amino acids. It also plays a possible to maintain adequate niacin status with a diet role in glycogen breakdown, fatty acid metabolism, relatively devoid of niacin but containing at least 100 g hormone metabolism, heme biosynthesis, and purine of protein a day: bio~ynthesis.'-~ The use of niacin as a druglike agent-it lowers serum levels of low-density lipoprotein (LDL) and very-LDL Various studies have found the prevalence of vitamin B6 deficiency to vary from 9% in preschool children to 68% (VLDL) cholesterol and triglycerides while raising the in low-income pregnant women. The average prevalence level of high-density lipoprotein (HDL) cholesterol-has generated much i n t e r e ~ tNicotinic .~~ acid given in doses of vitamin B6 deficiency is 25% in adult^.^ Studies in humans indicate that the bioavailability of of 1.5 to 3 g per day has been shown to decrease total vitamin B6 from natural sources is limited. For example, and LDL cholesterol values and increase HDL cholesterol concentration.There is also interest in its notorious, the vitamin B6 in whole wheat bread and peanut butter is 75% and 63%, respectively, as available as the vitamin B6 but not harmful, vasodilatory or "flushing" effect in increasingblood flow to the extremities in certain circulafrom tuna. Supplementation of vitamin B6 has been used in the tory disorders. This effect comes only from the nicotinic acid form, not the amide. There is no evidence that treatment of premenstrual syndrome: cardiovascular disorders? and diabetic neuropathy? The vitamin has levels above twice the RDA for niacin in healthy persons prevents disorders associated with high cholesterol (hypercholesterolemia) or other hyperlipidemias. The only evidence for a significantly higher intake of niacin above the RDA in healthy asymptomatic individuals comes from the prospective Birmingham Study.'O Researchers found that individuals with the least number of signs and symptoms associated with physical RDA EAR DRllRll Optimal UL Gender Age (yr) illness or degeneration were consuming an average of Male 11-14 17 9 12 25 20 115 mg of niacin a day, or approximately six or seven 30 30 15-18 20 12 16 times the RDA. 19-24 19 12 16 30 35 There has been considerable use of niacin as a treat12 25-50 19 16 30 35 ment for some forms of schizophrenia, first espoused 51+ 15 12 16 30 35 in the early 1950~."-'~ Niacinamide supplementation 25 20 Female 11-14 15 9 12 has also been suggested in the treatment of rheumatoid 30 11 14 25 15-18 15 arthriti~,'~,'~ and inositol nicotinate in intermittent 15 11 19-24 14 25 35 ~1audication.I~ 35 15 11 14 25 25-50 Because nicotinic acid can raise blood glucose levels, nicotinic acid supplementation is contraindicated in the 51+ 15 11 14 25 35 treatment of diabetes. Also, large intakes of nicotinic acid EAR, Estimated Average Requirement; Optimal, Suggested Optimal Nutrient (>lo00 mg) have been associated with stomach pain, Intake; RDA, Recommended Daily Allowance; DR//R//, Dietary Reference diarrhea, cardiac arrhythmias, itching, and n a ~ s e a . ' ~ J ~IntakedRecommended Intakes for Individuals; UL, Tolerable Upper Intake Level. '1 niacin equivalent = 1 mg niacin or 60 mg dietary tryptophan. These side effects have not been observed, however,

Suggested Optimum Nutrient Intake of Vitamins, Minerals, and Trace Elements also been demonstrated to treat carpal tunnel s y n d r ~ m e . ~Elderly - ' ~ people may have a greater requirement for vitamin B6 to maintain health, particularly for their immune systems. In one study, healthy elderly people were given either 50 mg/day of vitamin B6 or placebo. Those receiving the supplement had significant improvement in immunocompetence, especially lymphocytic a~tivity.'~ There is some emerging evidence that inadequate vitamin B6 status may contribute to the development of coronary heart disease through a rise in plasma homocysteine.'"" Homocysteine has been found to be highly atherogenic in animals and may contribute to atherosclerosis and myocardial infarction in humans.18Added evidence that vitamin B6 might be important in preventing cardiovasculardiseases comes from experimental studies in animals. When animals are given vitamin B6 deficient diets they demonstrate atherosclerotic lesions similar to those found in human atherosclerosis. Many women taking oral contraceptives have been shown in various studies to have low levels of vitamin B6.19-22Levels of this vitamin have also been found to be low in cigarette smokers.23Some evidence has been reported suggesting that inadequate vitamin B6 levels may raise the risk of some cancer^.^^,^ Although there is growing evidence for a role of vitamin B6 supplementation in preventing some kinds of cardiovascular diseases, and for e n h a n h g immunity, levels in healthy individualsneed not exceed 12to 15times the RDA, even in the elderly. Supplementation of vitamin B6 up to 200 mg/day is safe for most individuals. Very high doses of vitamin B6 have been associated with sensory and motor impairment.2"28Daily intakes up to 500 mg/day, which is 250 times the RDA, for up to 6 months appear to be safe.29Supplements of pyridoxal-5'-phosphate may be preferred over pyridoxine hydrochloric acid supplements in individuals wishing to avoid any reversible side effects from vitamin B6 supplementation. The mean intakes of vitamin B6 in the United States, based on the NHANES for 1999-2000, were 2 mg and 1.6 mg for males and females of all ages, respectively (Table 127-11).30

Riboflavin (Vitamin B2) The water-soluble vitamin riboflavin is a precursor of two coenzymes (riboflavin-5'-phosphate and flavin mononucleotide) needed for a wide variety of enzymes in intermediary metabolism. Riboflavin is also required as a precursor of several flavoenzymes that are needed by tissue proteins.'" Riboflavin is especially important for tissue repair, vision, and blood. The need for riboflavin varies with energy requirements, explaining why riboflavin-deficient people tire

Gender

Male

Female

Age (yr)

RDA

EAR

DRI/RII

Optimal

UL

11-14

1.7

0.8

1.o

2

60

15-18

2.0

1.1

1.3

5

80

19-24

2.0

1.1

1.3

10

100

25-50

2.0

1.1

1.3

10

100

51+

2.0

1.4

1.7

25

100

11-14

1.4

0.8

1.o

2

60

15-18

1.5

1.0

1.2

5

80

19-24

1.6

1.1

1.3

10

100

25-50

1.6

1.1

1.3

10

100

51+

1.6

1.3

1.5

20

100

EAR, Estimated Average Requirement: Optimal, Suggested Optimal Nutrient Intake; RDA, Recommended Daily Allowance: DRVRII, Dietary Reference Intakes/Recommended Intakes for Individuals; UL, Tolerable Upper Intake Level.

easily and have a poor appetite. Worldwide, intakes of riboflavin are OW.^-^ There is growing evidence that riboflavin may be important in preventing the development of cataracts, which are commonly associated with a g i ~ ~ gThere . ~ , ~is equivocal evidence that riboflavin supplementation may be required in people who exercise reg~larly.~J~ This latter issue may be more of a consideration if the exerciser is on a calorie-restrictive diet." Intakes of riboflavin significantly higher than SON1 or RDA have been employed in the treatment of migraine prophylaxis, with promising results. In one open pilot trial involving 25 patients with a history of migraine related to either the syndrome of mitochondria1 encephalomyopathy, lactic acidosis, or strokelike episodes (MELAS), 400 mg/day of riboflavin was given as a prophylactic treatment for migraine.12 On average, 68% of patients reported improvement on an index of severity. A second randomized, placebo-controlled trial involving 55 patients with similar migraines reported a 50% improvement among those receiving riboflavin, versus a 15% response in the placebo group.13It is theorized that in some migraine patients,